Synthesis, Characterization, and Molecular Docking Study of Some Novel Imidazole Derivatives as Potential Antifungal Agents

Abstract

The azole pharmacophore is still regarded as a viable lead structure for the synthesis of more effective antifungal agents. In this study, two novel series of imidazole derivatives containing dithiocarbamate (5a–5g) and (benz)azolethiol (6a–6n) side chains that are structurally related to the famous antifungal azole pharmacophore were synthesized, and the structures of them were characterized by spectral (IR, 1H NMR, 13C NMR, and MS spectra) analyses. The synthesized compounds were screened in vitro antifungal activity against pathogenic strains fungi. Theoretical ADME (absorption, distribution, metabolism, and excretion) predictions were calculated for final compounds. A molecular docking study of the most active compound with target “lanosterol 14α‐demethylase” (CYP51) was performed to unravel the mode of antifungal action. Compound 5e, which features imidazole and 4‐methoxybenzyl piperazine scaffolds, showed the most promising antifungal activity with an MIC50 value of 0.78 μg/mL against C. krusei. Effect of the compound 5e against ergosterol biosynthesis was observed by LC–MS–MS method, which is based on quantification of ergosterol level in C. krusei.

SAR Analysis of Heterocyclic Compounds with Monocyclic and Bicyclic Structures as Antifungal Agents

“…Imidazole as an important pharmacophore has a variety of activities, including anticancer, [64] anti-infective, [65] and antidengue virus activity. [66] Two series of imidazole derivatives (20 a-g and 21 a-n) [67] containing dithiocarbamate and (benz)azolethiol side chains were synthesized and evaluated for their antifungal activity against C. albicans, C. krusei, C. parapsilosis, and C. glabrata (Figure 17). Compounds 20 a-g (MIC 50 = 0.78-12.5 μg/mL) displayed better antifungal activity than compounds 21 a-n (MIC 50 = 25-200 μg/mL).…”

Synthesis and antimicrobial activity of 2‐(4‐(benzo[d]thiazol‐5‐ylsulfonyl)piperazine‐1‐yl)‐N‐substituted acetamide derivatives

“…It shows that the synthesized compound exhibited a good % ABS (% absorption). Absorption (% ABS) was calculated by formula: % ABS = 109 − (0.345 × TPSA) [ 25,26 ] ranging from 72.29 to 86.4%. However, the molecule likely to be developed as an orally active drug candidate should not be more than or equal to these four criteria [ 27 ] : miLog P (octanol‐water partition coefficient) ≤ 5, molecular weight ≤ 500, number of hydrogen bond acceptors ≤10 and number of hydrogen bond donors ≤5, and synthesized compounds were covered in all five Lipinski's rule, and there was no any violation of Lipinski's rule, values were calculated by using Molinspiration online property [ 28 ] calculation, larger the value of drug likeness model score, [ 29 ] the molecule having higher score and high probability, then it will be an active molecule.…”

Synthesis and antimicrobial activity evaluation of pyrazole derivatives containing the imidazo[2,1‐b][1,3,4]thiadiazole moiety

“…The amide bond is an important component of bioactive molecules and has attached much attention because of its unique structure and properties. A large number of pieces of literature proved that amide bonds play a prominent role in the antibacterial and antifungal aspects, such as compounds 6 ( C. albicans , MIC = 0.125 μg/mL), [ 50 ] 7 ( Candida krusei , [ 51 ] MIC 50 = 0.78 μg/mL), and 8 ( C. albicans , MIC = 0.5 μg/mL). [ 52 ]…”

“…[49] The amide bond is an important component of bioactive molecules and has attached much attention because of its unique structure and properties. A large number of pieces of literature proved that amide bonds play a prominent role in the antibacterial and antifungal aspects, such as compounds 6 (C. albicans, MIC = 0.125 μg/mL), [50] 7 (Candida krusei, [51] MIC 50 = 0.78 μg/mL), and 8 (C. albicans, MIC = 0.5 μg/mL). [52] Based on the literature review and our findings (compounds 1 and 4, Figure 2), we tried to substitute methylene amino-linkage with methylene amido-linkage and designed compounds 17a-m and 19a-g. To compare the influence of the methylene amido-linkage in 17a-m and 19a-g on antifungal activity, their regio isomers 18a-m and 20a-g with a different attachment of the same methylene amido-linkage on the other nitrogen atom of the pyrazole ring were also evaluated.…”