Diaryl Pyrazoline, 1,3,4-Oxadizole, and 1,2,4-Triazole Pharmacophore Hybridization: Design, Synthesis, HDAC Inhibition, and Caspase 3/7 Activation Studies

Abstract: Objective: The study aimed to employ the pharmacophore hybridization technique for the synthesis of novel anticancer compounds by combining the pyrazole moiety with 1,2,4-triazole and 1,3,4-oxadizaole moieties. Methods: Two series of compounds were synthesized, purified, and structurally characterized. The compounds were tested for HDAC inhibitory properties on HDAC4 and HDAC8 isoforms, with a focus on HDAC8 selectivity. Results: Among the synthesized derivatives, an intriguing HDAC8 selectivity was observed. Fourteen compounds were further evaluated for preliminary cytotoxicity across nine solid tumor cell lines. Compound (IXt) demonstrated notable activity against three cell lines. Detailed analysis revealed that caspase activation played a significant role in the cytotoxic effects of (IXt). Cell cycle analysis indicated disruption with decreased cell populations in S and G2/M phases. Discussion: The study underscores the potential of hybridizing diaryl pyrazolines with oxadiazole and triazole 5-membered heterocycles. The observed HDAC8 selectivity and significant cytotoxic effects, particularly with compound (IXt), suggest promising avenues for the development of novel anticancer leads. Conclusions: The hybridization strategy employed in this study, combining diaryl pyrazolines with specific heterocycles, presents a viable approach for the synthesis of anticancer compounds. The identified HDAC8 selectivity and cytotoxicity against multiple cell lines, especially with compound (IXt), warrant further exploration and development of these derivatives as potential anticancer agents. © Pleiades Publishing, Ltd. 2024.