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Silica catalyzed one pot synthesis of hybrid thiazolidin-4-one derivatives as anti-tubercular and anti-inflammatory agent via attenuating COX-2 Pathway
Abstract
A novel series of a hybrid class of hybrid thiazolidin-4-one derivatives were designed and synthesized through one-pot catalytic synthesis. The reaction was catalyzed in the presence of silica-H 2 SO4 ⁽⁺⁶⁾ . The derivatives computational ADMET profile was calculated. The study shows that most active derivatives have optimal logP, higher anti-inflammatory activity score, and poor metabolism at the sight of P450-3A4 and 2D6. The entire series of derivatives were further evaluated for anti-tubercular (against Mycobacterium tuberculosis H37Rv (Resistant strain)) and anti-inflammatory activity (in-vivo assay using Wistar rat). The result showed that derivatives 4c , 4h , and 4m have significant potency against tested M. tuberculosis . However, derivatives 4i and 4j found significantly active against inflammation. In vitro COX inhibition assay also supported the result in favor of selectivity and efficacy of derivatives.
... Inflammation is the sudden reaction of the tissues and cells against detrimental effects carried by pathogens or provocative effects of toxic chemical substances or physical injuries. The treatment of inflammation is overcome by the class of medicines named non-steroidal anti-inflammatory drugs [4]. Non-steroidal antiinflammatory drugs (NSAIDs) are the most often used antiinflammatory drug and they show anti-inflammatory action by preventing the production of prostaglandin which is a powerful mediator of inflammation [5]. ...
Thiazoles are notable five-membered heterocyclic rings and their moieties can be found in several biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. Inflammation is the common cause that is associated with different disorders and diseases such as psoriasis, arthritis, infections, asthma, cancer, etc. In this article, the synthesis pattern of these novel molecules are discussed and their anti-inflammatory activities against cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) were reviewed and documented. The potent 26 thiazole analogs were validated with molecular docking against main protease (6LU7) and spike binding domain ACE2 receptor (6M0J) to defeat from the COVID-19 infections. Among this, THI- 9a showed excellent binding energy and affinity against deadly SAR CoV-2. The reviewed and theoretical study information strongly suggested that thiazole derivatives can be used for the development of futuristic target drugs against death-causing diseases like SAR-CoV-2.
... Inflammation is the sudden reaction of the tissues and cells against detrimental effects carried by pathogens or provocative effects of toxic chemical substances or physical injuries. The treatment of inflammation is overcome by the class of medicines named non-steroidal anti-inflammatory drugs [4]. Non-steroidal antiinflammatory drugs (NSAIDs) are the most often used antiinflammatory drug and they show anti-inflammatory action by preventing the production of prostaglandin which is a powerful mediator of inflammation [5]. ...
Thiazoles are notable five-membered heterocyclic rings and their moieties can be found in several biologically active compounds of
natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. Inflammation is the common cause
that is associated with different disorders and diseases such as psoriasis, arthritis, infections, asthma, cancer, etc. In this article, the synthesis
pattern of these novel molecules are discussed and their anti-inflammatory activities against cyclooxygenase-1 (COX-1), cyclooxygenase-2
(COX-2) and lipoxygenase (LOX) were reviewed and documented. The potent 26 thiazole analogs were validated with molecular docking
against main protease (6LU7) and spike binding domain ACE2 receptor (6M0J) to defeat from the COVID-19 infections. Among this, THI-
9a showed excellent binding energy and affinity against deadly SAR CoV-2. The reviewed and theoretical study information strongly
suggested that thiazole derivatives can be used for the development of futuristic target drugs against death-causing diseases like SAR-CoV-2.
... Inflammation is the sudden reaction of the tissues and cells against detrimental effects carried by pathogens or provocative effects of toxic chemical substances or physical injuries. The treatment of inflammation is overcome by the class of medicines named non-steroidal anti-inflammatory drugs [4]. Non-steroidal antiinflammatory drugs (NSAIDs) are the most often used antiinflammatory drug and they show anti-inflammatory action by preventing the production of prostaglandin which is a powerful mediator of inflammation [5]. ...
Thiazoles are notable five-membered heterocyclic rings and their moieties can be found in several biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. Inflammation is the common cause that is associated with different disorders and diseases such as psoriasis, arthritis, infections, asthma, cancer, etc. In this article, the synthesis pattern of these novel molecules are discussed and their anti-inflammatory activities against cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) were reviewed and documented. The potent 26 thiazole analogs were validated with molecular docking against main protease (6LU7) and spike binding domain ACE2 receptor (6M0J) to defeat from the COVID-19 infections. Among this, THI-9a showed excellent binding energy and affinity against deadly SAR CoV-2. The reviewed and theoretical study information strongly suggested that thiazole derivatives can be used for the development of futuristic target drugs against death-causing diseases like SAR-CoV-2.
... MH involves the fusion of two or more recognized bioactive pharmacophoric subunits to give a new hybrid molecule with generally improved receptor affinity, pharmacological profile, and efficacy, relative to the parent molecules [32,33]. Accordingly, MH attempts of 1,3,4-thiadiazole and thiazolidine-4-one moieties have yielded interesting results with the hybrid molecules displaying encouraging anti-inflammatory, anticancer, antioxidant, antitubercular, and antimicrobial activities [34][35][36]. ...
