1,3-Dipolar cycloaddition of thiosemicarbazone and diarylnitrilimines: Design, synthesis, characterization, DFT studies, and computational evaluation

We reported herein the design, synthesis, characterization, and computational evaluation of isophorone-linked 1,3,4-thiadiazole analogs as potential inhibitors of three promising cancer drug targets, viz. B-cell lymphoma 2 (BCL2), Caspase-3, and epidermal growth factor receptor (EGFR). The compounds (7a-d) were designed based on previously reported 1,3,4-thiadiazole derivatives. The synthesized analogs were characterized using high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance 1 H & 13 C (NMR) spectroscopy. This study investigates the electronic and structural properties of ethanol and gas phase using Molecular Electrostatic Potential (MEP) analysis, topological studies, such as Electron Localization Function (ELF), Localized Orbital Locator (LOL), and Electrostatic Potential (ESP), as well as Hirshfeld surface analysis. The optimized structures (7a-d) in ethanol and gas phases were analyzed across four series. The results revealed significant variations in electronic distributions and intermolecular interactions. Additionally, UV-Vis absorption spectra were obtained, offering insights into the electronic transitions. This comprehensive computational approach enhances the understanding of chemical reactivity and molecular interactions of the derivatives. Furthermore, molecular docking studies predicted promising interactions of the derivatives with BCl2, caspase-3, and EGFR. Among them, compound 7a exhibited notably high binding affinity, with an interaction energy of -37.6 kJ/mol against the Caspase-3 protein. All designed 1,3,4-thiadiazole analogs displayed a favorable absorption, distribution, metabolism, excretion, toxicity (ADMET) profile and physicochemical properties. The molecular dynamics (MD) simulation study demonstrated that compound 7a forms a stable complex with caspase-3. The designed 1,3,4-thiadiazole derivatives 7a-d are considered promising leads for targeting BCl2, Caspase-3, and EGFR.