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Anti‐Proliferative 1,4‐Dihydropyridine and Pyridine Derivatives Synthesized through a Catalyst‐Free, One‐Pot Multi‐Component Reaction
ChemistrySelect
Abstract
In this study, we explored the catalyst‐free one‐pot multi‐component synthesis of 1,4‐dihydropyridine derivatives by following green chemistry protocol. The present approach shows the significant outcomes such as yield up to 94%, catalyst‐free reaction, easy workup procedure and shorter period of reaction time. In this work we also highlighted the comparison of the yields obtained under both neat and solvent media as well. The anti‐proliferative activity of all newly synthesized compounds has been assessed against six human solid tumor cell lines. Seven compounds show good activity against single cell line whereas, compounds having a pyridine scaffold showed significant anti‐proliferative activity. An expedient synthesis of 1,4‐dihydropyridines (DHPs) and pyridines under catalyst‐free condition is explored with excellent reaction yield up to 94%. All newly synthesized compounds were screened for anti‐proliferative activity against different human tumor cell lines. The remarkable results on yield, process, development of DHPs, anti‐proliferative activity, structure determination and single crystal study of DHPs discussed in this article.
... A significant feature of MCRs is the efficient incorporation of nearly all the reactant fragments into the end products, resulting in minimal by-product formation. [30,31] The Biginelli reaction, a one-pot cyclization reaction involving an aryl aldehyde, urea, and β-ketoester in the presence of mineral acids, producing 3,4-dihydropyrimidinones is one of the most crucial multi-component reactions (MCRs). [32] Due to their broad spectrum of applications, including anticancer activity, antihypertensive agents, anti-oxidants, and calcium channel blockers properties, dihydropyrimidinones (DHPMs) scaffolds are effective chemical moieties which have drawn significant attention from synthetic and medicinal chemists. ...
Sulfonated melamine‐formaldehyde (SMF) containing high dispersed TiO2 and ZnO nanoparticles were fabricated into magnetic nanocomposites by two different method material incorporation protocols, including calcination and wet impregnation. Their catalytic performance was investigated toward Biginelli reaction. For the preparation of the first catalyst series, a two‐step protocol was used. Initially, Fe3O4 nanoparticles were coated with SMF (Fe3O4/SMF). Subsequently, they were decorated consecutively with TiO2 (Fe3O4/SMF/TiO2) and ZnO (Fe3O4/SMF/ZnO). The second set of catalysts was prepared using a two‐step process. Fe3O4 nanoparticles were first used to modify SMF (SMF/Fe3O4). Following the initial step, the surface of SMF/Fe3O4 was decorated with both TiO2 (SMF/Fe3O4/TiO2) and ZnO (SMF/Fe3O4/ZnO). To understand the characteristics of the synthesized nanocomposites, a variety of characterization techniques were employed. New catalysts enabled the rapid synthesis (30–45 min) of a range of biologically active 3,4‐dihydropyrimidinones based on the Biginelli reaction with high yields (70–95 % isolated).
... The characteristics pattern of the formation of secondary and tertiary structural protein motifs are attributed to the presence of H-bonds [49][50][51][52][53][54]. The binding affinity of a given drug (TDN) towards the pro and anti-apoptotic proteins (1g5M and 4s0o) target during molecular dynamic simulation is properly elucidated by the presence or absence of hydrogen bonding [55][56][57][58][59]. ...
Cervical cancer is one of the most prevalent cancer-related diseases, causing accelerated morbidity and mortality rates in low-income countries and African states. This study explores the potential of (3 R ,3′ R )-2,2′,3,3′-tetrahydroneoprzewaquinone (TDN) as a treatment for cervical cancer by investigating its structural and molecular properties using molecular modelling technique, which include; DFT, molecular docking, molecular dynamic simulation. The results are promising, with TDN demonstrating exceptional stability in the energy gap ( E g ) as well as through natural bond order analysis (NBO). π → σ* electronic transitions were found to contribute mainly to the molecule’s stability, with an outstanding total stabilization energy ( E ⁽²⁾ ). Docking exercises showed that TDN binds more favorably to the pro-apoptotic receptor 4s0o with a stronger H-bond compared to the conventional DOX drug, which interacted less effectively with TDN and more strongly with the anti-apoptotic protein, forming an outstanding strong H-bond. Molecular dynamics simulations also revealed that TDNʼs interaction with the pro-apoptotic protein (TDN_4S0o) was more stable than the standard DOX drug (DOX_4s0o). The H-bond plot indicated that TDN could effectively interact with both anti and pro-apoptotic receptors, forming approximately 1 to 4 hydrogen bonds between TDN_1g5M with respect to each picosecond (ps) ranging from 0 to 1000 ps. In contrast, the number of hydrogen bonds fluctuated when DOX interacted with the anti-apoptotic protein (1g5M), ranging from 1 to 5 H-bonds. Overall, these results suggest that TDN may be a promising drug candidate for cervical cancer treatment.
... Calculating the electron density within atomic orbitals in a molecule is done using the Mulliken population analysis method [46]. This technique, created in the early 1900s by Robert S. Mulliken, is used to ascertain the charge distribution within a molecule [47]. The idea of "electron density," or the number of electrons found in each atomic orbital, is the foundation of this theory. ...
... Thus more than 100 crystal structures containing this aforementioned fragment are deposited with the CCDC [6]. On the other hand the number of reported crystal structures with N-based heterocyclic groups connected to the diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate-1-yl fragment are rare [11][12][13][14]. In all cases the heterocyclic rings are almost perpendicular to the mean plane of the 1,4-dihydropyridinyl fragment. ...
C21H23N5O6, monoclinic, P21/c (no. 14), a = 8.4861(4) Å, b = 16.3198(8) Å, c = 15.8521(8) Å, β = 97.605(5)°, V = 2176.1(2) Å3, Z = 4, Rgt(F) = 0.0463, wRref = 0.1201, T = 293(2) K.
... Compound 5 showed high antiproliferative activity against several human tumor cell lines. 54 Unusual path of the Hantzsch reaction was described by Shen et. al. 55 It was found that the solventfree reaction of ETFAA 1a, benzaldehyde, and ammonium acetate at 100 C proceeded with the loss of the water molecule to aff ord partially dehydrated 2-hydroxy-2,6-bis(trifl uoromethyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate 6. ...
The review is summarized and systematized the published data on the multicomponent reactions of ethyl trifluoroacetoacetate, carbonyl compounds (aldehydes and ketones), and nucleophilic reagents. The recent advances in the study of the Hantzsch and Biginelli reactions involving polyfluoroalkyl-3-oxo esters are analyzed. These transformations tolerated a broad range of the nucleophilic reagents thus allowing the synthesis of a wide variety of hetero- and carbocyclic compounds including the derivatives of pyridine, pyrimidine, pyrazole, pyran, dioxane, and isoxazole as well as their heterofused derivatives. The reactivity characteristics of ethyl trifluoroacetoacetate with different reagents in these multicomponent transformations are discussed.
... Dihydropyridine (DHP) is the active structural core of a wide variety of natural products, drugs, and functional materials [1]. Of the five possible isomers, only 1,2 and 1,4-DHP have been studied in depth [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Among them, 1,4-DHP is closest to NAD(P)H coenzyme; its biological applications are particularly extensive [17]. ...
In this paper, detailed comparisons of the driving force in thermodynamics and intrinsic force in the kinetics of 1,2-dihydropyridine and 1,4-dihydropyridine isomers of PNAH, HEH, and PYH in hydride transfer reactions are made. For 1,2-PNAH and 1,4-PNAH, the values of the thermodynamic driving forces, kinetic intrinsic barriers, and thermo-kinetic parameters are 60.50 and 61.90 kcal/mol, 27.92 and 26.34 kcal/mol, and 44.21 and 44.12 kcal/mol, respectively. For 1,2-HEH and 1,4-HEH, the values of the thermodynamic driving forces, kinetic intrinsic barriers, and thermo-kinetic parameters are 63.40 and 65.00 kcal/mol, 31.68 and 34.96 kcal/mol, and 47.54 and 49.98 kcal/mol, respectively. For 1,2-PYH and 1,4-PYH, the order of thermodynamic driving forces, kinetic intrinsic barriers, and thermo-kinetic parameters are 69.90 and 72.60 kcal/mol, 33.06 and 25.74 kcal/mol, and 51.48 and 49.17 kcal/mol, respectively. It is not difficult to find that thermodynamically favorable structures are not necessarily kinetically favorable. In addition, according to the analysis of thermo-kinetic parameters, 1,4-PNAH, 1,2-HEH, and 1,4-PYH have a strong hydride-donating ability in actual chemical reactions.
... 25 At present, this reaction is known as the Robinson-Schöpf reaction. Recently, a multicomponent synthesis of substituted piperidines was carried out applying ammonium acetate [26][27][28][29][30][31][32] , water ammonia [33][34][35] or amines 36,37 as a source of nitrogen. ...
