Synthesis, characterization, biochemical, and molecular modeling studies of carvacrol-based new thiosemicarbazide and 1,3,4-thiadiazole derivatives.

A series of carvacrol-based thiosemicarbazide (3a-e) and 1,3,4-thiadiazole-2-amine (4a-e) were designed and synthesized for the first time. The structures were characterized by nuclear magnetic resonance and high resolution mass spectroscopy techniques. All compounds were examined for some metabolic enzyme activities. Results indicated that all the synthetic molecules exhibited powerful inhibitory actions against human carbonic anhydrase I and II (hCAI and II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes compared to the standard molecules. Ki values of five novel thiosemicarbazides and five new 1,3,4-thiadiazole-2-amine derivatives (3a-e and 4a-e) for hCA I, hCA II, AChE, and BChE enzymes were obtained in the ranges 0.73-21.60, 0.42-15.08 µM, 3.48-81.48, 92.61-211.40 nM, respectively. After the experimental undertaking, an extensive molecular docking analysis was conducted to scrutinize the intricate details of interactions between the ligand and the enzyme in question. The principal focus of this investigation was to appraise the potency and efficacy of the most active compound. In this context, the calculated docking scores were noted to be remarkably low, with values of -8.65, -7.97, -8.92, and -8.32 kcal/mol being recorded for hCA I, hCA II, AChE, and BChE, respectively. These observations suggest a high affinity and specificity of the studied compounds toward the enzymes, as mentioned earlier, which may pave the way for novel therapeutic interventions aimed at modulating the activity of these enzymes.