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Synthesis and characterisation of halogenated bis(acylthiourea) derivatives and its antibacterial activities
Abstract
A total of 12 bis(acylthiourea) derivatives with different pharmacophores have been synthesized via nucleophilic substitution reaction of benzene-1,4-dicarbonyl isothiocyanate intermediate with aromatic amine bearing halogens at the ortho, meta and para positions. The structures of the synthesised compounds were confirmed by CHN elemental analysis, FT-IR, ¹H NMR and ¹³C NMR spectroscopies. Antibacterial studies of the compounds via the Kirby Bauer disc diffusion method against Escherichia coli (E.coli) ATCC 25922 and Staphylococcus aureus (S. aureus) S48/81 demonstrated that bis(acylthiourea) N¹,N⁴-bis[(2-chlorophenyl)carbamothioyl]terephthalamide (4) and N¹,N⁴-bis[(2-bromophenyl)carbamothioyl]terephthalamide (7) bearing Cl and Br at the ortho position exhibited excellent activities against both bacteria strains compared to ampicillin standard.
... The characterization 1a-1 h using FTIR depicted a strong absorption peak at 1490-1464 cm −1 indicating the formation of v(N=N) [3]. The v(C=O) peaks were observed at 1649-1685 cm −1 [21] while v(O-H) presence as a broad peak at 3426-3453 cm −1 [22]. The 1 H and 13 C NMR spectroscopy of 1a-1 h showed the presence of aromatic protons at 7.33-8.13 ...
... The antibacterial activity of the halogenated vanillin-azo series (1a-1 h) and halogenated vanillin-Schiff base series (2a-2 h) were carried out against S. aureus and E. coli using the turbidimetric kinetic method. However, several compounds encountered solubility restrictions and dissolution in the culture media caused the precipitation of the drug [2,21]. This occurrence has interfered with the measurement of biological activities. ...
... Additional interaction of the carbonyl and phenyl ring with the phosphates moieties on the bacteria's surface has also increased the antibacterial properties of a compound [33,34]. Besides, the presence of halogen atoms as substituents has also significantly increased the biological activity of the compounds by maintaining the non-hydrophobic interaction between halogen and the amino acid of the bacteria, [21]. It is worth mentioning that the integration of halogen substituents may result in steric hindrance of the molecule and increase its capacity to interact efficiently with the bacteria [34]. ...
Lead compounds containing nitrogen pharmacophores from natural resources have garnered interest among researchers due to their potential for drug development. However, the extractions of the active metabolites are usually labor-intensive and time-consuming. In this study, halogenated vanillin derivatives featuring azo dyes (N=N) (1a-1 h) and Schiff base (C=N) (2a-2 h) have been synthesized via diazonium coupling and nucleophilic substitution reaction, respectively. The comparative effect of N=N and C=N moieties was evaluated for antibacterial properties against Staphylococcus aureus and Escherichia coli via disc diffusion method. Incorporating C=N (8–13 mm) into the vanillin network showed excellent inhibition against S. aureus compared to N=N (7–8 mm) and the standard ampicillin (12 mm). While the halogenated vanillin featuring N=N (7–9 mm) and C=N (7–8 mm) moieties showed excellent zone of inhibitions against E. coli compared to the parent vanillin. The in-silico screening using AutoDock Vina, showed 2c-h (inhibition zone > 10 mm) with a high binding affinity against DNA gyrase enzyme with binding energy ranging from − 7.3 to − 7.9 kcal/mol, similar to re-docking of ampicillin − 7.6 kcal/mol and co-crystalize compounds BPH651 with − 7.5 kcal/mol. This research contributes a significant milestone in drug design, especially for the development of new antibacterial drugs with outstanding properties.
Graphical abstract
... [1][2][3] Thiourea is one of the promising class of compounds that possess good antibacterial, antifungal, anticancer, and other useful pharmaceutical properties. [3][4][5] The presence of N-H and C=S groups in the thiourea moieties act as active binding sites between the compounds with the protein receptor on the surface of microorganism. 1 The number of thiourea moieties in a molecular network plays a significant role in antibacterial properties. The ratio of binding sites in a compound with the surface of microorganism receptors increases as the number of thiourea moieties increases. ...
... The ratio of binding sites in a compound with the surface of microorganism receptors increases as the number of thiourea moieties increases. 6,7 We have reported on series of mono-substituted thiourea 4 , di-substituted thiourea derivatives bearing halogenated aryl groups (4a-l) 5 , bearing amino acids 8 and bearing alkyl chains 8,9 with excellent antibacterial activities against Escherichia coliform (E. coli). ...
... The spectroscopy characterization of compounds (4al) has corresponded to the reported literature. 5 General Procedure for the synthesis of 3a-l Isophthaloyl dichloride 1a (0.10 g, 0.5 mmol) in 10 mL of dry acetonitrile was added into a stirring suspension of potassium thiocyanate, KSCN (0.10 g, 1.0 mmol) in 10 mL of dry acetonitrile. The mixture was stirred for 1 hour at room temperature to form intermediate 2a. ...
... Disc diffusion assay was performed on honey in the culture medium of Staphylococcus aureus (S. aureus, N5923) 17 and E. coli (ATCC 25922) 18 with some modification. 19 These bacteria were used in Mueller-Hinton broth as inoculum and incubated overnight at 37 ° C with constant shaking at 200 rpm. The suspension bacteria (100 μL of target strain) were inoculated on a Mueller-Hinton agar plate and spread thinly with a sterile cotton-tipped swab. ...
... 40 Alternatively, the antibacterial activity of honey was demonstrated against S. aureus and E. coli, via the Kir-by-Bauer disc diffusion assay. [17][18][19] The inhibition zones are presented in Figure 2. The inhibition zone of SG01 -SG03 was evaluated against E. coli (9.0-19.0 mm). ...
... 48 Samples from the same geographical source do not differ significantly in the composition that could be important chemical markers and authentication for honey. 19,20 The quality of glucose in honey is influenced by botanical sources. Another factor such as bee species is also contributing to the difference of glucose content in honey from various places. ...
... Thiourea functionality as versatile precursor derives from its ability to form stable hydrogen bonds with recognition elements of biological targets, including proteins, enzymes and receptor as the hydrogen bond network is essential for stabilizing ligandreceptor interaction (Ronchetti et al., 2021). Consequently, reactive functional groups of thiourea, such as amino, imino, and thiol, can play important roles as precursor in the synthesis of organic molecules for various biological applications, as demonstrated in bacteriostatic activities, where they can be protonated under acidic conditions and reacted with the carboxyl and phosphate groups of the bacterial surface, resulting in prominent antibacterial activity (Ngaini et al., 2012;Halim & Ngaini, 2017). Additionally, thiourea is employed as an active ingredient in pharmaceuticals, which increases the usability of their derivatives as they will pose no adverse risk to natural living bodies (Ohammad, 2018). ...
... Standard antibiotics were used as positive controls, and DMSO served as the negative control (Ngaini & Mortadza, 2019). The results were classified as mild (6-13 mm) or moderate (14-16 mm) based on the inhibition zones (Halim & Ngaini, 2017). The antibacterial activity of thiourea compounds (1-10) against gram-positive bacteria is summarized in Table 5. ...