... Although, an eco-friendly and very efficient method for the synthesis of 1,4-DHPs based on imidazole moiety in EtOH at ambient temperature and 60°C was reported by Sharma et al. [19]. The yield of imidazole based 1,4-DHPs was between 40% and 60%. ...
A simple, environmentally friendly and highly efficient method has been developed for the synthesis of 1,4-dihydropyridine compounds. A number of aromatic aldehydes, ethylaceto acetate and urea converted into corresponding in l,4-Dihydropyridine derivatives via one-pot multicomponent reaction in sub-critical ethanol. This study shown that 1,4-dihyropyridines can be synthesized in sub-critical ethanol and has the advantage of excellent yields, short reaction time, and simple work-up conditions.
... The 1,4-DHP scaffold displays an extensive range of biological activities, including reversing multidrug resistance (through the inhibition of the P-glycoprotein) [26] and antiproliferative effects on human cancer cell lines [27]. We wondered whether the studied 1,2-DHPs could interfere with tumor cell growth. ...
A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of various 1,2-dihydropyridine derivatives using heterogenized phosphotungstic acid on alumina support (40 wt %). High yields of over 75% have been accomplished in just 2–3.5 h after screening several heterogeneous catalysts and investigating the optimal reaction conditions. The catalyst chosen has passed the heterogeneity test and was shown to have the potential of being reused for up to 8 consecutive cycles before having a significant loss in activity. In addition, aromatic aldehydes gave the aforementioned regioisomer while the classical 1,4-DHPs were obtained when carrying out the reaction using aliphatic aldehydes. The preliminary study of the antiproliferative activity against human solid tumor cells demonstrated that 1,2-DHPs could inhibit cancer cell growth in the low micromolar range.
... A number of crucial pharmaceuticals are made up of heterocyclic molecules [7,8] . Chemical and physical properties contribute to improved bioavailability and versatility relative to heterocyclic aromatic hydrocarbons [9][10][11] . The solubility in water and polarity of heterocyclic compounds is depends on the replacement of a single carbon atom with oxygen, nitrogen, or sulfur [1,12] . ...
This work aims to synthesize thiazolidinone derivatives using a rapid, safe and solvent-free grinding assisted approach. The newly synthesized compounds have been targeted due to their bioactivity in wide pharmaceutical uses, especially, as anti-proliferative agents. Two thiazolidinone derivatives having a diverse set of crucial functional groups were diagnosed with melting point (m.p), FT-IR, 1 H NMR, 13 C NMR, GC-Mass and CHNS. High outputs (98% and 96%) of thiazolidinone derivatives were offered by the grinding method and the final product was produced over short reaction times (5 min). This simple strategy would potentially be promising for the preparation of thiazolidinone derivatives in abundance. Followed by synthesis both of our molecules were considered for molecular docking study against the Cyclin-Dependent Kinase 2 (CDK2) protein. A number of potential binding interactions in terms of hydrogen and hydrophobic bonds were observed with the ligand-binding amino acid of CDK2 protein. The behavior of both molecules inside the CDK2 was explored through all-atoms molecular dynamics (MD) simulations. Several parameters calculated from the MD simulation were revealed that both molecules retained inside the receptor cavity of CDK2. Hence, green synthesized both compounds were found to show strong potentiality against the CDK2 and may have significant interests in the field of pharmaceutical chemistry.
... Amaridine is another marketed anticancer drug targeted at topoisomerase II, which is used in the treatment of leukemia. [28][29][30][31] After the exploration of experts, quinolones exert their biological activities by inhibiting the formation of bacterial DNA topoisomerase. The successful exploration of this mechanism provides the basis for the subsequent drug design. ...
The structural modification of quinolone derivatives has been a hot spot in recent years, especially the modification of the N-1 position, which is the part that this article focuses on. In this paper, series of synthesized quinoline quaternary ammonium salts with odd and even carbon number alkyl groups in N-1 position were used to explain the influence of the alkyl side chain on activity. With respect to all the recently synthesized twenty products, the biological activity results exhibited significant antitumor and antibacterial activity with obvious differences in the target alkyliodine substituted compounds and the antibacterial activities apparently had the prominent odd-carbon number predominance. Compound 8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quinolin-5-ium (4d) was found to be the most potent derivative with IC50 values of 4±0.88, 4±0.42, 14±1.96, and 32±3.66 against A-549, Hela, SGC-7901, and L-02 cells, respectively, stronger than the positive control 5-FU and MTX. Furthermore, it had the most potent bacterial inhibitory activity of MIC value against Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739) at 3.125 nmol mL⁻¹. With respect to molecular simulations, in order to illustrate the possible mechanism of the difference between the series of compounds in the even or odd carbon chain alkyliodine substitution, this paper simulated the conceivable mode and explained the main interactions. Finally, we could find that the position and proportion of hydrogen bonds and other interactions in each series were regarded as the main reasons for this difference in activity.
... [33][34][35][36] Signicantly, NADEMs are advantageous due to their cost-effectiveness, less toxicity, biodegradability, and large scope of production by choosing appropriate hydrogen bond donor and acceptor systems. 37 In continuation of our research interest for the development of novel nitrogen-containing heterocyclic scaffolds [38][39][40][41][42] here, we wish to report a substrate directed novel MCR of 5-MCR using water as a solvent, unfortunately in this experiment sticky reaction mass formation is observed. To overcome this, we replace water by ethanol as solvent and performed several reaction optimizations experiments, found the ideal reaction temperature and catalyst for the successful transformation. ...
A versatile and substrate oriented multicomponent reaction for the syntheses of novel highly diastereoselective tetrahydro-1′H-spiro[pyrazolo[4,3-f]quinoline-8,5′-pyrimidine]-2′,4′,6′(3′H)-triones (d.r. up to 20 : 1 (syn : anti)) and tetrahydro-8H-pyrazolo[4,3-f]pyrimido[4,5-b]quinoline-8,10(9H)-diones via formation of selective multiple C–C bonds under identical reaction conditions (viz. ethanol as a reaction medium and deep eutectic mixture as a catalyst) is demonstrated. Both approaches involve mild reaction conditions, use of non-hazardous solvents, and facilitate good to excellent reaction yields of the target compounds.
... Therefore, 5α-reductase is considered a useful therapeutic target in the treatment and prevention of the above deceases. In particular, many heterocyclic compounds based on oxygen and nitrogen atoms often have good antiproliferative activity against a variety of solid tumor cell lines and are expected to be seeds of new anticancer agents (Sharma et al., 2018;Petel et al., 2019). During our characterization studies on bioactive constituents from Thai natural medicines (Manse et al., 2017;Morikawa et al., 2018;Tanabe et al., 2018;Kobayashi et al., 2019), a methanol extract of the flowers of M. siamensis was found to inhibit 5αreductase activity (IC 50 = 2.4 µg/mL). ...
Geranylated coumarin constituents, kayeassamin I (1) and mammeasins E (2) and F (3) were newly isolated from the methanol extract of the flowers of Mammea siamensis (Calophyllaceae) originating in Thailand, along with five known isolates, such as mammea E/BC (23), deacetylmammea E/AA cyclo D (31), deacetylmammea E/BB cyclo D (32), mammea A/AA cyclo F (34), and mammea A/AC cyclo F (35). These compounds (1–3) were obtained as an inseparable mixture (ca. 1:1 ratio) of the 3″R and 3″S forms, respectively. Among the isolated coumarins from the extract, mammeasins E (2, 22.6 μM), A (4, 19.0 μM), and B (5, 24.0 μM), kayeassamins E (9, 33.8 μM), F (10, 15.9 μM), and G (11, 17.7 μM), surangin C (13, 5.9 μM), and mammeas A/AA (17, 19.5 μM), E/BB (22, 16.8 μM), and A/AA cyclo F (34, 23.6 μM), were found to inhibit testosterone 5α-reductase.
... As part of our program directed at the drug discovery of new antitumor agents, we have explored the anti-proliferative activity of small and focused libraries of compounds obtained by diverse types of MCRs (Fig. 1). For example, we have investigated pyrroles (1) [2], propargylic enol ethers (2) [3], Ugi adducts of grindelic acid (3) [4], Hantzsch derived 1,4-dihydropyridines (4) and pyridines (5) [5], pyrazolodihydropyridines (6) [6], Ugi and Passerini tocopherol mimetics (7 and 8, respectively) [7], as well as diazepinones (9-10) [8]. ...
Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI50) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na+- and Cl-- dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α-methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJ-hTERT.
... The design and development of novel synthetic strategies and introducing efficient and green methodology for the synthesis of such valuable heterocycles is a significant challenge for organic/medicinal chemists. Nowadays, synthetic chemists are interested in developing environmentally benign, solvent-free, catalyst-free, one-pot, and one-step synthesis procedures [23][24][25][26][27][28][29][30]. The shorter reaction times as well as the easy work-up and purification steps are some of the advantages for the solvent-free methods [31]. ...
