Novel thiourea compounds as dual-function microbicides

Sexually active women represent the fastest growing human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome risk group, In an effort to develop a vaginal microbicidal contraceptive potentially capable of prevent ing HIV transmission as well as providing fertility control, we previously reported the synthesis of novel nonnucleoside inhibitors (NNIs) of HIV-1 re verse transcriptase with sperm-immobilizing activity (SIA), To gain further insight into the structure-function relationship controlling these two pro perties of NNIs, we have rationally designed and synthesized 30 novel thiou rea compounds and examined them for dual-function, anti-HIV and spermicidal activity. Twelve of the 30 thiourea compounds exhibited potent anti-HIV ac tivity in the nanomolar range (IC50 = <1-9 nM), Nine of the 30 thiourea der ivatives exhibited both anti-HIV and spermicidal activity. Among the phenyl ring-containing thioureas, the 2-fluoro (HI-240) -substituted and 2-chloro (HI-253) -substituted derivatives exhibited potent anti-HIV activity (IC50 = <1 nM) with SIA (EC50 = 70 mu M and 147 mu M). Among the alicyclic ring- containing thioureas, the 5-bromo (HI-346) and 5-chloro (HI-445) functional ized cyclohexenyl ring-substituted thioureas were the most potent dual-func tion spermicides (EC50 = 42 and 57 mu M), with anti-HIV activity at nanomol ar range (IC50 = 3 nM). Unlike nonoxynol-9 (N-9), none of the potent dual-f unction thiourea compounds were cytotoxic to normal human vaginal, ectocerv ical, and endocervical epithelial cells at spermicidal concentrations. We c onclude that as potent anti-HIV agents with SIA and reduced cytotoxicity wh en compared with N-9, the phenyl-substituted and cyclohexenyl-substituted t hiourea derivatives, especially compounds HI-253 (N-[2-(2-chlorophenethyl)] -N'-[2-(5-bromopyridyl)-thiourea), HI-346 (N-[2(5-bromopyridinyl)]-N'-[2-(1 -cyclohexenyl)ethyl-thiourea), and HI-445 (N-[2-(5-chloropyridinyl)]-N'-[2- (1-cyclohexenyl)ethylthiourea) show unique clinical potential to become the active ingredients of a vaginal contraceptive for women who are at high ri sk for acquiring HIV by heterosexual vaginal transmission.