Non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis and biological evaluation of novel quinoxalinylethylpyridylthioureas as potent antiviral agents

New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyri dylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus ty pe 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopa thogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inh ibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, s howed inhibitory activity against wild-type RT as well as against mutant RT s containing the single amino acid substitutions L100I, K103N, V106A, Y181I and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluo ropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQ XPT). In cell-based assays on different cell lines and on human monocyte-ma crophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a pro mising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral ac tivity with zidovudine.