In the present study, the design and development of an efficient and green method for the synthesis of dialkyl 4-hydroxy-4H-chromene-2,3-dicarboxylate derivatives together with their biological evaluation are reported. A series of 4H-chromenes were synthesized in the presence of 1-hexyl-3-methylimidazolium bromide ([HMIM]Br) as an environmentally friendly media, without using any organic and toxic solvent and catalyst. The reaction was rapid and was conducted at room temperature with high-to-excellent yields. The antiproliferative potential of the synthesized compounds was evaluated against human lung (A549), breast (MCF-7), and colon (HT-29) cancerous cell lines by adopting MTT method. The tested chromenes showed cytotoxicity in the range of 8.8–82.3% against A549 cells at 200 μg/mL. Also, chromene derivatives were assessed for tyrosinase and α-glucosidase inhibitory activities. Based on IC50 values (2.99–4.39 mM), all chromenes exhibited significant α-glucosidase inhibition compared with acarbose (IC50 = 7.90 mM). Furthermore, the ability of the studied compounds to inhibit tyrosinase was evaluated and found to be moderate (IC50 = 3.50–12.20 mM). In silico studies were performed to explore the binding modes of the chromenes at the binding site of α-glucosidase and tyrosinase. Molecular docking results revealed the importance of hydrogen bonding, hydrophobic, π-π stacking, π-cation, and metal interactions between the target enzymes and the synthesized compounds. Collectively, the results obtained in the current work indicated that the studied chromenes may be regarded as lead compounds for designing new chemicals potentially effective in conditions such as skin disorders and diabetes mellitus.
... We performed this reaction via a one-pot strategy, which has been reported in many reactions, [5][6][7][8] because it has certain advantages based on green chemistry concepts such as the reduction of chemical waste, workup procedure, purication process, and time, which make the reaction greener. 9 In the literature, the one-pot reaction of aryl aldehyde, malononitrile and N-substituted 2-cyanoacetamide is mostly reported to use piperidine 10-12 as a catalyst. ...
In this study, we successfully explored the effect of steric hindrance on the one-pot reaction of different aryl aldehydes with malononitrile and N-substituted 2-cyanoacetamide in the presence of piperidinium acetate as the catalyst. It involved the Knoevenagel condensation of the aldehyde and malononitrile to produce arylidene malononitrile as an intermediate, which was further treated with N-substituted 2-cyanoacetamide to give 6-amino-2-pyridone-3,5-dicarbonitrile derivatives when the less steric bulky group was involved. High steric hindrance changed the earlier reaction route and gave N-substituted 2-cyanoacrylamides via a slower route.
... A new family of tacrine dihydropyridine hybrids, named as tacripyrine was found as a potent and selective inhibitor AChE. Some derivatives of dihydropyridines are available commercially for the treatment of hypertension such as nifedipine (1), amlodipine (2), felodipine (3) and nicardipine (4) (Nasr-Esfahani et al., 2014) Likewise it was reported that this class of compounds shown remarkable biological properties like antiinflammatory, anti-ulcer, anti-convulsant, anti-tubercular and anti-microbial (Joshi et al., 2014, Sharma et al., 2018. A recent study on dihydropyridines showed that the compound (5) and its derivatives were identified as a new class of anti-oxidants and it was predicted that these compounds could serve as a lead molecule in the development of new antioxidants with therapeutic potential (Anwar et al., 2014). ...
Twelve derivatives of dihydropyridine derivatives (6-17) were synthesized and evaluated for in-vitro cholinesterases (AChE, BChE) inhibitory activity. All compounds showed potent activity with IC50 values between 0.21±0.003 to 147.14±0.12μM for AChE and among them five compounds showed potent activity with IC50 values 17.16±0.02 to 231.6±0.12μM for BChE when compared with standard Eserine (IC50 = 0.85±0.0001 μM (AChE) & 0.04±0.0001μM (BChE). The most potent compound 11 can be considered as potential lead compound showed an inhibition of 95.35±0.11 and IC50= 0.21±0.003 while compound 7 showed an inhibition of 83.45±0.13 and IC50= 17.16±0.02. It is concluded from structural activity relationship that the presence of nitro group at C-2 and C-4 position of dihydropyridine ring increase the acetyl cholinesterase and butyrylcholinesterase activities of these compounds while presence of -Br and -Cl also enhances the activities.
... A new family of tacrine dihydropyridine hybrids, named as tacripyrine was found as a potent and selective inhibitor AChE. Some derivatives of dihydropyridines are available commercially for the treatment of hypertension such as nifedipine (1), amlodipine (2), felodipine (3) and nicardipine (4) (Nasr-Esfahani et al., 2014) Likewise it was reported that this class of compounds shown remarkable biological properties like antiinflammatory, anti-ulcer, anti-convulsant, anti-tubercular and anti-microbial (Joshi et al., 2014, Sharma et al., 2018. A recent study on dihydropyridines showed that the compound (5) and its derivatives were identified as a new class of anti-oxidants and it was predicted that these compounds could serve as a lead molecule in the development of new antioxidants with therapeutic potential (Anwar et al., 2014). ...
Twelve derivatives of dihydropyridine derivatives (6-17) were synthesized and evaluated for in-vitro cholinesterases (AChE, BChE) inhibitory activity. All compounds showed potent activity with IC 50 values between 0.21±0.003 to 147.14±0.12μM for AChE and among them five compounds showed potent activity with IC 50 values 17.16±0.02 to 231.6±0.12μM for BChE when compared with standard Eserine (IC 50 = 0.85±0.0001 µM (AChE) & 0.04±0.0001µM (BChE). The most potent compound 11 can be considered as potential lead compound showed an inhibition of 95.35±0.11 and IC 50 = 0.21±0.003 while compound 7 showed an inhibition of 83.45±0.13 and IC 50 = 17.16±0.02. It is concluded from structural activity relationship that the presence of nitro group at C-2 and C-4 position of dihydropyridine ring increase the acetyl cholinesterase and butyrylcholinesterase activities of these compounds while presence of-Br and-Cl also enhances the activities.
Obesity represents a significant global health issue that continues to escalate in prevalence. Interestingly, there is a less explored connection between obesity and compromised leptin function. Prior studies have highlighted the limited availability of drugs to address this issue hence, the relentless struggle against obesity persists and the need to develop new therapeutic strategies becomes necessary. In the present study, fatty acids from the seed of Cola lepidota were utilized to prevent antibody Fab fragment (9F8) (3VG0), an antagonist of leptin from binding to the leptin pocket of the human obesity receptor (ObR) thereby restoring ‘satiety’. This study is the first to investigate the effect of plant derived fatty acids from C. lepidota seed for the purpose of reversing leptin resistance in obesity condition. Our research employed experimental GCMS extraction technique and theoretical FT-IR and UV–vis analysis and compared result with those reported in literature. All computational methodologies were carried out within the framework of density functional theory (DFT) at the B3LYP/6-311++G(d,p) level of theory while molecular docking and pharmacokinetics studies were employed to investigate the biological activities and druglikeness of the compounds. Result shows that linoleic acid (LA), methylhexadecanoate (HXD), ocatadecanoic acid methyl ester (ODA) and Bis(2-ethylhexyl) phthalate (BISP) recorded energy gaps of 2.8216 eV, 7.4230 eV, 7.4244 eV, and 5.5849 eV respectively, suggesting that LA is the most reactive while BISP is the most stable as they recorded lowest and highest energy gaps respectively. The dipole moment ( μ ) result shows that LA recorded the highest dipole moment at 6.1119 Debye (D) indicating that it has the highest polarizability capacity. The order of polarizability is LA > BISP > HXD > ODA. The visualized electron localization function result shows that the red regions are electron rich, followed by yellow region then green and finally blue region. Electron density was distributed within the O and H atoms of the molecules indicating strong electronegativity nature of oxygen and hydrogen atoms of the compounds. LA, ODA and HXD absorbed light at the vacuum level UV region while BISP absorbed light at the UV visible region. The compounds exhibited C–H and C–O stretching vibrations except for ODA that lacks the C–O functional group. The compounds exhibited biological activities with the target receptor protein (leptin antagonist) with bis(-2ethylhexyl) phthalate (BISP) having a docking score of −4.4 kcal/mol and containing the highest number of favorable hydrogen bond interactions with LYS41, PRO42, GLN44, GLY43 residues along the polypeptide L chain and PRO173 along the polypeptide H chain of the receptor. These interactions predominantly induced conformational changes in the amino acid sequence of the protein, thereby disrupting its three-dimensional structure and mitigating the antagonistic effects at the leptin binding domain (LBD) of the human obesity receptor (ObR), thus, effectively reversing leptin resistance in obese condition. Importantly, the pharmacokinetics revealed favorable drug-like properties with no toxicity effects with respect to hepatotoxicity, immunotoxicity, cytotoxicity, mutagenicity, carcinogenicity and did not also penetrate the blood-brain barrier (BBB) or exhibit clearance delays. The therapeutic strategy presented in this study is highly thoughtful and capable of recording huge success in obesity management, thereby reducing the burden of obesity on other chronic diseases. Therefore, these compounds have positioned themselves as promising agents in leptin resistance reversal and obesity management, warranting significant interest as potential drug candidates.