A simple and efficient protocol was developed to synthesize a new library of thiazolidine-4-one molecular hybrids (4a-n) via a one-pot multicomponent reaction involving 5-substituted phenyl-1,3,4-thiadiazol-2-amines, substituted benzaldehydes and 2-mercaptoacetic acid. The synthesized compounds were evaluated in vitro for their antidiabetic activities through α-glucosidase and α-amylase inhibition as well as their antioxidant and antimicrobial potentials. Compound 4e exhibited the most promising α-glucosidase and α-amylase inhibition with an IC50 value of 2.59 μM, which is ∼1.5- and 14-fold superior as compared to the standard inhibitor acarbose. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the phenyl rings had a significant effect on the inhibitory potency.
... MH involves the fusion of two or more recognized bioactive pharmacophoric subunits to give a new hybrid molecule with generally improved receptor affinity, pharmacological profile, and efficacy, relative to the parent molecules [32,33]. Accordingly, MH attempts of 1,3,4-thiadiazole and thiazolidine-4-one moieties have yielded interesting results with the hybrid molecules displaying encouraging anti-inflammatory, anticancer, antioxidant, antitubercular, and antimicrobial activities [34][35][36]. ...
Background:
The persistence of breast cancer as the leading cause of mortality among women, coupled with drug resistance to tamoxifen, the standard endocrine therapy for the disease, exacts fixated attention. To this effect, molecular hybridisation offers an attractive route to drugs with improved bioactivity profile.
Objective:
The primary goal of this study was to examine the potentials of 1H-1,2,3-triazole linked quinoline-isatin molecular hybrids as drug candidates against breast cancer and methicillin-resistant Staphylococcus aureus (MRSA) cells.
Methods:
The quinoline-isatin hybrids were synthesised via click chemistry-mediated molecular hybridisation strategy. Anti-breast cancer activity was determined in 3-(4,5-dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using estrogen-responsive (ER+) MCF-7 and MDA-MB-231 (triple-negative breast cancer -TNBC) cells while antimicrobial efficacy was established via the broth dilution method. Also, the toxicity profile of potent compounds to non-cancerous cells was determined using human embryonic kidney cells (HEK293) and human red blood cells (hRBCs). In silico techniques were employed to predict the drug-like properties of potent compounds and understand their binding modes with estrogen receptor alpha (ERα).
Results:
Compounds 7g-i exhibited the strongest cytotoxicity to MCF-7 cells with IC50 values of 23.54, 23.66, and 32.50 μM, respectively. Interestingly, compound 7h also emerged as the best drug candidate against MDA-MB-231 and MRSA cells with IC50 = 71.40 μM and MIC80 = 27.34 μM, respectively. Structure-activity relationship analysis revealed that quinoline-2-carbaldehyde and 5,7- disubstituted isatin moieties confer desirable potency. These compounds showed no significant cytotoxic or haemolytic effects on HEK293 or hRBCs in vitro at their active concentrations; hence, eliciting their selectivity for cancer cells. In silico studies also presented the drugability of potent compounds and the likely structural features interacting with amino acid residues at the ligand-binding domain of ERα.
Conclusion:
These results suggest that the identified 1H-1,2,3-triazole-linked quinoline-isatin hybrids are viable chemotypes that can be adopted as templates for the development of new anti-breast cancer and anti-MRSA agents.
N‐(benzo[d]thiazol‐2‐ylcarbamothioyl)benzamide (H2L2) was synthesized as a novel thiosemicarbazide containing benzothiazole moiety, by the reaction of benzoyl isothiocyanate with 2‐aminobenzothiazole in benzene. The (H2L2) thiosemicarbazide and its isolated Cr(III), Fe(III), and Co(II) complexes were fully analyzed by different spectroscopic techniques. The thermal fragmentation of [Cr (HL2)Cl2(H2O)2].10H2O, [Co (HL2)Cl(H2O)2].6H2O, and [Fe(L2)Cl(H2O)2] were analyzed. We have also calculated the thermal parameters with using two different methods. The ligand undergoes tranamidation in the presence of PdCl2. Crystal structure of the product obtained by tranamidation is measured. Biological activities of those compounds were assessed as antioxidants, anticancer, and antimicrobial.
In the present investigation, we devolved and synthesized a new series of pyrazole‐embedded thiazolidin‐4‐one derivatives (9a–p) with the goal to produce promising antitubercular leads. The in vitro antimycobacterial activity of the synthesized compounds was tested against replicating and nonreplicating Mtb H37Rv strains. With MIC ranging from 3.03 to 22.55 µg/ml, five compounds (9a, 9c, 9d, 9e, and 9f) emerged as promising antitubercular agents. The active molecules were nontoxic to normal Vero cells. All the synthesized compounds were evaluated for in vitro anti‐inflammatory studies. Compounds 9a, 9b, 9c, 9h, and 9i exhibited excellent anti‐inflammatory efficacy. Docking study was performed to understand the binding pattern of the significantly active compound 9a with 1P44. A new series of pyrazole embedded thiazolidin‐4‐one derivatives (9a–p) were developed to produce promising antitubercular leads. The in vitro antimycobacterial activity of the synthesized compounds was tested against replicating and nonreplicating Mtb H37Rv strains. Five compounds (9a, 9c, 9d, 9e, and 9f) emerged as promising antitubercular agents while being nontoxic to normal Vero cells.
The preparation, characterization, and catalytic investigation of NiFe2O4@SiO2 grafted 3-(propyl azanediyl)bis(ethane-2,1-diyl) bis(hydrogen sulfate) nanoparticles (A) is described. The catalyst was characterized by FT-IR, XRD, FE-SEM, and DLS techniques. The main particle size by the DLS technique was determined as 52 nm. The catalyst was found to be efficient for the condensation of 9-methyl-9H-carbazol-3-amine, thioglycolic acid, and aldehydes lead to the formation of 3-(9-methyl-9H-carbazol-3-yl)-2-arylthiazolidin-4-one derivatives (1d-11d) under reflux in DMF DMF (Time: 1–2 h; Yields: 76–98%) and ultrasonic irradiation in DMF (Time: 0.8–1 h; Yields: 85–97%). The effect of solvent, temperature, and catalyst dosage on the reaction was studied. The catalyst can be recovered and reused 11 times.
Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine–1,2,4‐triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods (1H and 13C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram‐positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram‐negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant‐to‐moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure–activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for further development of new broad‐spectrum antibacterial agents.
The aim of the current research was to investigate the anti-hepatic and anti‐breast cancer activity of Polygonatum verticillatum rhizome extract embedded silver nanoparticles (Pv-AgNPs). The addition of AgNO3 (1 mM) in the process of synthesis, showed change in color of the rhizome extract from brown to dark brown, suggested the formation of silver nanoparticles. Further, FTIR spectra of Pv-AgNPs showed polyphenolic vibrational peaks of hydroxyl groups (3734 - 3367 cm-1 range) that are responsible for the stabilization of nanoformulation. SEM, TEM, EDX, and XRD analysis showed that nanoparticles contain spherical shape, irregular size and well dispersed throughout the plane. Whereas, the elemental analysis results confirmed that 93.28 % of Ag ions were present in the formulation. In-vitro anticancer evaluation showed that Pv-AgNPs (86.58 ± 0.84 - 46.17 ± 1.27 % cell viability) have dose-dependent
inhibition potency against HepG-2 and MCF‐7 cancer cells lines. The comparison study also suggested that Pv-AgNPs consist higher anticancer efficacy than rhizome extract. Computational ADMET and topoisomerase activity prognosis showed optimal drug like properties of major phyto-compounds, which were adsorbed on the surface of silver during the synthesis of nanoformulation. Docking and molecular dynamics simulation study confirmed that the selected phyto-compounds anthraquinones, diosgenin, 5 hydroxymethyl-2-furaldehyde, and santonin have strong tendency to interact with the topoisomerase enzyme. The overall computational studies illustrated that phytocompounds have mild tendency to act as anticancer agents but the experimental assay showed that in a combination such as whole extract of rhizome and Pv-AgNPs possessed significant potency against the breast and hepatic cancer.
A three-component domino Knoevenagel-hetero-Diels-Alder (DKHDA) reaction between 1,3-dicarbonyl, aldehyde/ketone, and alkenes/alkynes leading to the divergent synthesis of chromenones, dihydrochromenones, and spirocyclic chromenones is reported. The reaction was carried out under solvent free condition using a magnetically separable silica (Fe3O4@SiO2) catalyst. While two component DKHDA reaction is known, this is the first example of three component DKHDA reaction involving 1,3-dicarbonyl, ketone, and alkynes producing spirocyclic pyranone derivatives. Twenty-six different highly substituted chromenones was synthesized using the methodology. Wide substrate scope due to multicomponent nature of the reaction, high atom economy, use of inexpensive and non-toxic recyclable silica as catalyst, and solvent free reaction condition makes it an advantageous process. The catalyst was characterized using different analytical techniques like, XRD, IR, HRTEM, VSM, and TGA. Based on the earlier reports a mechanism has also been proposed.
Inflammation acts as an alarming signal for the progression of various biological complications. Various literatures revealed that heterocycle containing synthetic compounds have restorative capability against acute and chronic inflammatory stages. In the current study, we synthesized a series of 1, 2, 4-triazole conjugated 1, 3, 4-thiadiazole hybrid scaffolds and evaluated their impacts against carrageenan-induced paw edema and pro-inflammatory markers in Wistar rats. Further, 3D-QSAR study, ADMET profiling, and docking studies were performed to determine the possible mechanism of action of the derivatives. The study shows that most active derivatives 13f and 13g have optimal logP, higher anti-inflammatory activity score, and poor metabolism at the various site of cytochrome-P450. The Docking studies recommended that synthesized compounds have similar affinity as ligand A307, 63X, and S58 to interact with TNF- α, COX-1, and COX-2 receptor. So, these molecules will definitely hold a promise for the future drug development initiative.
Twelve new derivatives of benzothiazole bearing benzenesulphonamide and carboxamide were synthesised and investigated for their in vivo anti-inflammatory, analgesic and ulcerogenic activities. Molecular docking showed an excellent binding interaction of the synthesised compounds with the receptors, with 17c showing the highest binding energy (–12.50 kcal/mol). Compounds 17c and 17i inhibited carrageenan-induced rat paw oedema at 72, 76, and 80% and 64, 73, and 78% at 1 h, 2 h, and 3 h, respectively. In the analgesic activity experiment, compounds 17c, 17 g, and 17i had ED50 (µM/kg) of 96, 127, and 84 after 0.5 h; 102, 134, and 72 after 1 h and 89, 156, and 69 µM/kg after 2 h, respectively, which were comparable with 156, 72, and 70 µM/kg for celecoxib. The ulcerogenic index of the most active derivatives 17c and 17i were 0.82 and 0.89, respectively, comparable to 0.92 for celecoxib. The physicochemical studies of the new derivatives showed that they will not have oral bioavailability problems.
To determine the risk of stroke associated with non-steroidal anti-inflammatory drug (NSAID) use.
Retrospective cohort study of 162,065 Australian veterans with incident dispensing of an NSAID between 1 January 2001 and 31 December 2008, using prescription event sequence symmetry analysis.
