Breast cancer is the most frequent female cancer and second cause of cancer-related deaths among women around the world. Two thirds of breast cancer patients have hormone-dependent tumors, which is very likely be treated with hormonal therapy. Aromatase is involved in the biosynthesis of estrogen thus a critical target for breast cancer. In this study, in order to identify new aromatase enzyme inhibitors, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by ¹H NMR, ¹³C NMR, and MS spectra analyses. In the in vitro anticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5a exhibited the most potent activity with IC₅₀ values of 5.165 ± 0.211 μM and 5.995 ± 0.264 μM against MCF-7 and HepG2 cell lines. Compound 5a was included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5c was also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 cell line. In vitro, enzymatic inhibition assays of aromatase enzyme were performed for compound 5a acting on the MCF-7 cell line. For compound 5a, in silico molecular docking and dynamics simulations against aromatase enzyme was performed to determine possible protein-ligand interactions and stability. DFT study was performed to evaluate the quantum mechanical and electronic properties of compound 5a. Finally, the theoretical ADME properties of the potential aromatase inhibitor compound 5a were analyzed by calculations. Communicated by Ramaswamy H. Sarma

Discovery of novel anticandidal agents with clarified mechanisms of action, could be a rationalist approach against diverse pathogenic fungal strains due to the rise of resistance to existing drugs. In support to this hypothesis, in this paper, a series of benzimidazole-oxadiazole compounds were synthesized and subjected to antifungal activity evaluation. In vitro activity assays indicated that some of the compounds exhibited moderate to potent antifungal activities against tested Candida species when compared positive control amphotericin B and ketoconazole. The most active compounds 4h and 4p were evaluated in terms of inhibitory activity upon ergosterol biosynthesis by an LC-MS-MS method and it was determined that they inhibited ergosterol synthesis concentration dependently. Docking studies examining interactions between most active compounds and lanosterol 14-α-demethylase also supported the in vitro results.

Alzheimer’s disease (AD), one of the main causes of aged dementia, is a progressive and degenerative neurological disorder characterized by loss of cognition and memory. Although the symptomatic treatment of AD, particularly acetylcholinesterase inhibitors (AChEIs) based on the ‘cholinergic hypothesis’, has been successful in clinic, at present there is no cure for this disease. In this study, we designed compounds carrying benzimidazole and triazole rings on the same chemical skeleton so as to investigate their potential acetylcholinesterase and butyrylcholinesterase activity. Furthermore, molecular modeling study was performed to determine the binding mode of the best inhibitor to the AChE. Among them, compounds 3d and 3h, which featured 3,4-dihydroxy substitution at the phenyl ring and 5(6)-chloro substitution at the benzimidazole ring were found to be potent inhibitors of AChE. The inhibition kinetics of the two most active derivatives 3d and 3h were further studied. The kinetic displayed increasing slope and increasing intercept, which is consistent with a mixed inhibition. The IC₅₀ and K_i values of 3d are 31.9 ± 0.1 nM and 26.2 nM, respectively. Compound 3h exhibited IC₅₀ of 29.5 ± 1.2 nM and K_i of 24.8 nM. The above data compared favorably with data for donepezil (21.8 ± 0.9 nM) the reference compound in our study.

Invasive fungal infections (IFIs) are increasing as major infectious diseases around the world, and the limited efficacy of existing medications has resulted in substantial morbidity and death in patients due to the lack of effective antifungal agents and serious drug resistance. In this study, a series of benzimidazole-1,2,4-triazole derivatives (6a-6l) were synthesized and characterized by ¹H NMR, ¹³C NMR, and HR-MS spectral analysis. All the target compounds were screened for their in vitro antifungal activity against four fungal strains, namely, C. albicans, C. glabrata, C. krusei, and C. parapsilopsis. The synthesized compounds exhibited significant antifungal potential, especially against C. glabrata. Three compounds (6b, 6i, and 6j) showed higher antifungal activity with their MIC values (0.97 μg/mL) compared with voriconazole and fluconazole. Molecular docking provided a possible binding mode of compounds 6b, 6i, and 6j in the 14α-demethylase active site. Our studies suggested that the benzimidazole-1,2,4-triazole derivatives can be used as a new fungicidal lead targeting 14α-demethylase for further structural optimization. In addition, their effects on the L929 cell line were also investigated to evaluate the cytotoxic effects of the compounds. SEM analyses were performed to examine the effects of compounds 6a, 6i, and 6j on C. glabrata cells under in vivo experimental conditions.

Owing to the growing need for antifungal agents, we synthesized a new series 2-((5-(4-(5-substituted-1H-benzimidazol-2-yl)phenyl)-4-substituted-4H-1,2,4-triazol-3-yl)thio)-1-(substitutedphenyl)ethan-1-one derivatives, which were tested against Candida species. The synthesized compounds were characterized and elucidated by FT-IR, ¹H-NMR, ¹³C-NMR and HR-MS spectroscopies. The synthesized compounds were screened in vitro anticandidal activity against Candida species by broth microdiluation methods. In vitro cytotoxic effects of the final compounds were determined by MTT assay. Microbiological studies revealed that compounds 5m, 5o, 5r, 5t, 5y, 5ab, and 5ad possess a good antifungal profile. Compounds 5w was the most active derivative and showed comparable antifungal activity to those of reference drugs ketoconazole and fluconazole. Cytotoxicity evaluation of compounds 5m, 5o, 5r, 5w, 5y, 5ab and 5ad showed that compounds 5w and 5ad were the least cytotoxic agents. Effects of these two compounds against ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of ergosterol level in C. albicans. Compounds 5w and 5d inhibited ergosterol biosynthesis concentration dependently. A fluorescence microscopy study was performed to visualize effect of compound 5w against C. albicans at cellular level. It was determined that compound 5w has a membrane damaging effect, which may be related with inhibition of biosynthesis of ergosterol.

In this study, some benzimidazole-oxadiazole derivatives were synthesised and tested for their in vitro anticancer activities on five cancer cell lines, including HeLa, MCF7, A549, HepG2 and C6. Their structures were elucidated by IR, ¹H-NMR, ¹³C-NMR, 2 D-NMR and HRMS spectroscopic methods. Among all screened compounds; 5a, 5b, 5d, 5e, 5k, 5l, 5n and 5o exhibited potent selective cytotoxic activities against various tested cancer cell lines. Especially, compounds 5l and 5n exhibited the most antiproliferative activity than Hoechst 33342 and doxorubicin against HeLa cell line, with IC₅₀ of 0.224 ± 0.011 µM and 0.205 ± 0.010 µM, respectively. Furthermore, these potent lead cytotoxic agents were evaluated in terms of their inhibition potency against Topoisomerase I and it was determined that selected compounds inhibited the Topoisomerase I. Docking studies were performed and probable interactions in the DNA-Topo I enzyme complex was determined.