The renewable 5‐hydroxymethylfurfural (5‐HMF) has gained a wide interest from the chemistry community as a valuable biobased platform opening the way to many applications. Despite an impressive number of publications reporting either its preparation or its functionalization, its direct use in fine chemistry, and especially in multi‐component reaction (MCR), is less reported. Here, we report a complete study of the use of 5‐HMF in the Hantzsch dihydropyridines synthesis. The strategy was applied to a scope of β‐dicarbonyl molecules (including β‐ketoesters and 1,3‐diketones) in a 3‐component procedure leading to a series of symmetrical 1,4‐dihydropyridines derived from 5‐HMF in excellent yields. The study was extended to the 4‐component protocol using one equivalent of a β‐ketoester and one equivalent of 5,5‐dimethyl‐1,3‐cyclohexanedione (dimedone), which efficiently provided the corresponding unsymmetrical dihydropyridines.
Lymphoma, a type of cancer that affects the lymphatic system—an essential element of the body's immune defense—has captured increased interest from modern researchers. This study, investigate the possible antilymphoma characteristics of benzo bisthiazole using both experimental and theoretical investigations at DFT/B3LYP-GD3BJ/6–311++G(d, p) level of theory. This study aims to provide a comprehensive understanding of the electronic and spectroscopic behavior of benzo[1,2_d:4,5] bisthiazole (BBT), given the diverse range of applications for thiazole derivatives. We investigate the impact of solvation on BBT's molecular structure, spectral characteristics, quantum chemical properties, vibrational modes, electronic features, and its interaction through molecular docking. Our findings reveal intriguing insights into BBT's reactivity, highlighting its enhanced reactivity in benzene with an energy gap of 4.6406 eV, while demonstrating greater stability in water with an energy gap of 4.6490 eV. Notably, the analysis of high-energy transitions reveals prevalent n-π* transitions, while some transitions, though absent in UV spectra due to their low oscillator strength, are also identified. The dominant transitions, constituting around 74.85 to 75.57% contribution, are characterized across various solvents, emphasizing their significance. Impressively, molecular docking underscores BBT's potential bioactivity against lymphoma, with a docking score of -6.3 kcal/mol. Moreover, the interaction analysis with 6TOF-BBT reveals favorable hydrogen bonding with essential amino acids, histidine (HIS: 116), and glycine (GLY:55), along the polypeptide chain A of the receptor. These hydrogen bonds are notably well-structured at bond distances of 2.75 Å and 2.99 Å, respectively, further elucidating BBT's unique interaction mechanisms.
The pharmacologically privileged DHP derivatives were synthesized using the pragmatic multicomponent Hantzsch synthesis to screen the antidiabetic activity. Initially, the candidates were screened using an in vivo blood glucose test, where compound 8b showed the most prominent antidiabetic effect (% potency = 218%) compared to glimepiride. Then, a propositioned structure− activity relationship study was executed to reveal that longer side chains decreased the DHP’s antidiabetic action. Mechanistically, compound 8b diminished ROS in β-cells and muscle cells simultaneously, which was proved by enhanced serum biochemical
markers. Also, compound 8b decreased blood glucose by α- glucosidase inhibition (IC50 = 4.48 ± 0.32 μM), compared to acarbose (7.40 ± 0.41 μM), based selectively on the plasma window of 8b. Acarbose demonstrated auspicious inhibitor activity according to the binding affinity (ΔGbinding), which was slightly lower than that of compound 8b (−54.7 and −46.8 kcal/mol, respectively). During the 100 ns molecular dynamics simulations, the structural and energetic assessments exposed the high consistency of compound 8b to bind to the α-glucosidase.
Multicomponent reactions (MCRs) have emerged as key green tool in organic synthesis for their methodological simplicity. MCRs have made heterocycle synthesis more versatile. The most crucial molecule among the most often used heterocycles is pyridine, which is widely used in biological, industrial, and pharmaceutical sectors. In light of this, our mini‐review highlights the literature on substituted pyridine synthesis published from the year 2016 to early 2022 via multicomponent approach.
In the current work, we describe the synthesis of 1,4‐dihydropyridine (1,4‐DHP) derivatives via Hantzsch multicomponent reaction and their evaluation as photosystem II (PSII) inhibitors through chlorophyll a fluorescence bioassay. Among all the compounds tested, 1,1'‐(2,4,6‐trimethyl‐1,4‐dihydropyridine‐3,5‐diyl)bis(ethan‐1‐one) (4b) showed best results, reducing the parameters performance index on absorption basis (PIabs) and electron transport per reaction center by 61% and 49%, respectively, as compared to the control. These results indicate the inhibitory activity of PSII over the electron transport chain. Additionally, a molecular docking approach using the protein D1 (PDB code 4V82) was performed in order to assess the structure‐activity relationship among the 1,4‐DHP derivatives over the PSII, which revealed that both,size of the group at position 4 and the carbonyl groups at the dihydropyridine ring are important for the ligand's interaction, particularly for the hydrogen‐bonding interaction with the residues His215, Ser264, and Phe265. Thus, the optimization of these molecular features is the aim of our research group to extend the knowledge of PSII electron chain inhibitors and the establishment of new potent bioactive molecular scaffolds.
In this study, we demonstrate a simple, highly efficient, rapid and convenient series of 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones 4a-v. Microwave irradiation facilitates the one-pot multicomponent reaction of different aromatic aldehydes, 6-amino-2,4-dimethoxypyrimidine and dimedone using glacial acetic acid. Metal-free multicomponent synthesis, shorter reaction time, higher product yield, easy product purification without column chromatography and outstanding green credential parameters are the key features of this protocol. We analysed 4a-v against six human tumour cell lines for antiproliferative activity. 4h, 4o, 4q and 4v show good antiproliferative activity with a good in silico ADMET profile. Furthermore, 4h, 4o, 4q and 4v also show drug-likeness properties by obeying drug-like filters.
A series of new nicotinonitrile derivatives 3-18 bearing substituents at positions 2, 4, and 6 are prepared under microwave reaction conditions. The higher yields were obtained in a shorter time under microwave irradiation with a percentage of 1.19% when compared with conventional method. All the newly synthesized molecular structures are elucidated via spectral techniques. The in vitro antimicrobial properties for all newly prepared derivatives were performed. The results obtained showed that new nicotinonitrile derivatives Ethyl 2-((3-cyano-6-(2,4-dichlorophenyl)-4-(3,4-dichlorophenyl)pyridin-2-yl)oxy) acetate (15) and Ethyl 2-((4-(4-bromophenyl)-3-cyano-6-(2,4-dichlorophenyl)pyridin-2-yl)oxy)acetate (16); which bearing ester substituent at position 2 for nicotinonitrile ring displayed excellent antimicrobial activity. Moreover, a computational molecular modeling study was initiated with an average least binding energy of −9.5 kcal/mol to support the assumed mode of action for tested compounds and optimize a reliable model for predicting novel effective antibacterial.
Background
Solvent- and catalyst-free synthesis of 1,4-dihydropyridines (1,4-DHPs) under microwave radiation is directly dealt with the concept of green chemistry. They are the class of pharmacological agents and drugs used as Ca2+ channel blockers, and they behave as the photoelectronic functional materials to exhibit fluorescence because of the electron donating and withdrawing groups present in them.
Objective
An efficient and rapid microwave assisted synthesis of 4-(3-bromo-4-hydroxy-5-methoxyphenyl)-3,5-dicarbmethoxy-2,6-dimethyl-1,4-dihydropyridine (4) has been achieved under solvent- and catalyst-free conditions using three components 3-bromo-4-hydroxy-5-methoxybenzaldehyde, 3-oxobutanoic acid methyl ester, and ammonium carbonate in 25 minutes, which was then subjected to spectroscopic characterization, single-crystal X-ray and fluorescence study.
Methods
The characterization methods were 1H and 13C NMR, FT-IR, LC-MS, and elemental analysis. The single-crystal structure was developed using a mixture of Methanol: Tetrahydrofuran and was determined by single-crystal X-ray diffraction method. The fluorescence study was accomplished in a spectrofluorometer by taking cresyl violet as a reference with two organic solvents, methanol and chloroform.