Hospitalisation for stroke, ischaemic stroke or haemorrhagic stroke.
The absolute risk of stroke was low: 7.1/1000 people/year. Incident use of NSAIDs was associated with a 1.88 times increased risk (95% CI, 1.70-2.08) of hospitalisation for stroke (ischaemic or haemorrhagic) following first ever dispensing of an NSAID. This equates to an increased absolute risk of 13.4 strokes/1000 people/year. Significant positive associations between starting an NSAID and having a hospitalisation for stroke were found for most NSAIDs, with adjusted sequence ratios ranging from 1.44 (95% CI, 1.16-1.80) for indomethacin to 1.80 (95% CI, 1.59-2.04) for rofecoxib.
Incident use of NSAIDs was associated with an increased risk of stroke. Increased awareness of the potential for serious adverse cardiovascular events, together with individual assessment of cardiovascular risk, careful deliberation of the balance between risk and benefits and appropriate supervision, is required when initiating NSAID therapy.
New series of fused 1,2,4-triazoles such as, 6-(aryl)-3-(5-nitrofuran-2-yl)-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 4-8, 6-(alkyl/aryl amino)-3-(5-nitrofuran-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 9-13 and 6-(4-substituted phenyl)-3-(5-nitrofuran-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 14-18 have been synthesized via the reaction of 4-amino-5-(5-nitrofuran-2-yl)-4H-1,2,4-triazole-3-thiol 3 with various reagents such as hetero aromatic aldehydes, alkyl/aryl isothiocyanates and 4-substituted phenacyl bromides, respectively. The structures of the newly synthesized compounds have been confirmed on the basis of elemental analysis and spectral studies. The newly synthesized triazolo derivatives have been investigated for their in vitro antibacterial activity. Most of the tested compounds showed interesting antibacterial activity against Staphylococcus aureus. Furthermore, the most potent antibacterial compounds 11-13 were evaluated for their in vitro cytotoxic activity against human cancer cell lines. It was found that compounds 11 and 13 showed higher cytotoxicity against Hep-G2 cell line as compared to standard.
Starting from 4-chlorobenzoic acid, 10 new 5-(4-chlorophenyl)-N-substituted-N-1,3,4-thiadiazole-2-sulfonamide derivatives were synthesized in six-steps. Esterification of 4-chlorobenzoic acid with methanol and subsequent hydrazination, salt formation and cyclization afforded 5-(4-chlorophen-yl)-1,3,4-thiadiazole-2-thiol (5). Conversion of this intermediate into sulfonyl chloride 6, followed by nucleophilic attack of the amines gave the title sulfonamides 7a-7j whose structures were confirmed by NMR, IR and elemental analysis. The bioassay tests showed that compounds 7b and 7i possessed certain anti-tobacco mosaic virus activity.
Multidrug-resistant strains of Mycobacterium tuberculosis seriously threaten tuberculosis (TB) control and prevention efforts. Molecular studies of the mechanism of action of antitubercular drugs have elucidated the genetic basis of drug resistance in M. tuberculosis. Drug resistance in M. tuberculosis is attributed primarily to the accumulation of mutations in the drug target genes; these mutations lead either to an altered target (e.g., RNA polymerase and catalase-peroxidase in rifampicin and isoniazid resistance, respectively) or to a change in titration of the drug (e.g., InhA in isoniazid resistance). Development of specific mechanism-based inhibitors and techniques to rapidly detect multidrug resistance will require further studies addressing the drug and drug-target interaction.
The peroxisome proliferator-activated receptors are a family of three ligand-activated transcription factors. Fibrate antihyperlipidemic drugs and thiazolidinedione antihyperglycemic drugs were recently identified as synthetic ligands for these receptors. In addition, certain unsaturated fatty acids and eicosanoids were shown to bind the receptors, and thus represent naturally occurring PPAR ligands. The synthetic and natural ligands have proven to be powerful tools in dissecting the biology of these orphan receptors.
Indirect drug susceptibility tests of Mycobacterium tuberculosis was done to investigate the accuracy and feasibility of a broth microdilution method (BMM) for determining minimal inhibitory concentrations of conventional drugs against M. tuberculosis. Test drugs included isoniazid (H), rifampicin (R), ethambutol (E), streptomycin (S) and pyrazinamide (Z). Fifty isolates of M. tuberculosis from patients who had never received drug therapy, and H37Rv strain for control, were evaluated in the system. When comparing this method with the gold standard proportional method in Lowenstein-Jensen medium, sensitivity of 100% for all drugs and specifities of 91, 100, 96, 98 and 85% were observed respectively for H, R, E, S and Z. The BMM was read faster (14-20 days) than the proportional method (20-28 days). The microdilution method evaluated allows the testing of multiple drugs in multiple concentrations. It is easy to perform and does not require special equipment or expensive supplies. In contrast to radiometric method it does not use radioactive material.
