Design, Synthesis, and Evaluation of a novel Curcumin–Isoniazid Bis- Hydrazone Conjugate as an HIV-1 Reverse Transcriptase Inhibitor

Abstract The development of structurally novel HIV-1 reverse transcriptase (RT) inhibitors remains important for addressing the challenges associated with drug resistance and the limited chemical diversity of existing antiretroviral agents. In the present study, a novel curcumin–isoniazid bis-hydrazone conjugate was synthesized by condensation of curcumin with isoniazid and characterized using spectroscopic techniques. The conjugate was obtained as a yellow-orange solid in 45% yield, with its structural characteristics supported by FTIR, 1 H NMR, 13 C NMR and ESI-MS analyses. The inhibitory activity against recombinant HIV-1 RT was evaluated using a colorimetric reverse transcriptase assay. The conjugate exhibited concentration-dependent inhibition, increasing from 38.65 ± 3.25% at 2.56 µM to 87.59 ± 1.23% at 164.29 µM, with an estimated IC₅₀ of 10.6 µM (6.44 µg/mL). Nevirapine, used as the reference inhibitor, showed an IC₅₀ of 6.5 µM under the experimental conditions. Molecular docking against the Y181C mutant HIV-1 RT structure (PDB ID: 1JLB) showed a predicted binding energy of − 8.1 kcal mol⁻¹ for the conjugate, compared with − 6.9 kcal mol⁻¹ for nevirapine. The conjugate formed hydrogen-bond interactions with Arg172 and Gln161, together with multiple additional contacts within the binding pocket. These findings identify the curcumin–isoniazid bis-hydrazone conjugate as a novel HIV-1 RT inhibitory scaffold and provide a basis for further structural optimization and biological evaluation.