The rise of multidrug-resistant microbial pathogens has increased the demand for highly effective antibiotics. Five nitrobenzoylthiourea ligands (1–5) with amino acid side chains and their corresponding Cu(II) complexes (6–10) were synthesised with yields ranging from 43% to 90%. The successful synthesis of ligands 1-5 were confirmed by the absence of the ν(NCS) stretching band and the presence of the ν(NH) band, indicating the complete reaction of all (NCS) with a series of amino acids as well as the appearance of two N-H signals in the 1H NMR spectra of all the synthesised ligands. On the other hand, the shift of the (C=O) carboxylic peaks in the Cu(II) complexes suggested successful coordination of ligands to the metal ion via the carboxylate group. The antibacterial activities of these compounds were tested against six bacteria: Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa using the disc diffusion method. The Cu(II) complexes (6-10) exhibited enhanced antibacterial activity compared to the ligands (1-5), especially against gram-negative bacteria (E. coli, K. pneumoniae, and P. aeruginosa). For example, compound 4 showed moderate activity against K. pneumoniae with a 14 mm inhibition zone while its Cu(II) complexes, 8 recorded better inhibition against K. pneumoniae with a 16 mm inhibition zone. Molecular docking studies on all complexes (6-10) also revealed higher binding affinity with targeted proteins with binding energy between -10.4 kcal/mol to -9.0 kcal/mol, in comparison with ligand 2 and 4 with the binding energy of only -7.7 kcal/mol (against S. aureus) and -6.9 kcal/mol (against K. pneumoniae). The enhanced antibacterial activity of all complexes correlates with the higher binding affinity obtained for all complexes. Hence, this study concludes that the nitrobenzoylthiourea derivatives, and particularly their Cu(II) complexes can show potential as antibacterial agent although more thorough investigation are required to develop these compounds into useful drugs.
... The presence of aryl/alkyl and -N=N-groups resulted in the remarkable biological properties of azo derivatives. In acidic conditions, the N=N moiety is easily protonated, which improves the biological properties of the compound (Ngaini et al. 2022;Abd Halim and Ngaini 2017). The incorporation of halogens as substituents in a molecular network has also been reported to increase biological activity which is vital for pharmaceutical usage (Mortadza et al. 2021;Ho et al. 2017). ...
... The addition of halogen as a substituent further boosted the compound's ability to enhance biological activity by stabilising the non-hydrophobic connection between the bacterium and the halogen substituent through halogen bonding with the bacteria's amino acids (Abd Halim and Ngaini 2017). However, steric repulsion of the molecule, increasing its mass and impairing its ability to interact with the bacterium, may be the source of the compound's weak antibacterial and lack of inhibitory actions (Ngaini et al. 1970). ...
Chemical modification of active scaffolds from natural products has gained interest in pharmaceutical industries. Nevertheless, the metabolites extraction is time-consuming while the lead is frequently mismatched with the receptor. Here, the diazo coupling approach was introduced to generate a series of vanillin derivatives featuring halogenated azo dyes (1a-h). The vanillin derivatives showed effective inhibition of S. aureus (7-9 mm) and E. coli (7-8 mm) compared to the parent vanillin, while 1b had the highest inhibition zone (9 mm) against S. aureus comparable to the reference ampicillin. The presence of N = N, C = O, -OH, -OCH3 and halogens established strategic binding interactions with the receptor. The potential vanillin-azo as an antimicrobial drug was supported by in silico docking with penicillin-binding proteins and DFT (using Gaussian 09) with binding affinity -7.5 kcal/mol and energy gap (Egap) 3.77 eV, respectively. This study represents a significant advancement in drug discovery for effective antibiotics with excellent properties.
... A method for the formation of substituted (cycloalkylcarbonylthioureido)aryl-(benzyl-)carboxylic(sulfonic) acids (26,27) as promising plant growth regulators with fungicidal activity has been proposed [17]. The authors showed that the latter are easily formed by the sequential interaction of cyclopropanecarbonyl chloride (20), ammonium isothiocyanate and aminoaryl (benzyl-) carboxylic, sulfanilic acids or sulfamide (Fig. 8). ...
... Methods for the synthesis of bis-(arylcarbamothioyl) terephthalamides (63) with different "pharmacophore" groups have been developed according to the standard procedure, namely the nucleophilic addition reaction of halogen-substituted anilines to tere-phthaloyl diisothiocyanate (62) (Fig. 18) [27]. Studies on antibacterial activity by Kirby-Bauer disk diffusion against E. coli and S. aureus showed that N 1, N 4 -bis-[(2-chlorophenyl)-and N 1 , N 4bis-[(2-bromophenyl)-carbamothioyl]tere-phthalamide have a higher activity (growth inhibition zone 18 mm) compared to Ampicillin. ...
Acyl isothiocyanates and their functional derivatives (acyl thioureas and acyl thiosemicarbazides) are an important group of organic compounds that are widely used in the synthesis of heterocycles and in chemistry as catalysts, ligands, colorimetric hemosensors, etc. In recent years, there has been an increased interest towards this class of compounds as promising biologically active compounds, especially since the latest advances in medicinal chemistry for them are not sufficiently studied.
The aim. To summarize and systematize information for the last 10 years on methods of synthesis and biological activity of substituted acyl thioureas and acyl thiosemicarbazides.
Materials and methods. Web-tools for finding scientific information (Reaxys, Scopus, Google Scholar, ScienceResearch, SciFinder, Web of Science, etc.).
Results and discussion. Literature sources related to the methods of synthesis of substituted acyl thioureas and acyl thiosemicarbazides were systematized and analyzed. The main approaches for the formation of these compounds are revealed: stepwise formation from carboxylic acids, through acyl chlorides and acyl isothiocyanates followed by nucleophilic addition of amines or hydrazides of carboxylic acids ("one-pot synthesis"), nucleophilic addition of amines or hydrazides of carboxylic acids directly to acyl isothiocyanates and parallel microwave synthesis using acyl isothiocyanates and amines as reagents. The possibility of their use as ligands for the formation of complex compounds with transition metal ions was discussed. In the review biological activity of these structures, namely antimicrobial, fungicidal, antitumor, antiviral, antifungal and other activities was detailazed.
Conclusions. The basic approaches to the synthesis of substituted acylthuoureas and acyl thiosemicarbazides which include the application of carboxylic acids, their derivatives (acyl halides and isothiocyanates) and N-nucleophiles as initial compounds were discussed. It was shown that aforementioned class of the compounds reveals the versatile biological activity and are promising for further structural modification aimed to the search of novel drugs
... The antibacterial mechanism of thioureaderived analogs is proposed to be about the inhibition of topoisomerase II, DNA gyrase, and topoisomerase IV (4,5,(10)(11)(12). Copper (II) complexes of 3-(trifluoromethyl)phenyl thiourea showed stronger inhibition activity towards Staphylococcus aureus DNA gyrase than the topoisomerase IV during the preliminary study (9). ...
Background and purpose
The incidence of antibiotic resistance rapidly emerges over the globe. In the present study, the synthesis of thiourea derivatives as antibacterial agents and their biological evaluation are reported.
Experimental approach
Preliminary studies were done by molecular docking of four analogs of 1-allyl-3-benzoylthiourea, clorobiocin, and ciprofloxacin on the DNA gyrase subunit B receptor (PDB: 1KZN). The nucleophilic substitution reaction of benzoyl chloride analogs to the allylthiourea yielded four 1-allyl-3-benzoylthiourea analogs (Cpd 1-4). The reactions were done by a modified Schotten Baumann method. The in vitro antimicrobial activities were determined using the agar dilution method against methicillin-resistant Staphylococcus aureus (MRSA), Salmonella typhi, Escherichia coli , and Pseudomonas aeruginosa.
Findings/Results
The in-silico study showed that Cpd 1-4 possesses a good interaction on the DNA gyrase subunit B receptor compared to the ciprofloxacin. Cpd 3 had the best binding affinity with a rerank score of - 91.2304. Although the candidate compounds showed unsatisfactory antibacterial activity, they indicated an increasing trend of growth inhibition along with the increment of concentration. Cpd 1 and 4 exhibited in vitro antibacterial activities against MRSA with a minimum inhibitory concentration value of 1000 µg/mL, better compared to the other compounds.
