Urea-thiazole/benzothiazole hybrids with a triazole linker: synthesis, antimicrobial potential, pharmacokinetic profile and in silico mechanistic studies
“…To evaluate the stability of the protein–ligand complexes formed by the potential antifungal compounds 5c and 5f with Candida sterol 14-α demethylase, 100 ns duration MD simulations were performed. , Also, the complex of the standard compound voriconazole with CYP51 was simulated for MD validation and compared with the complexes with synthesized compounds 5c and 5f (Figure S2). Charmm36m force fields for topology files of CYP51 and compounds 5c and 5f were chosen to be compatible with protein–ligand complexes containing the heme structure.…”
In this study, some new compounds, which are 2aminothiadiazole derivatives linked by a phenyl bridge to the 2position of the benzimidazole ring, were designed and synthesized as antimicrobial agents. The structures of the compounds were elucidated by 1 H and 13 C NMR spectroscopy, high-resolution mass spectrometry, and elemental analysis. The antifungal activities of the synthesized compounds were tested on Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compound 5f is more active against C. albicans and C. glabrata than standard fluconazole and varicanazole. Compounds were also evaluated for their counteracting activity against Gram-positive Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas aeruginosa and Gram-negative Enterococcus faecalis, Bacillus subtilis, and Staphylococcus aureus. Compounds 5c and 5h had minimum inhibitory concentrations against E. faecalis close to that of the standard azithromycin. Molecular docking studies were performed against Candida species' 14-α demethylase enzyme. 5f was the most active compound against Candida species, which gave the highest docking interaction energy. The stabilities of compounds 5c and 5f with CYP51 were tested using 100 ns molecular dynamics simulations. According to the theoretical ADME calculations, the profiles of the compounds are suitable in terms of limiting rules. HOMO−LUMO analysis showed that 5h is chemically more reactive (represented with the lower ΔE = 3.432 eV) than the other molecules, which is compatible with the highest antibacterial activity result.
“…To evaluate the stability of the protein–ligand complexes formed by the potential antifungal compounds 5c and 5f with Candida sterol 14-α demethylase, 100 ns duration MD simulations were performed. , Also, the complex of the standard compound voriconazole with CYP51 was simulated for MD validation and compared with the complexes with synthesized compounds 5c and 5f (Figure S2). Charmm36m force fields for topology files of CYP51 and compounds 5c and 5f were chosen to be compatible with protein–ligand complexes containing the heme structure.…”
In this study, some new compounds, which are 2aminothiadiazole derivatives linked by a phenyl bridge to the 2position of the benzimidazole ring, were designed and synthesized as antimicrobial agents. The structures of the compounds were elucidated by 1 H and 13 C NMR spectroscopy, high-resolution mass spectrometry, and elemental analysis. The antifungal activities of the synthesized compounds were tested on Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compound 5f is more active against C. albicans and C. glabrata than standard fluconazole and varicanazole. Compounds were also evaluated for their counteracting activity against Gram-positive Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas aeruginosa and Gram-negative Enterococcus faecalis, Bacillus subtilis, and Staphylococcus aureus. Compounds 5c and 5h had minimum inhibitory concentrations against E. faecalis close to that of the standard azithromycin. Molecular docking studies were performed against Candida species' 14-α demethylase enzyme. 5f was the most active compound against Candida species, which gave the highest docking interaction energy. The stabilities of compounds 5c and 5f with CYP51 were tested using 100 ns molecular dynamics simulations. According to the theoretical ADME calculations, the profiles of the compounds are suitable in terms of limiting rules. HOMO−LUMO analysis showed that 5h is chemically more reactive (represented with the lower ΔE = 3.432 eV) than the other molecules, which is compatible with the highest antibacterial activity result.
“…Based on the structures found, it is possible to conclude that there were two types of scaffolds used: one in which the thiazole and 1,2,3-triazole rings are linked directly but with different linking positions ( a – b ) [ 52 , 53 ], and the other one in which the rings are clubbed through various linkers and variable linking positions ( c – e ) [ 54 , 55 , 56 , 57 ] ( Figure 30 ).…”
Section: Structure–activity Relationships In Antimicrobial Thiazole-b...mentioning
Antimicrobial resistance is an increasing problem for global public health. One of the strategies to combat this issue is the synthesis of novel antimicrobials through rational drug design based on extensive structure–activity relationship studies. The thiazole nucleus is a prominent feature in the structure of many authorized antimicrobials, being clubbed with different heterocycles. The purpose of this review is to study the structure–activity relationship in antimicrobial thiazoles clubbed with various heterocycles, as reported in the literature between 2017 and 2023, in order to offer an overview of the last years in terms of antimicrobial research and provide a helpful instrument for future research in the field.
“…Compound 101 showed maximum inhibition (MIC = 0.0071 µmol/ml) and also better than standard drug ciprofloxacin (MIC = 0.0094 µmol/mL) against Pseudomonas fluorescence . SAR study depicted that the existence of the p- OCH 3 group at the phenyl urea moiety improved the antibacterial activity [ 64 ]. Scheme 21 Preparation of urea benzothiazole-triazole derivative ( 101 ) …”
Section: Other Miscellaneous Benzothiazole Derivatives As Antibacteri...mentioning
Antimicrobial resistance (AMR) is a worldwide concern among infectious diseases due to increased mortality, morbidity and treatment cost. According to WHO 2019 report, among the 32 antibiotics in the clinical trials, only six were classified as innovative and containing novel moiety. The remaining antibiotics from this list contain previously known moiety (WHO AMR 2019). Therefore, the development of novel antibiotics to control resistance problems is crucial. Benzothiazole derivatives are of great interest due to their wide range of biological activities and medicinal applications. Reported data indicated that benzothiazole derivatives displayed antibacterial activity by inhibiting the dihydroorotase, DNA gyrase, uridine diphosphate-n-acetyl enol pyruvyl glucosamine reductase (MurB), peptide deformylase, aldose reductase, casdihydrofolate reductase, enoyl acyl carrier protein reductase, dialkylglycine decarboxylase, dehydrosqualene synthase, dihydropteroate synthase and tyrosine kinase. The present review analyzed the synthesis, structure-activity relationship (SAR) and mechanism of action studies of benzothiazole derivatives as antibacterial agents reported by various research groups in the last five years (2018–2022). Different patents on the antimicrobial activity of benzothiazole derivatives have also been summarized. The finding of the present review will be beneficial for the researchers in the development of novel antibacterial molecules based on benzothiazole moiety.
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