Results
The crystal structure is monoclinic, space group P21/n with a = 11.0557(3) Å, b = 7.3544(2) Å, c = 22.4852(7) Å and β = 104.107(2)°. The used single-crystal size is 0.200 × 0.200 × 0.200 mm3. The NH....O type intermolecular hydrogen bond is observed between N(1) and O(2) atoms. The absorption and fluorescence spectra were found to depend on the chemical nature of the substituents available on C(4), C(2), and C(3) atoms of the 1,4-DHP ring and solvent properties.
In this communication, we wish to report a click, simple and efficient one‐pot four component synthesis of a new series of 3‐(2‐(2,4,5‐triphenyl‐1H‐imidazol‐1‐yl)ethyl)‐1H‐indoles using catalytic quantity of acetic acid. The synthesized compounds were evaluated for their in‐vitro antibacterial activity against gram‐positive (Staphylococcus aureus) and gram‐negative (Escherichia coli) bacteria. Tetracycline was used as standard in this antibacterial investigation. The present protocol has several advantages such as excellent yields, very shorter reaction time, operational simplicity, mild reaction conditions, easy work up, inexpensive, easily available catalyst and starting materials, a cleaner reaction media and no need for any chromatographic separation techniques. The synthesized compounds were characterized by ¹H, ¹³C‐NMR and ESI‐MS analyses.
In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3‐diones. The reaction was catalyzed by lanthanum triflate and completed within 1–1.5 h, with 74–97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 μM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1–3.1 μM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P‐glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco‐friendly access to benzyloxy DHPMs as potential anticancer drugs. In vitro antiproliferative assays of 20 benzyloxy dihydropymidinones against six solid human tumor cell lines are reported in this study. Among them, six compounds showed good antiproliferative activity with GI50 values below 5 μM. The two most potent compounds, 4p and 4q, were evaluated for drug‐like properties, which comply with the recommended drug properties.
In the present study, CuII immobilized on functionalized magnetic mesoporous MCM‐41 (Fe3O4@MCM‐41‐GPTMS‐Gu‐CuII) was prepared as a new, versatile, and magnetically nanocatalyst and characterized by FT‐IR, XRD, small‐angle XRD, BET, TEM, SEM, EDX, EDX‐mapping, TGA, VSM, XPS, and ICP techniques. The characterizations show the presence of MCM‐41 with a hexagonal structure, superparamagnetic behavior, and an average particle size of 8–25 nm. The catalytic activity of the nanocatalyst was evaluated towards the synthesis of structurally different 5‐phenyl‐5,10‐dihydropyrido[2,3‐d : 6,5‐d′]dipyrimidine‐2,4,6,8(1H,3H,7H,9H) tetraone derivatives through one‐pot multicomponent condensation under green conditions. Fe3O4@MCM‐41‐GPTMS‐Gu‐CuII catalyzed many consecutive trials at least five runs. High to excellent yields in short reaction times, simple procedure, environmental friendliness, less toxic solvents, high stability, and reusability of the catalyst are considerable advantages of the prepared catalytic system.
This article provides an update on the most recent reactions and applications of dihydropyridines, tetrahydropyridines and piperidines. The different isomeric forms of the latter aforementioned nitrogen-containing heterocycles undergo a variety of metal and non-metal mediated transformations, including asymmetric transformations. Furthermore, their applications towards natural product synthesis have been highlighted in selected examples.
New ß-lactam- N-(thiazol-2-yl) benzene sulfonamide hybrids were synthesized via [2+2] keteneimine cycloaddition (Staudinger reaction) reaction starting from sulfathiazole, a versatilesynthetic precursor. The structures of the newly synthesized compounds were supported by theirspectral data. Some of the newly synthesized compounds exhibited promising antimicrobialactivities against resistant strains. For all newly synthesized compounds, in silico ADME werecalculated and the molecular docking studies were carried out with the target penicillin-bindingprotein 2a (PDB ID: 1VQQ) from a methicillin-resistant S. aureus strain to study good bindinginteractions. In vitro cytotoxicity and haemolysis effects were also evaluated
Recently, inhibition studies of pentose phosphate pathway (PPP) enzymes have come out as an encouraging approach for pharmacological intervention in a variety of disorders. For this purpose, the rhodanines (Ph-Rhs) containing different benzene moiety were obtained via a green synthetic approach over a one pot reaction. We tested their inhibition effect on PPP enzymes glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD). As a result of these studies, inhibition constant (Ki) of Ph-Rhs on PPP enzymes were found in the range of 6.57 ± 2.03 to 91.60 ± 9.25 μM for G6PD and 11.17 ± 3.01 to 64.51 ± 4.26 μM for 6PGD. Moreover, binding energies were calculated with docking studies as −5.234 and −5.071 kcal/mol for G6PD and 6PGD, respectively.
Synthesis of novel bio-functional substituted-thiophene scaffolds (3−15) employing the previously obtainable 2-cyanoacetamide-3, 4, 5-substitued thiophene compound (1) is described through its tandem nucleophilic and cyclization reactions. The structures of the novel compounds are confirmed by micro and spectroscopic analyses. The reactive chemical and biological sites in the molecules are illustrated by computational assay based on their frontier molecular orbitals (FMO's) study. The synthesized compounds are examined in vitro against selected human cell lines of primary liver cancer (HEPG-2) and mammary gland carcinoma (MCF-7). The preliminary bioassay results indicate that the tested compounds exhibit variable degrees of inhibiting tumors growth respected to their structures.
Non-small-cell lung cancer is one of the principal causes of cancer-related death around the world. Chemotherapy is commonly used to treat wild type of epidermal growth factor receptor non-small-cell lung cancer. (-)-Epigallocatechin-3-gallate is the most abundant and active catechin. However, (-)-epigallocatechin-3-gallate has limited clinical application due to its poor stability and absorption. Herein, we report that a glycosylated azide undergoes a click reaction with the terminal alkyne of (-)-epigallocatechin-3-gallate to yield a triazole-linked glucose-(-)-epigallocatechin-3-gallate derivative and have evaluated its in vitro anticancer activity against human non-small-cell lung cancer cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The product inhibits human non-small-cell lung cancer cell lines with wild type of epidermal growth factor receptor and in combination with cisplatin/paclitaxel results in more pronounced proliferation inhibition than when used alone. Stability investigations indicates that the conjugated glucose residue can improve the stability of the (-)-epigallocatechin-3-gallate scaffold. Our studies suggest that the combination of the glucose-(-)-epigallocatechin-3-gallate derivative and chemotherapeutic drugs may provide a novel strategy for the treatment of non-small-cell lung cancer.
A convenient synthesis of pyrimidinthiones was carried out in presence of thiourea and easily available catalyst sulfamic acid (2a‐t). One‐pot Biginelli reaction is very important due to the use of simple and readily available chemicals, less reaction time, economically friendly, and furnishing good yield. Structures of the synthesized compounds are characterized by spectral techniques like IR, 1H‐NMR, 13C‐NMR, and LC–MS. Synthesized compounds were studied for their antimicrobial activity against several strains of bacteria (E. coli, P. aeruginosa, and S. aureus, S. pyogenes) and fungi (C. albicans, A. niger, and A. clavatus) using serial dilution method.
A green approach is designed for the synthesis of 1,4‐dihydropyrine derivatives catalyzed by triethylamine with water as solvent and under microwave irradiation conditions. The title reaction involved the one‐pot condensation of four components, namely aryl aldehyde, benzyl acetoacetate, 5‐methyl‐1,3‐cyclohexanedione and ammonium acetate. Good to excellent yields (88‐98%), short reaction times (10 min), green solvent and simple workup are attractive features for the approach. The method requires no further chromatographic separation. The structures of all the ten new derivatives were fully characterized by spectroscopic analysis with ¹H NMR, ¹³C NMR, ¹⁵N NMR and HRMS.
A one-pot procedure for the preparation of functionalized 1,4-dihydropyridines by three-component reaction using substituted heterocyclic aldehydes, ammonium acetate, and substituted β-ketoesters catalyzed by L-proline was described. Present protocol offers excellent yield up to 92%, flexibility with different substitution, convenient operation, and eco-friendliness. The synthesized products were confirmed by ¹H-NMR, ¹³C-APT, and IR spectroscopy. Herein, final confirmation of the targeted motif was made by X-ray single-crystal analysis of representative compounds (4f, 4j, 4k, 4l, and 4o). The chemically synthesized compounds were evaluated for the antiproliferative activity by cell viability (MTT) assay and dual AO/EB (acridine orange/ethidium bromide)-staining method against human A549 lung cancer cell lines. The viability of the treated cell was evaluated adopting MTT assay. According to associated changes in cell membranes during the process of apoptosis, a clear difference was observed between normal cells, early and late apoptotic cells, and necrotic cells. All compounds were found effective against Saccharomyces cerevisiae which was confirmed by increased reactive oxygen species production and DNA damage as compared to untreated yeast cell culture. Altogether, these compounds showed promising hope for application in pharmaceutical aid against yeast infections.