Conclusion and implication
Despite lacking antibacterial activity, all the synthesized compounds showed an increased trend of growth inhibition along with the increment of concentration. Therefore, additional development should be implemented to the compounds of interest in which optimization of lipophilicity and steric properties are suggested.
... It is known that Mycobacterium tuberculosis, the causative agent of tuberculosis, is responsible for the death of around 1.73 million people annually. The increase of resistance to multiple drugs and the little development of new specific compounds, has complicated and prolonged the treatment of tuberculosis [2,3]. ...
... iourea is known as a versatile compound that has been intensely synthesised due to its ability to undergo structural modification [4]. Having two units of reactive primary amine group has led thiourea to be a suitable precursor for the synthesis of many derivatives in new compounds [5]. Oxygen, nitrogen, and sulphur atoms of thiourea derivatives provide a multitude of bonding possibilities that may contribute to a broad spectrum of thiourea applications in the pharmaceutical field, such as antiparasitic, anticancer, antioxidant, antibacterial, antifungal, antimalarial, and anti-HIV [6][7][8]. ...
Isomers of monothioureas, 2a – 2d , derived from the reaction of disubstituted benzoyl isothiocyanate and dibenzylamine were synthesised and characterised by using elementary analysis CHNS and IR, ¹ H NMR, and ¹³ C NMR spectroscopies. The compounds were screened for their in vitro antibacterial activity by using selected Gram-positive bacteria, and moderate inhibition activity was displayed for compound 2b with the value of inhibition zone 11 ± 0.8 mm at a concentration of 50 mg/ml. The outcomes of Lipinski’s rule of five assessment appeared to be in agreement with all compounds as they adhered to most of the rules, in which they can be preliminarily classified as active drug-like. The frontier molecular orbitals (HOMO and LUMO) for halogen-substituted 3,4-dichloro ( 2a ) and 3,4-difluoro ( 2b ) were also determined by applying the computational method of density functional theory (DFT) to determine their relationship as a molecular descriptor in antibacterial activities. The value of LUMO energy for compound 2b (1.8229 eV) is lower than that of compound 2a (1.8492 eV) which indicates higher antibacterial activities.
The exploitation of naturally derived drugs can become a replacement for ineffective drugs due to the relentless antimicrobial resistance. A series of natural-product-based coumarin-chalcones (4a-4i) were synthesised via facile Steglich esterification. The coumarin-chalcones (4a-4i) showed effective inhibition against P. aeruginosa (7-13 mm) and E. coli (8-12 mm) in comparison to the standard drug ampicillin and coumarin alone. Compounds 4b and 4g exhibited the highest inhibition zone against P. aeruginosa (13 mm) and E. coli (12 mm) respectively. The hybridisation of chalcone in the coumarin network introduced active C = CH, C = O and C-O moieties, contributing to significant microbial inhibition. The molecular docking of 4b exhibited the highest binding affinity -10.1 kcal/mol as compared to 4a, 4c and 4g -9.2 kcal/mol, -9.2 kcal/mol and -9.1 kcal/mol respectively. The ADMET studies also supported natural-product-based coumarin-chalcones as suitable drug candidates. This study is noteworthy for coumarin-based drug development in the medicinal field.
Methicillin-resistant Staphylococcus aureus (MRSA) can easily form biofilms on food surfaces, thus leading to cross-contamination, which is difficult to remove. Therefore, there is an urgent need to find alternatives with good antibacterial and antibiofilm effects. In this study, two indole sesquiterpene compounds, xiamycin (1) and chlorinated metabolite chloroxiamycin (2), were isolated from the fermentation liquid of marine Streptomyces sp. NBU3429 for the first time. The chemical structures of the two compounds were characterized by spectroscopic data interpretation, including 1D NMR and HRESIMS analysis. Antimicrobial test showed that chloroxiamycin (2) (minimum inhibitory concentration, MIC = 16 μg/mL) exhibited superior antibacterial activity than xiamycin (1) (MIC = 32 μg/mL) against MRSA ATCC43300. Moreover, compound (2) decreased the biofilm formation rate of MRSA ATCC43300 by 12.7%-84.6% in the concentration range of 32-512 μg/mL, which is relatively stronger than xiamycin (1) (4.1%-49.9%) as well. Antibacterial/antibiofilm mechanism investigation indicated that chloroxiamycin (2) could disrupt the cell wall and membrane of MRSA, inhibiting the production of biofilm extracellular polysaccharides. All these results illustrated that chloroxiamycin (2) is an effective antibacterial/antibiofilm agent, which makes it an attractive candidate for food preservatives.
N,N'-((dodecane-1,12-diylbis(azanediyl))bis(carbonothioyl))bis(4-nitrobenzamide) 5 and N,N'-((dodecane-1,12-diylbis(azanediyl))bis(carbonothioyl))bis(3-nitrobenzamide) 6 as bis acyl thiourea derivatives were synthesized and their molecular structures were characterized using 1H NMR, 13C NMR, COSY, DEPT, HMQC, FT-IR, and HRMS techniques. The acid dissociation constants (pKa) of the bis-acyl thiourea derivatives 5, 6 were determined potentiometrically and spectrophotometrically. The pKa values of products 5, 6 were determined in 50% (v/v) dimethyl sulfoxide–water hydro-organic solvent in the presence of 0.1 molL1 ionic strength of NaCl and in the acidic medium at 25±0.1 °C, and two pKa values were calculated for each compound with the HYPERQUAD computer program using the data obtained from the potentiometric titrations performed. In addition, three pKa values for each compound were determined in the calculations using the HypSpec program from the data obtained from the spectrophotometric titrations performed under the conditions where the potentiometric titrations were performed. For compounds 5 and 6, spectrophotometrically, pKa1 was 3.56±0.08 and 3.87±0.01, respectively, pKa2 was 7.11±0.08 and 7.05±0.01, respectively, and pKa3 was 12.30±0.08 and 11.82±0.02, respectively. It can be said that pKa1, pKa2, and pKa3 values may belong to enol, enthiol, and NH, respectively. Moreover, for compounds 5 and 6, potentiometrically, pKa2 was 7.06±0.13 and 6.94±0.11, respectively, and pKa3 was 12.11±0.06 and 11.17±0.06, respectively, and it can be said that pKa2 and pKa3 values may belong to enthiol and NH, respectively. It is seen that the pKa values determined spectrophotometrically and potentiometrically are compatible with each other.
Recently, there has been a rise in interest in the synthesis of chemical compounds with biological
activity, especially in the fight against cancer, which is regarded as a modern-day disease. The
present study was conducted to synthesize thiourea benzamide derivative ligands and their metal
complexes with Cu(II). Thiourea benzamide derivative ligands and their metal complexes with
Cu(II) were synthesized. The structures of the synthesized complexes were elucidated by mass
spectra, FT-IR, 13C-NMR, and 1H-NMR spectra. Molar conductivity, magnetic susceptibility,
SEM, EDX, and TG analyses were also performed. The in vitro anticancer activity of the
compounds was examined against the breast cancer cell line MCF-7. Molecular docking of
complexes (1) and (2) was performed with breast cancer proteins. The synthesized compounds
include {[Cu(L)2Cl2].nH2O, where L= ( N-((3-nitrophenyl) carbamothioyl) benzamide (L1, n= 2,
(1)), N-(naphthalen-1-ylcarbamothioyl) benzamide (L2, n= 2, (2)), 4-nitro-N-((4-nitrophenyl)
carbamothioyl) benzamide (L3, n= 0, (3)), 4-nitro-N-(p-tolylcarbamothioyl) benzamide (L4, n=
2, (4)), N-((4-chlorophenyl) carbamothioyl)-4-nitrobenzamide (L5, n= 4, (5). The ligands behave
as bidentate donors and are associated with Cu(II) in a 1:2 (M:L) ratio. Also, the geometric shapes
of the prepared complexes were octahedral. The in vitro cellular toxicity evaluation showed that
the compounds have low efficacy except for complexes (1) and (2), which have high effectiveness.