To examine the metabolic pathways by which troglitazone improves insulin responsiveness in patients with type 2 diabetes, the rate of muscle glycogen synthesis was measured by 13C-nuclear magnetic resonance (NMR) spectroscopy. The rate-controlling steps of insulin-stimulated muscle glucose metabolism were assessed using 31P-NMR spectroscopic measurement of intramuscular glucose-6-phosphate (G-6-P) combined with a novel 13C-NMR method to assess intracellular glucose concentrations. Seven healthy nonsmoking subjects with type 2 diabetes were studied before and after completion of 3 months of troglitazone (400 mg/day) therapy. After troglitazone treatment, rates of insulin-stimulated whole-body glucose uptake increased by 58+/-11%, from 629+/-82 to 987+/-156 micromol x m(-2) x min(-1) (P = 0.008), which was associated with an approximately 3-fold increase in rates of insulin-stimulated glucose oxidation (from 119+/-41 to 424+/-70 micromol x m(-2) x min(-1); P = 0.018) and muscle glycogen synthesis (26+/-17 vs. 83+/-35 micromol x l(-1) muscle x min(-1); P = 0.025). After treatment, muscle G-6-P concentrations increased by 0.083+/-0.019 mmol/l (P = 0.008 vs. pretreatment) during the hyperglycemic-hyperinsulinemic clamp, compared with no significant changes in intramuscular G-6-P concentrations in the pretreatment study, reflecting an improvement in glucose transport and/or hexokinase activity. The concentrations of intracellular free glucose did not differ between the pre- and posttreatment studies and remained >50-fold lower in concentration (<0.1 mmol/l) than what would be expected if hexokinase activity was rate-controlling. These results indicate that troglitazone improves insulin responsiveness in skeletal muscle of patients with type 2 diabetes by facilitating glucose transport activity, which thereby leads to increased rates of muscle glycogen synthesis and glucose oxidation.
We evaluated the long-term antidepressant safety and response of adjunctive pramipexole, a D2-D3 dopamine agonist, in the course of drug-resistant depression. Twenty-three patients with treatment-resistant major depressive episode (MDE) were followed up after a 16-week pramipexole add-on trial. Pramipexole was added to current treatment with TCA or SSRI, at increasing doses from 0.375-1.500 mg/day. The LIFE scale was administered at baseline of the acute trial, at Weeks 16, 32, and 48. Patients were analyzed for sustained remission (score= <2 at LIFE for at least 8 weeks) and recurrence (after remission score > =3 at LIFE for at least 2 weeks) of depression. Of 23 patients, 12 had major depression and 11 had bipolar depression (16 women; mean age=52.8 years). Mean age of onset and median duration of current MDE were 35.1 years and 6 months, respectively; all subjects had at least two prior MDEs. Mean pramipexole dose was 0.990 mg/day. Median duration of follow-up was 28 weeks. Mean baseline MADRS and CGI-S scores were 33.7+/-8.4 (sd) and 4.6+/-0.8, respectively. Median time to sustained remission from baseline was 10 weeks and overall 60.9% (14/23) of subjects recovered within Week 22. Recurrence of depression occurred in 35.7% (5/14) of remitters after Week 24 and within Week 28 from remission. Although there were no sleep attacks, two cases of hypomania and one case of psychotic mania occurred at Weeks 22, 24, and 30, respectively. Pramipexole augmentation of antidepressant treatment was relatively safe and presumably effective in the long-term course of treatment resistant depression.
New acylated 5-thio-beta-D-glucopyranosylimino-disusbstituted 1,3,4-thiadiazols 8, and 11 were prepared, via spontaneous rearrangements, by cycloaddition of the glycosyl isothiocyanate 2 with the reactive intermediates 1-aza-2-azoniaallene hexachloroantimonates 4 and 6, respectively. Reaction of 2 with aminoacetone or chloroethylamine afforded the acylated 5-thio-beta-D-glucopyranosyl-4-imidazoline-2-thione nucleoside 16 and glucopyranosylamino-2-thiazoline derivative 18, respectively. Deblocking of 8, 11, 17 and 19 furnished the free nucleoside analogues 9, 12, 18 and 20, respectively. Analogously, treatment of 2 with chloroethylamine in the 1:2 ratio afforded the thioureylendisaccharide 21. No in vitro antiviral activity against HIV-1, HIV-2, human cytomegallovirus (HMCV), has been found for the new synthesized compounds.
Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained at a SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and bioactive probability is described. The design methods are implemented now at www.chemosophia.com web-site for online computational services.
A series of novel triazolothione, thiadiazole, triazole functionalized furo/thieno [2,3-b] pyridine derivatives 9a-l respectively were prepared starting from 2 (1H) pyridone 3 via selective O/S-alkylation followed by Thorpe-Ziegler cyclization to form furo/thieno [2,3-b] pyridine derivatives 6. Compounds 6 on reaction with hydrazine hydrate resulted carbohydrazide derivatives 7 further reacted with diverse substituted phenyl isothiocyanates to form phenyl hydrazine carbothiamide derivatives 8. Each compound 8 is independently reacted in presence of NaOH, H2SO4 and N2H4.H2O to form triazolothione, thiadiazole, triazole functionalized furo/thieno [2,3-b] pyridine derivatives 9a-l respectively. All the products 9a-l were screened against Gram +ve, Gram –ve bacteria and fungal strains. Compounds 9c-h showed high activity against Bacillus Subtilis MTCC121 at <8.0 micro molar concentration. Promising compounds further screened for minimum bactericidal concentration against Bacillus Subtilis MTCC 121 using ciprofloxacin as standard and found to show very good activity. These compounds also screened for bio-film inhibition activity against Bacillus Subtilis MTCC 121 using Erythromycin as standard and confirmed the high activity.
Background:
In 1979, R.D.Cramer and M.Milne made a first realization of the above mentioned principles attempting to compare molecules by aligning them in space and by mapping their molecular fields to a 3D grid. Further, this approach was developed as the DYLOMMS (DYnamic Lattice-Oriented Molecular Modelling System) approach. In 1984, H.Wold and S.Wold proposed the use of partial least squares (PLS) analysis, instead of principal component analysis, to correlate the field values with biological activities. Then, in 1988 the method which was called CoMFA (Comparative Molecular Field Analysis) was introduced and the appropriate software became commercially available. Since 1988, a lot of 3D QSAR methods, algorithms and their modifications are introduced for solving of virtual drug discovery problems (e.g., CoMSIA, CoMMA, HINT, HASL, GOLPE, GRID, PARM, Raptor, BiS, CiS, ConGO,). All the methods can be divided into two groups (classes):1. Methods studying the exterior of molecules; 2) Methods studying the interior of molecules.
