title: Novel thiourea compounds as dual-function microbicides.
abstract: 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 preventing HIV transmission as well as providing fertility control, we previously reported the synthesis of novel nonnucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase with sperm-immobilizing activity (SIA). To gain further insight into the structure-function relationship controlling these two properties of NNIs, we have rationally designed and synthesized 30 novel thiourea compounds and examined them for dual-function, anti-HIV and spermicidal activity. Twelve of the 30 thiourea compounds exhibited potent anti-HIV activity in the nanomolar range (IC(50) = <1-9 nM). Nine of the 30 thiourea derivatives 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 (IC(50) = <1 nM) with SIA (EC(50) = 70 microM and 147 microM). Among the alicyclic ring-containing thioureas, the 5-bromo (HI-346) and 5-chloro (HI-445) functionalized cyclohexenyl ring-substituted thioureas were the most potent dual-function spermicides (EC(50) = 42 and 57 microM), with anti-HIV activity at nanomolar range (IC(50) = 3 nM). Unlike nonoxynol-9 (N-9), none of the potent dual-function thiourea compounds were cytotoxic to normal human vaginal, ectocervical, and endocervical epithelial cells at spermicidal concentrations. We conclude that as potent anti-HIV agents with SIA and reduced cytotoxicity when compared with N-9, the phenyl-substituted and cyclohexenyl-substituted thiourea 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)ethyl-thiourea) show unique clinical potential to become the active ingredients of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
authors.affiliation: Drug Discovery Program, Departments of Reproductive Biology, Chemistry, and Virology, Parker Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: O J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D013081:Sperm Motility / Q000187:drug effects; D013089:Spermatocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D014621:Vagina / Q000166:cytology / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; C412305:HI 253; C412304:HI 445; D011725:Pyridines; D013089:Spermatocidal Agents; D013890:Thiourea