The molecular docking analysis indicated that the compounds would specifically target PR (PDP:
4OAR) and Akt (PDP: 5KCV) proteins, which had the lowest values of binding energy and
RMSD. The findings of this study reveal that these compounds can be used for therapeutic
purposes.
The reaction of the N,N-diethyl-N'-(p-nitrobenzoyl)thiourea with K2[PtCl4] results in the complex of configurational cis-[Pt(L-kS,O)2], and structurally characterized by elemental analyses, FT-IR, ¹H NMR, ¹³H NMR, UV–Vis spectroscopy, and cis-[Pt(L-kS,O)2] complex have been also characterized by a single-crystal X-ray diffraction study. The cis-[Pt(L-kS,O)2] crystallizes in the monoclinic crystal system, space group P21/c, with Z = 4, and unit cell parameters, a = 15.09299(15) Å, b = 15.26600(14) Å, c = 14.39268(14) Å, α = 90°, β = 107.6347(11)° and γ = 90°. The single-crystal diffraction analysis of the complex shows that the molecular configuration of cis-[Pt(L-kS,O)2] is a slightly distorted square-planar geometry, and both deprotonated ligands (L) contribute one O atom and one S atom coordinate with a central Pt(II) ion. The intermolecular interactions in the cis-[Pt(L-kS,O)2] complex were analyzed using the Hirshfeld surface method, including 2D fingerprint plots. In addition, the fluorescence properties of the compounds at room temperature were also studied. The results show that both ligands and complexes have good fluorescence properties, and the fluorescence intensity of the coordination compound enhances.
Graphical Abstract
In this paper, single-crystal X-ray analysis shows cis-[Pt(L-kS,O)2] belongs to monoclinic crystal system, space group P21/c. The connectivity of the ligand to the metal as 2:1 and the platinum atom is coordinated with two N,N-diethyl-N'-(p-nitrobenzoyl)thiourea ligands in a distorted square-planar geometry.
Chalcone is a naturally derived compound which has well-known for its antimicrobial potency. Different factors reduced the efficiency of drug derivatives effective drugs always remain in demand. In this present work, bioisosteric replacement of carboxyl group is described in 1a–h, 2a–h, 3a–h and 4a–h) via microwave-assisted synthesis with excellent yields (46.76–94.59%). The antimicrobial evaluation against S. aureus depicted excellent inhibition of 1b, 1h and 3a–h with higher inhibition zones (11–18 mm) compared to that of ampicillin (11 mm). The structure-activity relationship was supported by molecular docking studies of 1b and 3h on S. aureus 4-pql protein with the binding affinity of −6.7 and −7.8 kcal/mol respectively. The DFT studies depicted the energy gap (ΔE) values 4.12 eV and 4.48 eV for compounds 1b and 3h, respectively. The presence of electron-withdrawing group (EWG) of fluorine substituent on the pyrazoline network has increased the antimicrobial activity as compared to chalcone derivatives. This study is profitable to medicinal industries in designing new drugs that benefit mankind.
New mono aspirinate thiourea-azo derivatives 2a–f were synthesized using aspirin as a natural product-based precursor, with 4-aminophenylazophenol derivatives in excellent 70–90% yields. Overall, 2a–f gave excellent antibacterial activity against Staphylococcus aureus S48/81 and 2-(((3-((2-bromophenyl)diazenyl)-4-hydroxyphenyl)carbamothioyl)carbamoyl)phenyl acetate (2d) exhibited a larger zone of inhibition 10 mm, comparable to the standard ampicillin. The molecular docking analysis of 2d against S. aureus tyrosyl-tRNA synthetase protein displayed a free energy interaction of −7.7 kcal/mol compared to aspirin (−6.4 kcal/mol).
In this study, a series of chalcone derivatives (1a–c) were synthesized via Claisen‐Schmidt condensation, followed by aza‐Michael addition to form pyrazoline derivatives (2a–c and 3a–c). The reaction was performed via microwave radiation to give excellent yields (77–93%) in 1–3.5 min. Microwave‐assisted reaction of Fischer esterification of pyrazolines (2a–c and 3a–c) afforded heteroaromatic pyrazoline esters (4a–c) in high yield (83–96% in <2 min) compared to conventional reflux (55–79% in 30 min). Compounds 1a–c and 3a–c demonstrated excellent antibacterial activity against Staphylococcus aureus via disc diffusion assay with inhibition zone with 13 and 19 mm compared to a standard drug, ampicillin (11 mm). Structure activity relationship of 1b and 3b were visualized via molecular docking interaction against 4pql protein of S. aureus with binding free energy −7.0 and −8.0 kcal/mol, respectively. This study is significant in drug discovery process particularly for pharmaceutical industries. Synthesis of Heteroaromatic Chalcone Derivatives, Molecular Docking and Antibacterial Activities.
Bacterial diseases cause hazardous infections due to the occurrence of bacterial resistance. Drugs production to cure bacterial resistance from natural sources has become ineffective to execute the resisted bacteria due to the unsuitable binding interaction of active sites with the receptors. Drug link to natural products moieties such as chalcones and pyrazolines, which originated from plants extracts, has become attractive among researchers due to its significant pharmaceutical moiety. In this study a series of chalcone derivatives (1 a–d) has been synthesized via Claisen‐Schmidt condensation, followed by cyclization to form pyrazolines (2 a–d, 3 a–d). Fischer esterification of pyrazolines formed 4 a–d in moderate to good yield (42.91‐88.23 %). Antimicrobial activities of all the synthesized compounds were evaluated against Escherichia coli and Staphylococcus aureus via disc diffusion. Among all compounds, pyrazolines 3 c and 3 d showed the highest zone of inhibition (17 mm) compared to 1 a‐d (5‐11 mm) and standard ampicillin (11 mm). The exchange of α, β‐unsaturated carbonyl showed phenomenal increment in the biological activities. Structure activity relationship of 1 a, 1 d, 3 a and 3 d was analyzed via molecular docking of N‐terminal domain having deoxyribonucleic acid (DNA) binding protein (4pql) with excellent binding energy of −6.2, −6.6, −7.1 and −7.2 kcal/mol, respectively. This work is significant in designing new drugs with keto‐exchange relationship for medicinal industry.
Bis‐thiourea derivatives have distinguished synthetic potentialities. They are interesting substrates for construction of various classes of heterocycles, such as thiazoles, thiadiazoles, imidazoles, bis‐thiazoles, bis‐thiadiazoles, and fused heterocyclic systems. The current review is concerned on disclosing the synthetic and research applications of bis‐thioureas that were reported in the literature during the last decade.
In searching for drugs from natural product scaffolds has gained interest among researchers. In this study, a series of twelve halogenated thiourea (ATX 1-12) via chemical modification of aspirin (a natural product derivative) and evaluated for cytotoxic activity against nasopharyngeal carcinoma (NPC) cell lines, HK-1 via MTS-based colorimetric assay. The cytotoxicity studies demonstrated that halogens at meta position of ATX showed promising activity against HK-1 cells (IC50 value ≤15 µM) in comparison to cisplatin, a positive cytotoxic drug (IC50 value =8.9 ± 1.9 µM). ATX 11, bearing iodine at meta position, showed robust cytotoxicity against HK-1 cells with an IC50 value of 4.7 ± 0.7 µM. Molecular docking interactions between ATX 11 and cyclooxygenase-2 demonstrated a robust binding affinity value of −8.1 kcal/mol as compared to aspirin’s binding affinity value of −6.4 kcal/mol. The findings represent a promising lead molecule from natural product with excellent cytotoxic activity against NPC cell lines.