Methods:
A series of grid-based computational technologies for Continual Molecular Interior analysis (CoMIn) is invented in the current paper. The grid-based analysis is fulfilled by means of a lattice construction analogously to many other grid-based methods. The further continual elucidation of molecular structure is performed in various ways. (i) In the terms of intermolecular interactions potentials. This can be represented as a superposition of Coulomb, Van der Waals interactions and hydrogen bonds. All the potentials are well known continual functions and their values can be determined in all lattice points for a molecule. (ii) In the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum free-orbital approach AlteQ is proposed. All the functions can be calculated using a quantum approach at a sufficient level of theory and their values can be determined in all lattice points for a molecule. Then, the molecules of a dataset can be superimposed in the lattice for the maximal coincidence (or minimal deviations) of the potentials (i) or the quantum functions (ii).
Results:
The methods and criteria of the superimposition are discussed. After that a functional relationship between biological activity or property and characteristics of potentials (i) or functions (ii) is created. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page.
Conclusions:
Therefore, a set of 3D QSAR approaches for continual molecular interior study giving a lot of opportunities for virtual drug discovery, virtual screening and ligand-based drug design is invented. The continual elucidation of molecular structure is performed in the terms of intermolecular interactions potentials and in the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum free-orbital approach AlteQ is proposed. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page.
Titanium dioxide is a widely used material. It is white pigment and a very effective UV filter, nano-particles of titanium dioxide show effective photocatalytic properties. Also, it is used in the manufacturing of dye-sensitized solar cells. Recent experimental studies show that the properties (e.g. photocatalytic performance, adsorption, reflectance, adhesion, carrier transportation properties, nano-toxicity, etc.) of the titanium dioxide nano-particles are dependent on their shape, sizes and surface morphology. Therefore, both experimental and computational study of TiO2 nano-clusters and the development of both experimental and computational techniques for the study are the actual goals. Thus, in the current work, a theoretical study of anatase nano-particles, their shape, electron characteristics, surface morphology, the influence on adsorption has been performed. A new methodology based on AlteQ approach for the accurate estimation of the electron density, surface, volume characteristics in a reasonable time for theoretical study of nineteen anatase nano-clusters of different forms (cub, ellipsoid, sphere, cuboid) and sizes from Ti25O50 to Ti650O1300 has been applied. The comparison of the AlteQ and the first principles methods has been performed and the applicability of the AlteQ approach has been confirmed. The computations have been performed at http://www.chemosophia.com/ using "Electron properties calculation: Integration over atomic basins" software. The study showed that the ratio of the summary atomic external surface area of oxygens varies in the wide range 0.42-0.65 dependently on the shape and the surface morphology of a nano-cluster. The maximal values (0.52-0.65) are typical of elongated nano-clusters with deep and long furrows observed on the faces parallel to c axis while the least values (0.42-0.43) are observed in the cases of spherical nano-clusters with smoother surface. Thus, elongated TiO2 nano-clusters with deep and long furrows can adsorb preferably positively charged and acidic centers of compounds which are mostly complementary to the oxygens of TiO2 nano-particles, while spherical nano-clusters with smoother surface are mostly effective in the interactions with the negatively charged and basic adsorptive centers of compounds. Linear relations of the number of electrons observed in the atomic overlaps to the number of electrons belonging to separatrices and to the atomic volume have been obtained.
Background:
The present study reports the synthesis and biological evaluation of thiazolidinone derivatives bearing benzenesulfonamide investigated for cyclooxygenase-2 (COX-2) inhibitory activity and in vivo anti-inflammatory activity.
Methods:
The synthesis of 4-(4-oxo-2-substituted-1,3-thiazolidin-3-yl) benzenesulfonamide derivatives were carried out by conventional synthesis, involves the one-pot condensation reaction of sulfanilamide. The synthesized compounds were evaluated against COX-1 and human recombinant COX-2 by using colorimetric enzyme assay kit and in-vivo study was carried out by carageenan induced rat paw edema method.
Results:
Five derivatives 3a, 3b, 3f, 3g, and 3j showed pronounced COX-2 percentage inhibition (55.76, 61.75, 46.54, 43.32, and 49.77% respectively). Structure activity relationship suggested that the compound with a 4-hydroxy group on phenyl ring leads to more selective inhibition of COX-2 than celecoxib, which is supported by molecular docking study. In silico ADME properties showed that compound 3a, 3b, 3f, 3g, and 3j complies Lipinski's rule of five and show no violation. Molecular docking study divulged the binding interactions of thiazolidinone derivatives into the active site of COX-2 and thereby helps to design the potent inhibitors.
Conclusion:
The overall studies inferred that compound 3b rendered it as a good lead-candidate for the further development of more potent anti-inflammatory agent.
