Synthesis and In vitro-In silico Evaluation of Thiazolo-triazole Hybrids as Anticancer Candidates

To meet the growing need for stable and clinically effective chemotherapeutic agents, herein, we have synthesized a series of acyl-functionalized thiazolo[3,2-b]-[1,2,4]triazole derivatives in highly efficient and regioselective manner. The structure of newly synthesized regioisomeric products was unambiguously characterized by multinuclear 2D-NMR [(H-1-C-13) HMBC, (H-1-C-13) HMQC] spectroscopic data. To assess the anticancer and pharmacokinetic profile of the synthesized compounds, we performed in silico, and ex vivo binding studies of compounds with calf-thymus deoxyribonucleic acid (ct-DNA) and bovine serum albumin (BSA), respectively, and also tested their efficacy against five human cancer cell lines. viz., MCF-7 (breast cancer), BT-474 (breast cancer), A549 (lung cancer), MOLT4 (acute lymphoblastic leukemia), and BxPC3 (pancreatic cancer). Compounds (2-(4-chlorophenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(4-fluorophenyl)methanone 6 l, (4-chlorophenyl)(2-(4-chlorophenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone 6 m and (2-(4-chlorophenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(4-methoxyphenyl) methanone 6 q exhibited excellent anticancer potential among the screened derivatives. Furthermore, ex-vivo mechanistic investigations showed the static mode of quenching and moderate bindings between the ligand and biomolecules; DNA (Kq=2.01-2.24*10(12) M-1 s(-1)) and BSA (Kq=2.25-.2.72*10(12) M-1 s(-1)). Moreover, fluorescence displacement assay demonstrated a groove binding mode of interaction with ct-DNA, which was supported by UV-Visible absorption spectrum, circular dichroism, and viscosity analysis.