The synthesis of five N,N'-substituted thiocarbamides, namely N-(naphthyl)-N'-(pentoxycarbonyl) thiocarbamide (H2L1), N-(2-Chloro-4-nitrophenyl)-N'-(pentoxycarbonyl) thiocarbamide(H2L2), N-(2-methoxy-4-nitrophenyl)-N'-(pentoxycarbonyl) thiocarbamide (H2L3), N-(3-nitrophenyl)-N'-(pentoxycarbonyl) thiocarbamide (H2L4) and N-(naphthyl)-N'-(2, 2, 2-trichloroethoxycarbonyl) thiocarbamide (H2L5) was performed by the reaction of pentoxycarbonyl chloroformate with naphthyl amine, 2-chloro-4-nitroaniline, 2-methoxy-4-nitroaniline, 3-nitroaniline, respectively, for the first four and by the reaction of 2, 2, 2-trichloroethoxycarbonyl chloroformate with naphthyl amine for the last compound. These compounds were fully characterized by using various spectroscopic (FT-IR, ¹H and ¹³C NMR) and single crystal X-ray studies of H2L1 and H2L5. In the crystal structure of both the compounds the (C═S) and (C═O) groups are trans to each other across the C−N bond. The crystal packing of H2L1 shows that the molecules form centrosymmetric dimers connected by N2−H∙∙∙∙∙S hydrogen bonds. In H2L5 an offset face-to-face π–π stacking is observed between two naphthalene rings of two molecules. In vitro cytotoxicity of synthesized compounds was evaluated using five human carcinoma cell lines 2008, C13* (cervical carcinoma), A2780, A2780/CP and IGROV-1 (ovarian carcinoma). The IC50 values of compounds H2L2 ─ H2L4 demonstrated them to be very promising anticancer agents.
Graphical Abstract
Synthesis, molecular structure exploration and in vitro cytotoxicity screening of five novel N, N'- disubstituted thiocarbamide derivatives
All authors
Sunil K. Pandey, Seema Pratap, Gaia Gozzi, Gaetano Marverti & R. J. Butcher
https://doi.org/10.1080/10426507.2018.1452234
Published online
15 March 2018
Since Rheumatoid arthritis (RA) is one of the major human joint diseases with unknown etiology, the early diagnosis and treatment of RA remains a challenge. In this contribution we have explored the possibility to utilize novel nanocomposites of tetera suplhonatophenyl porphyrin (TSPP) with titanium dioxide (TiO2) nanowhiskers (TP) as effective bio-imaging and photodynamic therapeutic (PDT) agent for RA theranostics. Our observations demonstrate that TP solution PDT have an ameliorating effect on the RA by decreasing significantly the IL-17 and TNF-α level in blood serum and fluorescent imaging could enable us to diagnose the disease in subclinical stages and bio-mark the RA insulted joint.
A series of bisthiourea ligands, namely 1,2-bis(N'-2-methoxybenzoylthioureido)-4-nitrobenzene (T1), 1,2-bis(N'-3-methoxybenzoylthioureido)-4-nitrobenzene (T2) and 1,2-bis(N'-4-methoxybenzoylthioureido)-4-nitrobenzene (T3) have been successfully synthesised. The reaction was performed using 2: 1 ratio. The structures of the ligands have been characterised by elemental analysis (CHNS), IR spectroscopy, H-1 Nuclear Magnetic Resonance (NMR) and melting point determination method. The thiourea ligands were screened for their antibacterial activity using disc diffusion method against Gram-positive bacteria (Bacillus subtillis ATCC 6633, Staphylococcus aureus ATCC 29213 and Lactobacillus casei ATCC 393) and Gram-negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 10145, and Shigella sonnei ATCC 9290). The efficacy of the compounds against Gram-positive bacteria is higher than Gram-negative bacteria. (C) 2012 Published by Elsevier B. V. Selection and/or peer review under responsibility of Asia-Pacific Chemical, Biological & Environmental Engineering Society
A series of symmetrical 1,3-bis thiourea 1a–e and 1,4-bis thiourea derivatives 2a–e have been successfully synthesized from the reactions of amines with 3-acetylbenzoyl isothiocyanate and 4-acetylbenzoyl isothiocyanate, respectively. All the synthesized compounds were characterized by FT-IR spectroscopy and 1H and 13C NMR spectroscopy. The compounds were screened for their antibacterial activity by turbidimetric method using gram-negative bacteria (E. coli ATCC 8739) using turbidimetric method. The newly synthesized bis-thiourea derivatives bearing aryl side chains showed good antibacterial activity against E. coli. The effect of the molecular structure of the synthesized compounds on the antibacterial activity is discussed.
The emergence of new infectious diseases, the resurgence of several infections that appeared to have been controlled and the increase in bacterial resistance have created the necessity for studies directed towards the development of new antimicrobials. Considering the failure to acquire new molecules with antimicrobial properties from microorganisms, the optimization for screening methods used for the identification of antimicrobials from other natural sources is of great importance. The objective of this study was to evaluate technical variants used in screening methods to determine antibacterial activity of natural products. Thus, a varied range of natural products of plant, fungi and lichen origin were tested against two bacterial species, Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922, by two variants of the agar diffusion method (well and disc), two variants of the bioautographic method (direct and indirect) and by microdilution assay. We concluded that the well-variant of the diffusion method was more sensitive than the disc-variant, whilst the direct-variant of the bioautographic method exhibited a greater sensitivity if compared to indirect-variant. Bioautographic and diffusion techniques were found to have similar sensitivity; however the latter technique provided more suitable conditions for the microbial growth. In this study, we also discussed the best conditions for the determination of minimal inhibitory concentration.
Thiourea derivatives display a broad spectrum of applications in chemistry, various industries, medicines and various other fields. Recently, different thiourea derivatives have been synthesized and explored for their anti-microbial properties. In this study, four carbonyl thiourea derivatives were synthesized and characterized, and then further tested for their anti-amoebic properties on two potential pathogenic species of Acanthamoeba, namely A. castellanii (CCAP 1501/2A) and A. polyphaga (CCAP 1501/3A). The results indicate that these newly-synthesized thiourea derivatives are active against both Acanthamoeba species. The IC50 values obtained were in the range of 2.39-8.77 µg·mL‑1 (9.47-30.46 µM) for A. castellanii and 3.74-9.30 µg·mL‑1 (14.84-31.91 µM) for A. polyphaga. Observations on the amoeba morphology indicated that the compounds caused the reduction of the amoeba size, shortening of their acanthopodia structures, and gave no distinct vacuolar and nuclear structures in the amoeba cells. Meanwhile, fluorescence microscopic observation using acridine orange and propidium iodide (AOPI) staining revealed that the synthesized compounds induced compromised-membrane in the amoeba cells. The results of this study proved that these new carbonyl thiourea derivatives, especially compounds M1 and M2 provide potent cytotoxic properties toward pathogenic Acanthamoeba to suggest that they can be developed as new anti-amoebic agents for the treatment of Acanthamoeba keratitis.
Microtubules are essential cytoskeletal components with a central role in mitosis and have been particularly useful as a cancer chemotherapy target. We synthesized a small molecule derivative of a symmetrical 1,3-phenyl bis-urea, (1,1'-[1,3-phenylene]bis[3-(3,5-dimethylphenyl)urea], named "41J"), and identified a potent effect of the compound on cancer cell survival. 41J is cytotoxic to multiple cancer cell lines at nanomolar concentrations. Cell death occurred by apoptosis and was preceded by mitotic arrest in prometaphase. Prometaphase arrest induced by 41J treatment was accompanied by dissociation of cyclin B1 levels from the apparent mitotic stage and by major spindle abnormalities. Polymerization of purified tubulin in vitro was directly inhibited by 41J, suggesting that the compound works by directly interfering with microtubule function. Compound 41J arrested the growth of glioblastoma multiforme xenografts in nude mice at doses that were well-tolerated, demonstrating a relatively specific antitumor effect. Importantly, 41J overcame drug resistance due to β-tubulin mutation and P-glycoprotein overexpression. Compound 41J may serve as a useful new lead compound for anticancer therapy development.
