Design, Synthesis, and In-silico Evaluation of Novel Pyrazole-Linked Methylenehydrazono-Thiazole Derivatives as Potential Biologically Active Agents

In medicinal chemistry, the exploration of novel scaffolds with diverse substituents has become paramount for the development of pharmacologically active compounds. This study focuses on a distinctive class of substituted pyrazole linked methylenehydrazono-thiazole derivatives (4a-h), synthesized through an efficient chemical approach. The synthesis involved the incorporation of various substituents at the thiazole moiety, aiming to explore their potential biological activities and enhance the pharmacological profile of the parent scaffold. The synthesized compounds were confirmed using spectroscopic methodologies such as FTIR, 1H-, 13C-NMR, elemental analysis, and Mass spectroscopy. The electronic and physicochemical properties of the newly synthesized compounds were evaluated through molecular modeling utilizing DFT/TDFT tool to evaluate its biological activities. DFT/TDFT results indicate promising activities for all compounds in comparison to the reference substituted pyrazole-linked methylenehydrazono-thiazolidinone (Ref), suggesting their potential as effective biological agents. In-silico pharmacokinetics studies (ADME) confirmed a favorable pharmacokinetic profile within an acceptable range and high % absorptions that ranged (78.24% to 92.62%). Specifically, compounds 4a, b, c, e, and f accomplished the Lipinski five roles, indicating their eligibility for oral availability. Moreover, molecular docking studies were conducted to assess the potential binding interactions between the synthesized compounds and Dihydrofolate Reductase (DHFR). The results of the docking revealed that, the binding energies of compounds (4a-h) followed this order order: 4d > 4f > 4h > 4g > 4b > 4e > 4c > 4a.