The new indole acetamide, N-(2-(2-(4-Chlorophenoxy)acetamido)phenyl)-2-carboxamide-1H-indole (5) has been synthesized with good yield by stirring the compound N-(2-Aminophenyl)-2-(4-chlorophenoxy)acetamide (3) with 1H-indole-2-carboxylic acid (4), in dry dichloromethane (DCM) followed by the addition of lutidine, and N,N,N′,N′-O-(Benzotriazole-1-yl)-tetramethyluronium tetrafluoroborate (TBTU) in cooled condition. The compound obtained was characterized by spectroscopic analyses (MS, FT-IR, 1H NMR, 13C NMR, UV–visible, and elemental). The anti-inflammatory activity was confirmed by in silico modeling study, which targets the cyclooxygenase COX-1 and 2 domains. The three-dimensional structure was determined using single-crystal X-ray diffraction studies. Geometry optimization of the compound was done using density functional theory calculations by employing B3LYP hybrid functional …
Nowadays, synthesis of novel nitrogen-bearing heterocyclic scaffolds is a challenging and demanding task as well. In our present work, we demonstrated a novel one-pot pseudo four-component reaction of 3,4-methylenedioxyaniline, N,N-dimethylbarbituric acid, and aryl/heteroaryl aldehyde for the regioselective construction of functionalized 6,8-dihydro-1'H,5H-spiro[[1,3]dioxolo[4,5-g]quinoline-7,5'-pyrimidine]-2',4',6' (3'H)-trione scaffolds using trimethyl glycine betaine based sustainable catalyst. The titled derivatives achieved through the formation of three new C-C bonds, one C-N bond, and generate two asymmetric carbon centers in final motif. Present protocol works efficiently, tolerate different substituents present in reactants, simple operational procedure, provide excellent reaction yield in short time, use of recyclable catalyst, up to 99.7% purity (HPLC) for the synthesized compounds, high diastereoselectivity (d.r.>50:1(syn:anti)), excellent Atom economy, Reaction mass efficiency, and Effective mass yield.
Dipolar and aprotic solvents are often required in acid‐catalyzed reactions, however, many of them are listed in solvent selection guides as not‐recommended due to their toxicity or explosivity. A catalytically functionalized ionic liquid, namely a sulfone‐containing imidazolium‐based Brønsted acid ionic liquid, was synthesized. It alleviates the detrimental effect of classical dipolar aprotic solvents because this ionic liquid integrates the function of a dipolar aprotic solvent able to stabilize carbocation intermediates and the activating effect of a strong Brønsted acid on electrophiles. The use of this tailor‐made ionic liquid was exemplified in some transformation reactions of indoles, which proceeded with high yield and selectivity using a green and an industrially acceptable solvent, butyl acetate. The recyclability of the ionic liquid catalyst was also demonstrated.
Here, we report the synthesis, characterization and antimicrobial activity evaluation of a series of triazolo‐thiadiazinyl coumarin derivatives 4 (a–j) and 6 (a–j). The triazolo thiadiazinyl coumarins were synthesized in a facile tandem solvent free one‐pot multi component reaction approach by taking various aliphatic/ aromatic/ heterocyclic carboxylic acids 1 (a–c) and 5 (a&b), Thiocarbohydrazide (2) and substituted 3‐(2‐bromoacetyl)coumarins 3 (a–h). The newly synthesized molecules were confirmed on the basis of physical, analytical and single crystal X‐ray diffraction data. The triazolo thiadiazinyl coumarins exhibited excellent antimicrobial activity against Gram positive, Gram negative and fungi microbial strains. Among the tested compounds, compounds 4 f (6‐Bromo), 4 g (6,8‐Dibromo), 6e (6,8‐Dichloro), 6 f (6‐Bromo) and 6 g (6,8‐Dibromo) exhibited potent antimicrobial activity at 25 μg / mL concentration against Gram positive and Gram negative bacterial strains.
Azo arylation of heteroarenes with aryldiazoniumtetrafluoroborate under transition metal/base‐free conditions has been described. The reactions proceed through ionic pathway without additives and oxidants. Under these conditions good to excellent yields of desired products were obtained with broad functional group tolerance. Applicability of the process for gram scale synthesis of two products has been demonstrated.
Herein, we established a straightforward synthetic route for biological relevant [1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)one scaffolds using the group‐assisted purification (GAP) chemistry via one‐pot and three component reaction of 3‐Amino‐5‐methylthio‐1H‐1,2,4‐triazole (1), Aryl aldehyde(2 a–g), and 1,3‐cyclodione (3 a–b) using L‐proline and aqueous ethanol (1:1, v/v) as green catalyst and reaction media respectively. This work shows some key features such as practical low Environment factor (E‐factor) values, excellent atom economy, reaction mass efficiency, mild reaction condition, metal‐free synthesis, and no use of column chromatography. In preliminary biological screening, the compounds, 2‐(methylthio)‐9‐(4‐nitrophenyl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 i) and 6,6‐dimethyl‐2‐(methylthio)‐9‐(pyridin‐4‐yl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 l) were found most potent against Gram‐negative bacteria (E. coli) than the standard drugs ampicillin and chloramphenicol. Moreover, compounds 2‐(methylthio)‐9‐phenyl‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 a) and 9‐(4‐methoxyphenyl)‐6,6‐dimethyl‐2‐(methylthio)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 f) exhibited excellent potency in comparison with the standard drugs ampicillin, chloramphenicol, and ciprofloxacin against Gram‐positive bacteria (S. aeruginosa and S. pneumoniae). In antifungal screening compounds, 9‐(4‐methoxyphenyl)‐2‐(methylthio)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 e) and 2‐(methylthio)‐9‐(4‐nitrophenyl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 i) efficiently inhibited C. albicans fungi strain than that of standard drug griseofulvin. Noteworthy compounds 6,6‐dimethyl‐2‐(methylthio)‐9‐phenyl‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 b), 9‐(4‐chlorophenyl)‐6,6‐dimethyl‐2‐(methylthio)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 d), and 2‐(methylthio)‐9‐(pyridin‐4‐yl)‐5,6,7,9‐tetrahydro‐[1,2,4]triazolo[5,1‐b]quinazolin‐8(4H)‐one (4 k) were exhibited better potency against M. Tuberculosis.
Catalyst‐free solid phase Hantzsch synthesis of symmetric 4‐(3‐bromo‐4‐hydroxy‐5‐methoxyphenyl)‐2,6‐dimethyl‐3,5‐dicarbethoxy‐1,4‐dihydropyridine (4 a) and 4‐(3‐bromo‐4‐hydroxy‐5‐methoxyphenyl)‐2,6‐dimethyl‐3,5‐dicarbmethoxy‐(4‐nitrophenyl)‐1,4‐dihydropyridine (4 b) was carried out at 400 W under the microwave irradiation. The molecular crystal of both compounds were developed in a suitable solvents and characterized by X‐ray crystallographic method along with other spectroscopic techniques (viz., FT‐IR, ¹H & ¹³C NMR, LC–MS, and elemental analysis). Single crystal structures of both compounds crystallizes in the orthorhombic and triclinic crystal systems with Cmc21 and P1 space groups consisting a=13.5755(13) Å, b=9.6755(9) Å, c=17.7625(17) Å, α=72.837(2)°, β=88.273(2)°, γ=75.221(2)° and a=8.9877(14) Å, b=11.1543(17) Å, c=12.2365(19) Å, α=90.00°, β=90.00°, γ=90.00° cell parameters, with 0.150 × 0.150 × 0.100 mm³ and 0.250 × 0.180 × 0.100 mm³ crystal size respectively. The 1,4‐DHP ring of both compounds have adopted a flattened boat‐type conformation and shows one and four intermolecular hydrogen bonds, respectively.
A novel green and efficient one-pot multicomponent reaction of dihydropyridine derivatives was reported as having good to excellent yield. In the presence of the catalyst ceric ammonium nitrate (CAN), different 1,3-diones and same starting materials as 5-bromothiophene-2-carboxaldehyde and ammonium acetate were used at room temperature under solvent-free condition for the Hantzsch pyridine synthesis within a short period of time. All compounds were evaluated for their in vitro antibacterial and antifungal activity and, interestingly, we found that 5(b–f) show excellent activity compared with Ampicillin, whereas only the 5e compound shows excellent antifungal activity against Candida albicans compared with griseofulvin. The cytotoxicity of all compounds has been assessed against breast tumour cell lines (BT-549), but no activity was found. The X-ray structure of one such compound, 5a, viewed as a colourless block crystal, corresponded accurately to a primitive monoclinic cell.
A simple, facile and convenient practical method for one-pot synthesis of biologically relevant alkyl/aryl/heteroaryl-substituted bis(6-aminouracil-5-yl)methane scaffolds (3a-3u) has been developed using ceric ammonium nitrate (CAN) as a commercially available and eco-friendly catalyst via pseudo three-component condensation reaction between aldehydes and 6-aminouracils in aqueous ethanol at room temperature The salient features of the present protocol are mild reaction conditions, good to excellent yields, high atom-economy, environmentally benign, easy isolation of products, no column chromatographic separation and reusability of reaction media.