A series of acetoxybenzoylthioureas derivatives with aryl and amino acid ester side chains were prepared by reaction of acetoxybenzoyl isothiocyanate, an acyloxy benzyl ester-based derivative of aspirin, with aryl amines or amino-functionalized amino acids with overall yields of 46–73%. The products that display a thiourea segment as a linker showed improved antibacterial properties in comparison with aspirin. The structures of the synthesized compounds were characterized by infra red spectroscopy, C nuclear magnetic resonance (NMR), and H NMR spectroscopy. The compounds were screened for their antibacterial activity by using gram-negative bacteria (E. coli ATCC 8739). [2-(phenylcarbamothioylcarbamoyl)phenyl] acetate showed the highest antibacterial activity against E. coli compared with other synthesized compounds.Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elementsto view the free supplemental file.
A series of urea and thiourea derivatives of s-triazine have been developed based on high yielding nucleophilic substitution of 2,4,6-trichloro-1,3,5-triazine by 4-hydroxy coumarin, cyclopropylamine and ammonia at suitable conditions. These were further treated with various substituted aryl isocyanate and aryl isothiocyanate. All the synthesized compounds were evaluated for their antibacterial activities against various Gram-positive and Gram-negative strains of bacteria. A few compounds showed good to superior in vitro antibacterial activity against S.aureus, B.subtilis, E.coli and P.aeruginosa respectively. The new synthesized compounds were characterized using IR, 1 H-NMR and elemental analysis.
Sixteen novel pyrazole acyl thiourea derivatives 6 were synthesized from monomethylhydrazine (phenylhydrazine) and ethyl acetoacetate. The key 5-chloro-3-methyl-1-substituted-1H-pyrazole-4-carbonyl chloride intermediates 4 were first generated in four steps through cyclization, formylation, oxidation and acylation. Thess were then reacted with ammonium thiocyanate in the presence of PEG-400 to afford 5-chloro-3-methyl-1-substituted-1H-pyrazole-4-carbonyl isothiocyanates 5. Subsequent reaction with fluorinated aromatic amines resulted in the formation of the title compounds. The synthesized compound were unequivocally characterized by IR, ¹H-NMR, ¹³C-NMR and elemental analysis and some of the synthesized compounds displayed good antifungal activities against Gibberella zeae, Fusarium oxysporum, Cytospora mandshurica and anti-TMV activity in preliminary antifungal activity tests.
A series of (E)-1-(4-alkyloxyphenyl)-3-(hydroxyphenyl)-prop-2-en-1-one have been successfully synthesised via Claisen-Schmidt condensation. The synthesised chalcone derivatives consisted of hydroxyl groups at either ortho, meta or para position and differed in the length of the alkyl groups, C (n) H(2) (n) (+1,) where n = 6, 10, 12 and 14. The structures of all compounds were defined by elemental analysis, IR, (1)H- and (13)C-NMR. The antimicrobial studies were carried out against wild-type Escherichia coli American Type Culture Collection 8739 to evaluate the effect of the hydroxyl and the alkyl groups of the synthesised chalcones. All the synthesised compounds have shown significant antimicrobial activities. The optimum inhibition was dependent on the position of the hydroxyl group as well as the length of the alkyl chains.
This article presents our research concerning the synthesis of new thiophene-thiourea derivatives (1-12) and their pharmacological properties. These novel thiophene-thiourea derivatives were synthesized and characterized by IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The crystal structure of N,N-diphenyl-N'-(thiophene-2-carbonyl)-thiourea was determined from single crystal X-ray diffraction data. It crystallizes in the monoclinic space group P21 with unit cell dimensions of a=11.7469(5) Å, b=6.0849(2) Å, c=12.5792(6) Å, β= 117.736(7) ° and V = 795.8(6) Å3. The mass fragmentation pattern has also been discussed. The synthesized compounds were screened for their in vitro antifungal activities against the standard strains: C. Albicans, C. Glabrata, and C. Tropicalis. The compounds N-thiophene-N',N'-bis(dimethyl-phosphinoylmethyl)thiourea, N-[(4-nitro-1H-imidazol-2-yl)carbamothioyl]thiophene-2-carboxamide and N,N-diethyl-N'-(thiophene-2-carbonyl)-thiourea showed significant antifungal activities against microbial species.
In this study, eight original N-phenyl-N′-[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl] thiourea derivatives were synthesized and tested for antituberculosis activity. Antituberculosis activities of the synthesized compounds were screened in vitro using BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv at 6.25 μg/ml. The highest inhibition observed with the synthesized compounds is 67% for N-phenyl-N′-[4-(5-cyclohexylamino-1,3,4-thiadiazole-2-yl)phenyl] thiourea. © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
Many currently available antifungal and antibacterial agents have undesirable toxic effects, and a wide spread use of these drugs has lead to rapid development of drug resistant strains which are the leading cause for treatment failure in both clinical and agricultural applications. The present article provides a synopsis of recent progress in investigations of new classes of antifungal compounds: disubstituted aliphatic and aromatic thioureas, triazole and thiazine compounds which act as ligands for transition metals. Antifungal effects of these compounds and selected metallic complexes versus representative plant pathogenic fungi are reviewed.
Three different acyl thiourea derivatives of chitosan (CS) were synthesized and their structures were characterized by FT-IR spectroscopy and elemental analysis. The antimicrobial behaviors of CS and its derivatives against four species of bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Sarcina) and four crop-threatening pathogenic fungi (Alternaria solani, Fusarium oxysporum f. sp. vasinfectum, Colletotrichum gloeosporioides (Penz.) Saec, and Phyllisticta zingiberi) were investigated. The results indicated that the antimicrobial activities of the acyl thiourea derivatives are much better than that of the parent CS. The minimum value of MIC and MBC of the derivatives against E. coli was 15.62 and 62.49 microg/mL, respectively. All of the acyl thiourea derivatives had a significant inhibitory effect on the fungi in concentrations of 50-500 microg/mL; the maximum inhibitory index was 66.67%. The antifungal activities of the chloracetyl thiourea derivatives of CS are noticeably higher than the acetyl and benzoyl thiourea derivatives. The degree of grafting of the acyl thiourea group in the derivatives was related to antifungal activity; higher substitution resulted in stronger antifungal activity.
Bacteriostatic activities of N-substituted tris-thioureas bearing amino acid and aniline substituentsAll authors
Wan Sharifatun Handayani Wan Zullkiplee, Maya Asyikin Mohd Ariff, Hasnain Hussain, Wan M. Khairul & Zainab Ngaini
https://doi.org/10.1080/10426507.2016.1192627
Published online
25 July 2016
In the present study, 18 new compounds were synthesized, 9 of which were urea (9a-e, 10a-d) while the others were thiourea (11a-e, 12a-d) derivatives. These derivatives were prepared by the reaction of 6-amino-5-nonsubstituted/chloro-3-methyl-2(3H)-benzoxazolones used as key intermediates with the appropriate isocyanates and isothiocyanates. The chemical structures of new compounds were confirmed by H-1-NMR, mass, and elemental analysis. The synthesized compounds were screened for their antibacterial and antifungal activities against some pathogenic strains. Compounds 9a, 9b, 9e, 10a, and 10c, urea derivatives, and compounds 12a and 12d, thiourea derivatives, exhibited a relatively good inhibitory profile against E. coli, with a MIC value of 32 mu g/mL when compared with the other target compounds.