A new series of 1,2,4-triazole derivatives 3a-i of (E)-4-(4- substitutedbenzylideneamino)-3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)-1H-1,2, 4-triazole-5(4H)-thione (2) were synthesized, deriving from 4-amino-3-((5- phenyl-1,3,4-oxadiazol-2-yl)methyl-1H-1,2,4-triazole-5(4H)-thione (1). The compounds were elucidated by IR, 1H NMR, 13C NMR, MS and elemental analyses. These compounds were screened for their antimicrobial activity. Among the synthesized compounds (E)-4-(4-chlorobenzylideneamino)-3- ((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)-2-(morpholinmethyl)-1H-1,2, 4-triazole-5(4H)-thione, 3c was found to exhibit most potent In vitro antimicrobial activity with minimum inhibitory concentrations (MIC) of 1.56, 3.125, 1.56, 25, 25 and 25 μg/ml against E. coli, S. typhimurium, L. monocytogenes, S. aureus, P. aeruginosa and S. pyogenes respectively. Compound (E)-4-(benzylideneamino)-3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl) -2-(morpholinmethyl)-1H-1,2,4-triazole-5(4H)-thione 3a was found to exhibit most potent In vitro antifungal activity with MICs 0.78 and 0.097 μg/ml against C. albicans and F. solani.
Thiadiazole compounds have versatile activities such as anti-microbial, anti-inflammatory, anticancer, etc. Present study involves design of thiadiazole compounds as antidiabetic agent using docking studies. The designed molecules were synthesized and subjected to antidiabetic activity by in vitro and in vivo method. Compound TD7 was found to show potent antidiabetic activity in alloxan induced diabetes rat model. Molecular docking revealed that synthesized derivatives and target proteins were actively involved in binding and had significant correlation with biological activity.
Inflammation is critical for tuberculosis (TB) pathogenesis. The nonresolving aspect of inflammation in TB is caused by sophisticated intracellular survival strategies of tubercle bacilli. TB is a continuum comprising a spectrum of lesions as a consequence of complex regulation of inflammation. Proinflammatory cytokines, including interferons, tumor necrosis factor and interleukin 1 along with microRNAs and eicosanoids form an interactive network during TB. Cross-regulation between proinflammatory mediators strongly impacts on infected cell death patterns. These processes, in concert with local concentrations of proteases, such as cathepsins, serpins and matrix-metalloproteinases, affect tissue integrity, shape the architecture of granulomas and modulate tissue repair. With inflammation networks being uncovered in TB, the relevance of several pathways for novel interventions becomes clearer.
A new series of ethyl 2-(substitutedbenzylidene)-5-methyl-3-oxo-7-(4-(3- phenylureido) phenyl)-3,7-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate derivatives (7a-k) were synthesized. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, LCMS mass and C, H, N analyses. All newly synthesized compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Streptococcus pyogenes and for antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Candida albicans, Penicillium marneffei and Mucor. Compounds 7b, 7e, 7f, 7g, 7h and 7j showed excellent in vitro antibacterial activity and antifungal activity compared with the standard drugs.
Heterocycles bearing nitrogen, sulphur and thiazole moieties constitute the core structure of a number of biologically interesting compounds. Benzothiazole, a group of xenobiotic compounds containing a benzene ring fused with a thiazole ring, are used worldwide for a variety of therapeutic applications. Benzothiazole and their heterocyclic derivatives represent an important class of compounds possessing a wide spectrum of biological activities. The myriad spectrum of medicinal properties associated with benzothiazole related drugs has encouraged the medicinal chemists to synthesize a large number of novel therapeutic agents. Several analogues containing benzothiazole ring system exhibit significant antitumour, antimicrobial, antidiabetic, anti-inflammatory, anticonvulsant, antiviral, antioxidant, antitubercular, antimalarial, antiasthmatic, anthelmintic, photosensitizing, diuretic, analgesic and other activities. This article is an attempt to present the research work reported in recent scientific literature on different pharmacological activities of benzothiazole compounds.
Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochemical features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clinical success. Physicochemical features of CNS drugs and features related to CNS blood–brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compounds differ from those of drug-like compounds is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chemical tools to probe biology space. All these topics frame the scope of this short review/perspective.Section Editors:Han van de Waterbeemd, Christopher Kohl – Pfizer Global Research & Development, Sandwich Laboratories, PDM (Pharmacokinetics, Dynamics and Metabolism), Sandwich, Kent, UK CT13 9NJIn the past, many clinical candidates failed during development. The reasons for failure are now much better understood. The author of this contribution, Chris Lipinski, was among the first to point out that drugs typically have physicochemical and structural properties within certain ranges. This review discusses the original rule-of-five concept and its variants, to be used in the design of orally active compounds. He also compares the concepts of drug-like, lead-like, and CNS-like compounds and drugs. It is important to consider differences better oral and non-oral drugs. Finally, the new idea of tool-like compounds is presented.
To perform a quantitative systematic review of observational studies on the risk of stroke associated with the use of individual NSAIDs.
Searches were conducted using the Medline database within PubMed (1990-2008). Observational cohort or case-control studies were eligible if reported on the risk of cardiovascular events associated with individual NSAIDs versus the nonuse of NSAIDs. We found 3193 articles, in which 75 were eligible for review and abstraction. Of the 75 articles, 6 reported relative risk (RR) of stroke. Data were abstracted into a database using a standardized entry form. Two authors assessed study quality, and discrepancies were resolved by consensus. The pooled RR of all subtypes of incident stroke was increased with the current use of rofecoxib (RR = 1.64, 95% CI = 1.15-2.33) and diclofenac (RR = 1.27, 95% CI = 1.08-1.48). The pooled estimates for naproxen, ibuprofen, and celecoxib were close to unity. The risk of ischemic stroke was also increased with rofecoxib (RR = 1.82, 95% CI = 1.09-3.04) and diclofenac (RR = 1.20, 95% CI = 0.99-1.45). Data were inadequate to estimate the pooled RR by dose and duration, for other individual NSAIDs or nonischemic stroke subtypes.