A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridine derivatives under solvent-free conditions using
silica sulphuric acid (SSA) as a heterogeneous and recyclable catalyst is reported.
Keywords1,4-dihydropyridines–Hantzsch 1,4-dihydropyridine synthesis–heterogeneous catalyst–silica sulphuric acid–multi-component organic reaction
In the armamentarium of calcium channel blockers appropriately functionalized 3,4-dihydropyrimidin-2(1H)-ones have received considerable attention in recent past owing to their structural similarity with 1,4-dihydropyridine based
drugs. In this review, we highlight detailed investigations in the calcium channel blocking and other activities of this category of compounds as well as trace their genesis from 1,4-dihydropyridine based drugs.
Small-molecule inhibitors of protein function are powerful tools for biological analysis and can lead to the development of new drugs. However, a major bottleneck in generating useful small-molecule tools is target identification. Here we show that Caenorhabditis elegans can provide a platform for both the discovery of new bioactive compounds and target identification. We screened 14,100 small molecules for bioactivity in wild-type worms and identified 308 compounds that induce a variety of phenotypes. One compound that we named nemadipine-A induces marked defects in morphology and egg-laying. Nemadipine-A resembles a class of widely prescribed anti-hypertension drugs called the 1,4-dihydropyridines (DHPs) that antagonize the alpha1-subunit of L-type calcium channels. Through a genetic suppressor screen, we identified egl-19 as the sole candidate target of nemadipine-A, a conclusion that is supported by several additional lines of evidence. egl-19 encodes the only L-type calcium channel alpha1-subunit in the C. elegans genome. We show that nemadipine-A can also antagonize vertebrate L-type calcium channels, demonstrating that worms and vertebrates share the orthologous protein target. Conversely, FDA-approved DHPs fail to elicit robust phenotypes, making nemadipine-A a unique tool to screen for genetic interactions with this important class of drugs. Finally, we demonstrate the utility of nemadipine-A by using it to reveal redundancy among three calcium channels in the egg-laying circuit. Our study demonstrates that C. elegans enables rapid identification of new small-molecule tools and their targets.
Background: We developed Multicomponent synthesis for novel Mannich products with biologically active quinoline nucleolus under solvent free condition. This methodology provided us good amount of yield with the exception of chromatographic separation. The structure of novel compounds (4d1-d13) was characterized by elemental, mass,¹H-NMR,¹³C-NMR and IR spectroscopic analysis. In vitro antimicrobial studies also indicate that most of the compounds are active against gram positive and gram negative bacteria. M. Tuberculosis activity of five compounds shows excellent properties. Methods: The present methodology deals with Multicomponent reaction, in which, the mixture of 2,4-dihydroxybenzophenone 1.07 gm (0.005 M), 2-chloro-6-methoxyquinoline-3-carboxaldehyde 1.105 gm (0.005 M), with various amines 0.30 gm (0.005M) and EAN 30 ml (1 M) was stirred at 80ºC temperature. The completion of reaction was monitored by TLC by using (chloroform/methanol, 70:30). On completion of the reaction, the reaction mixture was extracted thrice with 20 ml ethyl acetate. The extract was dried over anhydrous sodium sulfate, evaporated under vacuum and the residue was purified via recrystallisation from methanol or ethyl acetate to obtain pure new Mannich products 4(d1-d13). All synthesized compounds were screened for their in vitro antibacterial activity by using the agar dilution technique. Results: The promising results obtained using 1M EAN as catalyst at the 80ºC temperature encouraged us to investigate the feasibility of solvent-free MCRs protocol for the synthesis of new Mannich products 4(d1-d13). The recovery and recyclability of EAN were investigated for the synthesis of new Mannich products 4(d1-d13). It was found that, recycled ionic liquid was used up to four to five times without the loss of catalytic activity. The high yield (90-95%) of this products was observed at milder reaction condition compared to the other ionic liquid which rationalized due to high acidity associated with it (pH=5) along with its capacity to absorb water formed during the course of the reaction. All the compounds showed very good activity accept 4d13, especially against P. aeruginosa MTCC 1688 (MIC=25-75 µg/mL), E. coli MTCC 443 (MIC = 25-100 µg/mL) and S. aureus MTCC 96 (MIC=25–75 µg/mL) whereas, 4d3 and 4d12, were found to be more potent rather than standard drugs Chloramphenicol and Ciprofloxacin. All the compounds showed excellent antifungal activity against C. albicans MTCC 227 (MIC=75-100 µg/mL) and A. niger MTCC 282 (MIC=75-100 µg/mL) whereas, 4d2 to 4d7 were found more potent rather Nystatin and Griseofulvin. Antituberculosis activity of all the compounds showed excellent activity 0.10 µg/mL rather than standard drug isoniazide (0.20 µg/mL) accept 4d2 and 4d3 using L. J. medium conventional method. Conclusion: We developed an environmental friendly, high yield and mild condition protocol for the three-component Mannich-type reactions using EAN as ionic liquid. This method provided us several advantages by comparison with reported literature; which are as follows: (a) highly efficient catalyst activity, (b) ease of workable with green catalyst, (c) reaction proceeds without preparation of enol derivatives and pre-formed imines, (d) effective reusability of catalyst, making it a useful and attractive strategy. EAN was recovered and recycled four to five times without decreasing catalytic activity. Most of the compounds showed potential activities against Gram-positive bacteria rather than Chloramphenicol and Ciprofloxacin, accept 4d13. Compounds 4d3 to 4d12 were found to be more potent against C. Albicans and A. Niger rather than Nystatin and Griseofulvin. Antituberculosis activity of 4d8 to 4d12 compounds showed excellent activity rather than isoniazide against H37RV bacteria using L. J. medium conventional method.
Background: In these study we report here one-pot multi-component and solvent free Mannich reaction of U.V. absorbing material, five member heterocyclic ring system and amides/carbamates has been efficiently catalyzed by recyclable ethyl ammonium nitrate as ionic liquid at ambient temperature to produce mannich compounds in high yields. This method has advantages of mild condition, no environmental pollution, and simple work-up procedures to produce new mannich products 4(a-f). The synthesis of five member based heterocycles has been the point of attraction towards their pronounced biological activities and molecular docking studies. Methods: The present methodology deals with one pot three component MCR’S reaction of five member based 5-bromothiophene-2-carboxaldehyde, 2-hydroxy-4-methoxybenzophenone and various amides to synthesize new mannich products 4(a-f) in refluxing with ethyl ammonium nitrate as ionic liquid at ambient temperature within 4 to 5 hrs. The docking study was carried out with having receptor in Homo sapiens for antibacterial, Pseudomonas spp. LL2 for anti-fungal and Mycobacterium tuberculosis H37Rv for anti-TB. Results: A series of new synthesized mannich products shows in good to excellent yield (80-86%) via one pot three component reactions. After separation of ionic liquid, obtained products were isolated in good yield by the extraction of products thrice time in ethyl acetate. All of the isolated reaction products were characterised and confirmed through, ¹H-NMR, ¹³C-NMR, Mass spectra and elemental analyses. In obtained products, mainly 4b and 4c compound shows excellent property rather than 4e and 4f and provided desired products in excellent yields may be due to the presence of electron withdrawing groups in five member heterocyclic moiety. Some of the compounds showed in good agreement with its computationally predicted binding energy (MolDock score) with high score in comparison with the rest of the molecules. Conclusion: We have developed a green synthesis, good-yielding and mild reaction protocol for multi component reactions to synthesize new mannich products via one pot three component reaction in solvent free condition at 80°C. It provided several advantages such as mild conditions and shorter reaction time, simple and eco-friendly operational procedure. A significant activity was observed by the 4c and 4d compounds against four bacterial and fungal strains while compounds 4a, 4e and 4f possess poor activity. The anti-tuberculosis activity of four compounds shows poor activity as compare to the standard drug.
A novel green and efficient one-pot three-component synthesis of 2-aryl-pyridines in good to excellent yields has been reported. The methodology initially involved the formation of 1,2-dihydropyridine intermediates via reaction of a variety of aromatic aldehydes with ethyl (methyl) acetoacetate and ammonium acetate, which were the same starting materials as the Hantzsch reaction, under solvent-, catalyst- and heat-free (at room temperature) conditions, followed by air oxidation for 72 hours. In this paper, we also systematically reinvestigated the classic Hantzsch reaction under different reaction conditions, analyzed the main products as well as byproducts, corrected some mistakes in the literature and elucidated the reaction mechanism.
