Investigating the potential of thiazolyl carbohydrazides derivatives as anti-Candida albicans agents: An intuition from molecular modelling, pharmacokinetic evaluation, and molecular docking analysis

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With increasing incidences of antifungal resistance, biofilm formation, and its predilection for vulnerable populations, Candida albicans have been reported to cause a wide range of infections, from superficial skin irritations to life-threatening systemic diseases. Therefore, understanding and addressing the infections associated with Candida albicans has become an urgent imperative in the realm of global healthcare. As a result, this study employed DFT calculations at the DFT/ωB97XD/6–311++G (2d, 2p) level to optimize the geometric properties of two compounds: (Z)-N'-(4-(4-bromophenyl)-3-(4-fluorophenyl)thiazol-2(3H)-ylidene)-2-(thiophen-2-yl)thiazole-5-carbohydrazide (4-FBC) and (Z)-N'-(4-(4-bromophenyl)-3-(2-fluorophenyl)thiazol-2(3H)-ylidene)-2-(thiophen-2-yl)thiazole-5-carbohydrazide(2-FBC). Significantly, employing spectral analysis techniques such as FT-IR and NMR, the compounds were characterized and identified. Additionally, the compounds (4-FBC and 2-FBC) exhibited comparable reactivity and stability, with more promising reactivity potential in water than in the gas phase. The analysis of Molecular Electrostatic Potential (MESP) and the density of States (DOS) shed light on the electrical characteristics and intermolecular interactions occurring during chemical processes. Furthermore, the natural bond orbital (NBO) analysis provided insights into second-order perturbation energies and the presence of intense intermolecular interactions, as evident in the order of their increasing concentrated intermolecular interaction as thus: 4-FBC_gas (668.34 kcal/mol) > 4-FBC _water (563.98 kcal/mol) and 2-FBC _gas (978.64 Kcal/mol) > 2-FBC_water (696.46 Kcal/mol). The pharmacokinetics study indicated favorable intestinal absorption, low distribution, and cytotoxicity profiles, although 4-FBC required further optimization due to slower clearance, potential enzyme interactions, and immunotoxicity concerns. In addition, molecular docking analysis revealed robust binding affinities and the presence of significant conventional hydrogen bonds. The optimal binding positions (best pose) for the 4-FBC and 2-FBC complexes were determined to have binding affinities of -8.7, -8.4, -8.3 kcal/mol, and -8.6, -8.5, -8.3 kcal/mol, respectively, when interacting with 4YDE, 3DRA, and 1EAG. These findings provide strong evidence supporting the potential pharmacological suitability of 4-FBC and 2-FBC compounds as effective choices for inhibiting and treating Candida albicans.