This paper reports on the synthesis of a series of amide derivatives from acrylopimaric acid (APA). The derivatives contained aromatic groups and were characterized by IR, 1HNMR, MS, and elemental analysis. The antibacterial activity of the derivatives against Gram-negative bacteria and Gram-positive bacteria were also investigated. When compared with the other derivatives, compounds 3a and 3f showed much higher activity against Escherichia coli (Gram-negative bacteria) with inhibition zones of 5 mm and 5.5 mm, respectively. Structure-activity relationship analysis revealed that ortho-substituted phenyl derivatives and meta-substituted phenyl derivatives exhibited higher activity than the para-substituted derivatives. Meanwhile, the halogen-substituted compounds did not show visible antibacterial activity compared with other compounds, which may have been caused by the lower electron density of the halogensubstituted phenyl rings.
In an attempt to find the biorational pesticides, a series of novel acylthiourea derivatives of cantharidin were designed, synthesized and preliminarily evaluated for their bioactivities against Tetranychus cinnabarinus and Brevicoryne brassicae. All the new compounds showed significant acaricidal activities against T. cinnabarinus with LC50 values ranging from 0.695 to 2.934 mmol/L. In particular, compounds 6i and 6g exhibited the greatest acaricidal activity against T. cinnabarinus in all derivatives we prepared. Moreover, all of these compounds displayed better acaricidal activities against T. cinnabarinus than insecticidal activities against B. brassicae. Based on the observed bioactivities, the structure-activity relationship (SAR) of these analogs was also discussed. The present work indicated that some cantharidin derivatives can be used as potential lead compounds for developing novel insecticides and acaricides.
The structure of N-2-fluorobenzoyl-N′-4-methoxyphenylthiourea (C15H13N2OFS, Mr=288.34) (FBMPT) derived from X-ray diffraction of a single crystal has been presented. The crystals of FBMPT are in the triclinic, space group: P1¯, a=8.413(5), b=9.532(5), c=9.927(6)Å, α=66.24(2), β=85.40(2), γ=72.27(2)°, V=693.2(7)Å3, Z=2. FTIR, NMR, UV absorbance and fluorescence spectroscopy methods have been employed to study the structure of FBMPT. All of the experimental results have proven that there are intra-molecular hydrogen bond interactions. Theoretical calculations of bond parameters, harmonic vibration frequencies, nuclear magnetic resonance and vertical excitation energies are in good agreement with experimental results. The absorbance and fluorescence spectra of FBMPT have been investigated in several organic solvents. Both absorbance and fluorescence spectra exhibit a slight solvent dependence. Dual fluorescence has also been observed in polar solvent, consistent with excited state proton transfer or twisted intra-molecular charge transfer (TICT) emission. The solvent ethanol quenches fluorescence band, which is associated with intermolecular hydrogen bond interaction between FBMPT and ethanol.
Anion-selective solvent polymeric membrane electrodes based on hydrogen bond-forming, neutral ionophores with two urea or thiourea groups bridged by a m-xylylene unit are described. The use of α,α′-bis(N′-phenylthioureylene)-m-xylene results in ion-selective electrodes with a remarkable selectivity for sulfate. An electrode with this compound as ionophore, poly(vinyl chloride) (PVC) as polymeric matrix, 2-nitrophenyl octyl ether (o-NPOE) as plasticizer and cationic sites (50mol% relative to the ionophore) responds to sulfate in a Nernstian manner in the concentration range from 10−6 to 10−2M. In comparison to conventional anion-exchanger electrodes, the interference of SCN−, NO−3, Br−, and Cl− is significantly reduced, as shown by the selectivity coefficients determined with the matched potential method in the sulfate concentration range 1.0–10mM (logKpotsulfate,B: SCN−, +2.9; NO−3, +1.6; Br−, +1.1; Cl−, −0.1). The present electrode has a higher selectivity for sulfate than any previously reported ionophore-based ion-selective electrode. No significant changes in the detection limit and response slope were observed when the electrode was stored for 28 days in an aqueous buffer solution.
A new crystal of N-2-flurobenzoyl-N′-4-tolylthiourea (FBTT) was obtained from slow evaporation of solvent benzene and the crystal structure of FBTT was determined by X-ray diffraction method. The packing mode of FBTT molecules was affected by crystallization conditions. The new crystal of FBTT crystallizes in the monoclinic with the space group C2/c, and it was stabilized by two pairs of intermolecular interactions. The first pair of intermolecular hydrogen bonds are N(1#)–H(1#)⋯S(1) and N(1)–H(1)⋯S(1#1), the second pair of intermolecular hydrogen bonds, are C(11#)–H(11#)⋯O(1) and C(11)–H(11)⋯O(1#). There also have other unpaired intermolecular hydrogen bonds C(15)–H(15C)⋯O(1#1) and C(15#2)–H(15#2)⋯O(1). Double fluorescence bands are observed in both non-polar and polar solvents. The fluorescence emission at 350–360nm originates from the transitions of π∗→π state and is assigned to S2 fluorescence for the nature of LE state. The long wavelength fluorescence emission with large Stokes shift is the characteristic of ESIPT state. All experimental results are supported by MP2 and CASSCF calculations.
A series of copper(I) complexes of N,N'-disubstituted thioureas, [C(6)H(5)CONHCSNHR]Cu(I)Cl where R=C(6)H(5) (1a), 2-ClC(6)H(4) (2a), 3-ClC(6)H(4) (3a), 4-ClC(6)H(4) (4a), 2,3-Cl(2)C(6)H(3) (5a), 2,4-Cl(2)C(6)H(3) (6a), 2,5-Cl(2)C(6)H(3) (7a), 2,6-Cl(2)C(6)H(3) (8a), 3,4-Cl(2)C(6)H(3) (9a) and 3,5-Cl(2)C(6)H(3) (10a) have been synthesized. These complexes (1a-10a) have been characterized by elemental analyses, IR, (1)H and (13)C NMR spectroscopy, cyclic voltammetry and single crystal XRD for 1a and 8a, and for ligand 7. The X-ray crystal structures reveal that the complexes 1a and 8a are mononuclear in the solid state in which the copper atoms adopt a distorted tetrahedral geometry. In both the cases, the neutral N,N'-disubstituted thiourea ligands have been coordinated to the Cu(I) through the sulphur atom in a terminal mode. The complexes have been screened for their in vitro cytotoxic activity in human cell lines carcinomas A498 (Renal), EVSA-T (Breast), H226 (Lung), IGROV (Ovarian), M19 (Melanoma-Skin), MCF-7 (Breast) and WIDR (Colon). They show a moderate cytotoxicity against these seven human cancer cell lines comparable to that of the less active standard chemotherapeutic drugs used for comparison. They were also screened for their anti-bacterial activity and were found less active than the standard drug Imipenem.
Cyanopindolol (CYP) is a potent antagonist at the β 3 ‐adrenoceptor in rat ileum. Several analogues of CYP and pindolol were synthesized that also produced antagonist effects at the β 3 ‐adrenoceptor. However, at high concentrations, these compounds appear to act as ‘partial agonists’. This study was conducted to determine the structural requirements of CYP analogues necessary for antagonist activity and to examine the possibility that the agonist effects of CYP and its analogues may occur through a mechanism independent of β‐adrenoceptor activation.
Analogues of CYP and pindolol were tested for antagonist activity in rat ileum in which the β 1 ‐ and β 2 ‐adrenoceptors were blocked. Fourteen compounds were tested against (−)−isoprenaline, and four of the more potent analogues were then tested against BRL 37344. The two most potent antagonists were CYP and iodocyanopindolol. The p K b values (negative log of equilibrium dissociation constant) obtained against (−)−isoprenaline were significantly higher than those obtained against BRL 37344, but the cause of this difference is not known.