This meta-analysis supports an increased risk of ischemic stroke with the current use of rofecoxib and diclofenac. Additional studies are required to evaluate most individual NSAIDS, the effect of dose and duration, and the subtypes of stroke.
The synthesis of two groups of structure hybrids comprising basically the antipyrine moiety attached to either polysubstituted thiazole or 2,5-disubstituted-1,3,4-thiadiazole counterparts through various linkages is described. Twelve out of the newly synthesized compounds were evaluated for their anti-inflammatory activity using two different screening protocols; namely, the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays, using diclofenac Na as a reference standard. The ulcerogenic effects and acute toxicity (ALD(50)) values of these compounds were also determined. Meanwhile, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity. In general, compounds belonging to the thiazolylantipyrine series exhibited better biological activities than their thiadiazolyl structure variants. Collectively, compounds 6, 10, 26, and 27 proved to display distinctive anti-inflammatory and analgesic profiles with a fast onset of action. All of the tested compounds revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD(50)>3.0 g/kg). Meanwhile, compounds 7, 10, 11, and 23 are considered to be the most active broad spectrum antimicrobial members in this study. Compound 10 could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic and antibacterial profile.
The principles for the 3D/4D classification of drugs are introduced in this article. Based on these principles, new techniques for the reconstruction of complementary selfconsistent receptor fields for the classification of drugs, taking into account their multitautomeric and multiconformational states, are created. The series of examples of classification of drugs by their activity (active or nonactive), by their mechanisms of action, by their target and binding site and by the most important stages of their action are given. Prospects for rational drug design are highlighted.
This paper describes the synthesis and pharmacological evaluation of a number evaluation of a number of substituted 1,3,4-thiadiazoles. The first member of the series, 2-(aminomethyl)-5-(2-biphenylyl)-1,3,4-thiadiazole (7) was found to possess potent anticonvulsant properties in rats and mice and compared favorably with the standard anticonvulsant drugs phenytoin, phenobarbital, and carbamazepine in a number of test situations. The potency of compound 7 was maintained on alkylation of the side-chain nitrogen atom; however, aryl substitution or chain lengthening caused a drop in potency. Replacement of the 2-biphenylyl group by phenyl or benzyl also lead to inactive compounds.
Increasing attention has focused on the role of inflammation in various chronic diseases, including atherosclerosis. Recent compelling data have begun to unite work from various arenas, such as epidemiology and vascular biology, and even clinical trials to provide evidence for inflammation as a mechanism underlying cardiovascular disease. Inflammation has been implicated in the pathogenesis, progression, and complications of both atherosclerosis and diabetes mellitus-2 complex disorders often found intertwined in patients. Although this story continues to evolve, peroxisome proliferator-activated receptors (PPARs) have been implicated as a molecular pathway involved in both these disease processes. In vitro data, animal work, and some human studies suggest that synthetic PPAR agonists in clinical use, such as thiazolidinediones, may not only regulate metabolic processes but may also limit inflammatory responses, including some involved in atherosclerosis.
A method is presented for measuring the edema induced by injection of 0.05 ml of 1% solution of carrageenin, an extract of Chondrus, into the plantar tissues of the hind paw of the rat. Peak edema develops within the first 3 to 4 hours, and is inhibited by pretreatment of the animals by single oral doses of antiinflammatory agents, steroid or non-steroid. Log dose responses to drugs are linear and parallel, and yield potency ratios with relatively narrow confidence limits. The potency ratios obtained for aspirin, phenylbutazone and hydrocortisone are fairly close to the ratios of their respective daily doses in the treatment of rheumatic disease. A potent antihistaminic-antiserotonin compound, cyproheptadine, is without effect on carrageenin-induced edema.
NSAIDs used for pain relief after surgery may have only small, temporary negative effects on kidney function in adults with normal renal function Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to try and relieve pain after surgery. However, there have been concerns about the possible harmful effects of these drugs on the kidneys. The review of trials found that NSAIDs can cause small, temporary negative effects on the kidneys in adults, but no one in the trials experienced renal failure or serious kidney problems. These results may not apply to children or adults with decreased kidney function
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor overexpression correlates with a more aggressive clinical course. Taken together, these observations indicate that the EGFR is a promising target for cancer therapy. Monoclonal antibodies directed at the ligand-binding extracellular domain and low-molecular weight inhibitors of the receptor's tyrosine kinase are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. They also enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non-small-cell lung cancer, head and neck cancer, ovarian carcinoma, and renal cell carcinoma. Although antitumor activity is significant, responses have been seen in only a minority of the patients treated. In some clinical trials, anti-EGFR agents enhanced the effects of conventional chemotherapy and radiation therapy. Ongoing research efforts are directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies.
A series of 2-trifluoromethyl/sulfonamido-5,6-diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazole derivatives 15a-j have been synthesized by the reaction of 2-amino-5-trifluoromethyl/sulfonamido-1,3,4-thiadiazoles 14a-b and appropriately substituted alpha-bromo-1,2-(p-substituted)diaryl-1-ethanones 13a-h. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR, Mass, and HRMS data. The selected compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory activity against COX-2 and COX-1enzymes using colorimetric method. The compounds tested showed selective inhibitory activity toward COX-2 (80.6-49.4%) over COX-1 (30.6-8.6), amongst them compounds 15f and 15j showed appreciable COX-2 selective inhibitory activity. These compounds also exhibited significant anti-inflammatory activity (70.09-42.32%), which is comparable to that of celecoxib in the carrageenan-induced rat paw edema method.
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