Synthesis and anti-HIV Activity of New Benzimidazole, Benzothiazole and Carbohyrazide Derivatives of the anti-Inflammatory Drug Indomethacin

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains. New derivatives of the non-steroidal anti-inflammatory drug indomethacin bearing benzimidazoles, benzothiazole, purine and pyridine residues 8 - 13 were synthesized with the aim of developing new non-nucleoside reverse transcriptase inhibitors (NNRTIs).Alternatively, new imine analogs 16 - 20 were synthesized from condensation of indomethacinyl hydrazide 15, prepared from the ester 14, with various ketone precursors. Treatment of 15 with phenyl isothiocyanate or triethyl orthoformate afforded the phenylcarbonothioyl and the oxadiazole derivatives 21 and 22, respectively. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 9 and 10 were the most active in inhibiting HIV-2 and HIV-1, respectively, with EC50 ≥ 17.60 μgmL⁻¹ and > 1.15 μgmL⁻¹ (therapeutic indexes (SI) of ≥ 3 and < 1, respectively), and are leading candidates for further development.

Graphical Abstract

Synthesis and anti-HIV Activity of New Benzimidazole, Benzothiazole and Carbohyrazide Derivatives of the anti-Inflammatory Drug Indomethacin