Discovery and molecular docking studies of nitrogen containing naphthyridine derivatives as potent HIV1 NNRTIs with anticancer potential

Fourteen novel 2,4-disubstituted-1,6- and 1,7-naphthyridine derivatives were developed to enhance HIV-1 RT inhibition through molecular hybridization of NNRTIs. The compounds were synthesized from nicotinate analogues via nucleophilic substitution and Buchwald-Hartwig reactions. Among them, 2-cyanopyridinyl-1,6-naphthyridines 16a, 16b, and 19a showed stronger activity than nevirapine (IC₅₀ = 1.053 µM) with IC₅₀ values of 0.222, 0.218, and 0.175 µM, comparable to rilpivirine (0.063 µM) and efavirenz (0.058 µM). Molecular docking revealed that these naphthyridines aligned well within the HIV-1 RT binding pocket, forming hydrogen bonds with LYS101, PRO225, and PHE227, and π-π stacking with TYR181 and TRP229. Molecular dynamics simulations confirmed stable binding for 16a, 16b, 19a and rilpivirine. Pharmacokinetic analysis indicated that these compounds conformed to Lipinski's Rule of Five. All synthesized 1,6- and 1,7-naphthyridine derivatives were evaluated for cytotoxicity against cancer cells, with several showing notable anticancer activity. 17a exhibited significant cytotoxic activity against lymphoblastic leukemia cells (MOLT-3), cervical carcinoma cells (HeLa), and promyeloblast cells (HL-60) with IC₅₀ values of 9.1 ± 2.0, 13.2 ± 0.7, and 8.9 ± 2.2 µM, respectively. Additionally, naphthyridines 16a, 16b, and 19a displayed no toxicity toward normal embryonic lung cells (MRC-5). Thus, 2,4-disubstituted-1,6- and 1,7-naphthyridines could serve as promising HIV-1 RT inhibitors.