A new method is presented for the preparation of 1,2-disubstitued-1H-imidazole-5-carboxaldehydes by the reaction of N-monosubstituted amidines with 2-halo-3-alkoxy-2-propenals. The reaction is highly regioselective with ratios of 1,2,5:1,2,4-imidazolecarboxaldehydes ranging from 85:15 to 100:0. This methodology could be extended with similar results to the synthesis of imidazole-5-nitriles by the reaction of 2-bromo-3-methoxy-2-propenenitrile with N-monosubstituted amidines.
A simple, green and cost-effective protocol was achieved for the solvent free synthesis of 1,4-dihydropyridines catalyzed by AlCl3·6H2O as a mild and effective catalyst at 60°C in high yields. 1,4-Dihydropyridines thus formed were aromatized to pyridines by in situ generation of HOCl employing AlCl3·6H2O/H2O2/H2O/EtOH as an excellent reagent system under domestic microwave irradiation (MWI). Both the synthesis and oxidation steps were efficiently accomplished in one-pot four-component fashion following the same protocol.
Yb(OTf)3 catalyzed efficient Hantzsch reaction via four-component coupling reactions of aldehydes, dimedone, ethyl acetoacetate and ammonium acetate at ambient temperature was described as the preparation of polyhydroquinoline derivatives. The process presented here is operationally simple, environmentally benign and has excellent yield. Furthermore, the catalyst can be recovered conveniently and reused efficiently.
4-Aryl-1,4-dihydropyridine-3,5-dicarboxylic diestes of the nifedipine type have become almost indispensable for the treatment of cardiovascular diseases since they first appeared on the market in 1975. There are some twenty derivatives currently under clinical development worldwide and work in this area is continuing undiminished. The 1,4-dihydropyridines are the most effective of the calcium antagonists or calcium channel blockers. They are valued not only for their pharmacological effect, but also as a tool for the investigation of the calcium channel, particularly since the discovery that this class also includes compounds that have exactly the opposite action profile and are known as calcium agonists. There are even instances in which this reversal of activity is found between enantiomers. In view of the importance of chirality to pharmacological activity, the present article will describe methods for the separation of enantiomers, point out the structural differences between calcium antagonists and calcium agonists, and attempt to explain the difference in their behavior.
A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridine derivatives at room temperature using catalytic amount of iodine were reported with excellent product yields. An easy access to various substituted 1,4-dihydropyridine derivatives quantitatively using commercially available iodine as a catalyst.
A direct and efficient one-pot three-component synthesis protocol was developed for the synthesis of thiohydantoins from readily
and widely available substrates (isothiocyanates, ethyl chloroacetate, and amines) employing solvent-free conditions.
A series of twenty new 4-substituted-2,6-dimethyl-3,5-bis-N-(heteroaryl)-carbamoyl-1,4-dihydropyridines have been prepared from a three-component one-pot condensation reaction of N-heteroaryl acetoacetamide, an aromatic/heteroaromatic aldehyde, and ammonium acetate under four different experimental conditions. Except for the conventional method, all the experimental conditions were simple, eco-friendly, economical, and the reactions were rapid and high-yielding. The methods employed have been compared in terms of yields, cost, and simplicity. The synthesized compounds were characterized by different spectroscopic techniques and evaluated for their in-vitro anticancer, antibacterial, and antitubercular activities. Amongst the compounds tested, compound 25 exhibited the highest anticancer activity while compounds 14 and 18 exhibited significant antibacterial and antitubercular activities.
Cerium has ability to participate in one-electron transfer reactions and to exist in two stable, adjacent oxidation states +3 and +4 with configurations [Xe]4f1 and [Xe]4f0,respectively. The high reduction potential of Ce(IV) makes Ce(IV) a very efficient oxidizing reagent as compared to other cations. The cerium(IV) ammonium nitrate (CAN) is an excellent reagent for the oxidation of benzylic alcohols and cyclopropylcarbinols to the corresponding carbonyl compounds, but gives cleavage products when applied to other types of substrates such as 1,2-diarylethanols and bicyclo[2.2.1]heptan-2- ol derivatives. The association of CAN, in catalytic amounts, and N-bromosuccinimide (NBS) provides an efficient reagent for the direct transformation of aryl epoxides into α-hydroxyarylketones, although the reaction failed for alkyl and cyclic epoxides. CAN is a good initiator for the direct transformation of diethyl malonate into diethyl ketomalonate by molecular oxygen.
High levels of cholesterol are a primary risk factor in the development of cardiovascular diseases. In this review, we have summarized the structural, chemical and computational aspects of hypocholesterolemic drugs, both statins and non-statins, that target enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) to block cholesterol biosynthesis.
The 1,4-dihydropyridines (DHPs), a class of drugs, possess a wide variety of biological and pharmacological actions, have represented one of the most important groups of calcium-channel-modulating agents and have experienced widespread use in the treatment of cardiovascular disease. Moreover, it has been demonstrated that DHPs could prove to be highly important as multidrug-resistance-reversing agents in cancer chemotherapy. Recent reports suggest that this class also has other notable activities, particularly as antimycobacterial and anticonvulsant agents. Finally, it might be possible for the DHP motif to serve as a scaffold for other pharmacological applications.
A new, potent vasodilator (YC-93), 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methyl amino)] ethyl ester 5-methyl ester hydrochloride, competitively inhibited cyclic adenosine 3′,5′-monophosphate (cyclic AMP) phosphodiesterase in the 105,000 g supernatant solutions from canine basilar, carotid, coronary and femoral arteries. The inhibition constant (Ki) of YC-93 for these enzyme preparations was in the range of 2.0–4.3 μM at substrate concentrations near the low Km (about 1 μM for each enzyme preparation), and was 4.0–12 μM at substrate concentrations near the high Km (50–70 μM). The potency of YC-93 for inhibition of coronary phosphodiesterase at 1 μM cyclic AMP and 50 μM cyclic AMP was much greater than that of papaverine and 3-isobutyl-l-methyl xanthine (IBMX). Commercially available cyclic AMP phosphodiesterase purified from beef heart was also strongly inhibited by YC-93 in a competitive manner and its Ki value was 2.0 μM in the wide range of substrate concentrations tested. Studies on the structure-activity relationship using low Km phosphodiesterase from canine coronary artery and high Km phosphodiesterase from beef heart, demonstrated that 3,5-diethoxycarbonyl-1,4-dihydro-2, 4,6-collidine, the simplest 1,4-dihydropyridine derivative (tested in the present studies) resulted in slightly less inhibition than papaverine, and the inhibitory potency of the former compound was greatly increased mainly by two structural modifications. Firstly, addition of a nitrophenyl group at position 4 of the 1,4-dihydropyridine ring, secondly, the replacement of ethylester at position 3 of the 1,4-dihydro-pyridine ring by N-benzyl-N-methylaminoethyl ester. A few dihydropyridine derivatives together with YC-93 were the most potent inhibitors of cyclic AMP phosphodiesterase among the compounds tested. The finding that the level of cyclic AMP in canine arterial strips was increased by 64 per cent (P < 0.01) even after 1 min exposure to 1 μM YC-93 supports the possibility of at least a partial involvement of phosphodiesterase inhibition in vasodilation by the drug.
Over the past 15 years the privileged structure concept has emerged as a fruitful approach to the discovery of novel biologically active molecules. Privileged structures are molecular scaffolds with versatile binding properties, such that a single scaffold is able to provide potent and selective ligands for a range of different biological targets through modification of functional groups. In addition, privileged structures typically exhibit good drug-like properties, which in turn leads to more drug-like compound libraries and leads. The net result is the production of high quality leads that provide a solid foundation for further development. The identification of privileged structures will be discussed, emphasizing the importance of understanding the structure-target relationships that confer "privileged" status. This understanding allows privileged structure based libraries to be targeted at distinct target families (e.g. GPCRs, LGIC, enzymes/kinases). Privileged structures have been successfully exploited across and within different target families and promises to be an effective approach to the discovery and optimization of novel bioactive molecules. The application of the privileged structure approach, both in traditional medicinal chemistry and in the design of focused libraries, will be discussed with the aid of illustrative examples.
A sensitive and specific liquid chromatography-tandem mass spectrometric method has been developed and validated for the quantification of the five 1,4-dihydropyridine calcium channel antagonists amlodipine, lercanidipine, nitrendipine, felodipine, and lacidipine in human plasma. Sample preparation involved solid-phase extraction on RP-C18 cartridges with good recovery for all the compounds. Sample analysis was performed on a Luna RP-C18 analytical column (15 mm x 2 mm ID, 3.0 microm) with a Sciex API 365 triple quadrupole mass spectrometer with turboionspray source and multiple reaction monitoring. The method is sensitive with a limit of detection below 1 ng/mL for each drug in plasma, with good linearity (r(2) > 0.998), over the therapeutic concentration range (1 to 40 ng/mL). All the validation data, such as accuracy, precision, and interday repeatability, were within the required limits. The method can be used for pharmacokinetic studies and therapeutic drug monitoring of the compounds in humans.
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