Several structural requirements were determined for antagonist activity. Modification at the carbon atom alpha to the secondary amine caused the antagonist potency to fall as the level of saturation was reduced. Thus, a quaternary carbon group, such as t ‐butyl, produced the most potent antagonist. Substitution with a large moiety such as a cyclohexyl or benzyl group reduced antagonist activity, probably due to steric hindrance. Inclusion of an electron‐withdrawing group, such as a cyano or ethylester moiety, alpha to the indole nitrogen, also increased the potency. Iodination of CYP and ethylesterpindolol at the 3‐position of the indole ring did not increase antagonist potency. In contrast, iodination of the almost inactive analogues produced a significant increase in potency, suggesting that a beneficial electronic effect on the indole ring imparted by the iodo moiety may be able to offset partially the negative effects caused by either the steric hindrance, of lack of a quaternary carbon alpha to the secondary amine.
Values for pseudo‐pD 2 were also determined by conducting cumulative concentration‐response studies up to the limit of drug solubility. For nine of the compounds tested, the p K b was significantly higher than the pseudo‐pD 2 value.
The discrepancy between the p K b and pseudo‐p D 2 values was examined further. The agonist effects of iodocyanopindolol, the agonist with the highest potency, were not antagonized by CYP which was the most potent antagonist of (−)−isoprenaline and BRL 37344 at the β 3 ‐adrenoceptor. This suggests that the agonist effects of iodoCYP were produced through a different mechanism: either via another receptor, another isoform of the rat β 3 ‐adrenoceptor, or through a non‐receptor‐mediated effect. Pseudo‐pD 2 values did not correlate with log P values for these compounds, indicating that their relaxant effects were not simply a function of their lipid solubility.
This study has highlighted several structural requirements for antagonist binding potency at the rat ileum β 3 ‐adrenoceptor and should assist in the development of potent selective antagonists for this receptor.
The 1H and 13C NMR spectra of four series of 1-aroylthiourea derivatives in DMSO-d6 are reported. The NH signals for 3-alkyl substituted aroylthioureas are identified by their multiplicity and by homonuclear irradiation experiments. Correlation analyzes are made for NH, CO and CS signals in order to determine the best way to modulate the nucleophilic character of the CS group, as thioureas are well-known ionophore groups. Almost all 1,3-substituted thioureas (Series 2-4) show the reported chelated structure with the exception of those with CF3, CN and NO2 groups. Pyridine group promote a different equilibrium in solution. The fragment -CO-NH- transmits poorly the electronic effects of substituents in the aroylgroup.
Although biocides have been used for a century, the number of products containing biocides has recently increased dramatically with public awareness of hygiene issues. The antimicrobial efficacy of biocides is now well documented; however, there is still a lack of understanding of their antimicrobial mechanisms of action. There is a wide range of biocides showing different levels of antimicrobial activity. It is generally accepted that, in contrast to chemotherapeutic agents, biocides have multiple target sites within the microbial cell and the overall damage to these target sites results in the bactericidal effect. Information about the antimicrobial efficacy of a biocide (i.e. the eta-value) might give some useful indications about the overall mode of action of a biocide. Bacteriostatic effects, usually achieved by a lower concentration of a biocide, might correspond to a reversible activity on the cytoplasmic membrane and/or the impairment of enzymatic activity. The bacteriostatic mechanism(s) of action of a biocide is less documented and a primary (unique?) target site within the cell might be involved. Understanding the mechanism(s) of action of a biocide has become an important issue with the emergence of bacterial resistance to biocides and the suggestion that biocide and antibiotic resistance in bacteria might be linked. There is still a lack of understanding of the mode of action of biocides, especially when used at low concentrations (i.e. minimal inhibitory concentration (MIC) or sublethal). Although this information might not be required for highly reactive biocides (e.g. alkylating and oxidizing agents) and biocides used at high concentrations, the use of biocides as preservatives or in products at sublethal concentrations, in which a bacteriostatic rather than a bactericidal activity is achieved, is driving the need to better understand microbial target sites. Understanding the mechanisms of action of biocides serves several purposes: (i) it will help to design antimicrobial formulations with an improved antimicrobial efficacy and (ii) it will ensure the prevention of the emergence of microbial resistance.
Raman and IR spectra of two series of 1-furoylthiourea derivatives (19 compounds) were recorded and compared in order to identify the vibrations, which involve contributions from motions within the thioureido (NCSN) core. This procedure allowed an unequivocal identification of the nu(CS) vibration in these spectra. In 3-monosubstituted furoylthioureas (Series 2) the carbonyl group and the proton on N(3) are engaged in a strong hydrogen bond interaction. This leads to an "S"-shaped conformation of the CO and CS groups where these donor sites reach a maximum separation. In this conformation, the nu(CO) vibration is not influenced by the substituent. In the absence of that hydrogen bridge, in 3,3-disubstituted thiourea derivatives (Series 1), the CO and CS groups adopt an "U"-shaped conformation. In this conformation, the nu(CO) vibration shows a pronounced substituent dependence. These thiourea derivatives have been tested as ionophores for heavy-metal ion selective electrodes and their behavior in that sense correlates with the observed Raman and IR absorptions. The best performance in that application corresponds to compounds of Series 2, which showed the highest frequency values of the nu(CS) vibration. This fact was related to an appropriated nucleophilic character of the sulphur atom. From these data, Raman and IR spectra of these thiourea derivatives could be used as a predictor on their expected behavior in analytical applications as ionophores.
Compound solubility in buffers and dimethyl sulfoxide (DMSO) has emerged as an important issue. Many discovery compounds have low solubility but are potentially valuable as leads. Unfortunately, low solubility affects bioassays by causing underestimated activity, reduced HTS-hit rates, variable data, inaccurate SAR, discrepancies between enzyme and cell assays and inaccurate in vitro ADME-Tox testing. Strategies for optimizing bioassays include: considering solubility in HTS-library design; early screening for solubility; improving storage and handling of DMSO stocks; optimizing dilution protocols; and ensuring that low-solubility compounds are fully solubilized in bioassays. These approaches allow for adequate assessments of valuable pharmacophores for which solubility can be chemically optimized at a later date.
As a continuation of our previous efforts on N-alkyl/aryl-N'-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1-19 and N-alkyl/aryl-N'-[4-(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thioureas 20-22, a series of novel 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones 23-26 and several related thioureas, N-alkyl/aryl-N'-{4-[(4-alkyl/aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy]phenyl}thioureas 27-42 were synthesized for evaluation of their antiviral potency. Structures of the synthesized compounds were confirmed by the use of (1)H NMR, (13)C NMR and HR-MS data. All compounds 1-42 were evaluated in vitro against HIV-1 (IIIB) and HIV-2 (ROD) strains in MT-4 cells, as well as other selected viruses such as HSV-1, HSV-2, Coxsackie virus B4, Sindbis virus and Varicella-zoster virus using HeLa, Vero, HEL and E6SM cell cultures, and anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv. Compounds 4 and 5 showed weak activity against HSV-1, HSV-2 and TK(-) HSV, whereas eight compounds showed marginal activity against Coxsackie virus B4. The most active derivative in this series was compound 38 which showed moderate protection against Coxsackie virus B4 with an MIC value of 16 microg/ml and a selectivity index of 5. This compound was also active against thymidine kinase positive Varicella-zoster virus (TK(+) VZV, OKA strain) with an EC(50) value of 9.9 microg/ml. Compound 38 was the most active compound with 79% inhibition against M. tuberculosis H37Rv.