We have previously demonstrated that tetrahedral bis(cyclopentadienyl)vanadium(IV) complexes and square pyramidal oxovanadium(IV) complexes of vanadium are rapid and selective spermicidal agents at low micromolar concentrations. This study investigated the potential utility of oxovanadium in combination with thiourea non-nucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) for the development of an effective dual-function anti-HIV spermicide. Two rationally designed substituted phenyl-ring containing pyridyl thiourea NNIs, N-[2-(2-chlorophenethyl)]-N'-[2-(5-bromopyridyl)-thiourea] [1] and N-[2-(2-methoxyphenethyl)]-N'-[2-(pyridyl)-thiourea] [2] that exhibited subnanomolar IC50 values against the drug-sensitive, drug-resistant, and multidrug-resistant strains of HIV-1, were complexed with oxovanadium. The oxovanadium-thiourea [OVT] NNIs, C29H27Br2Cl2N6O2S2V [3], and C31H35N6O4S2V [4], were synthesized by reacting VOSO4, a V-1V compound, with the corresponding deprotonated thiourea NNI compounds as ligands. Elemental analysis showed that each OVT-NNI used two thiourea molecules as ligands. The existence of the V=O bond (968 cm(-1)) was confirmed by IR spectroscopy. No d-d bands were observed in the visible spectra of OVT-NNIs and their EPR spectra were featureless, indicating that the vanadium centers were oxidized to V-V. The new OVT-NNIs as well as their thiourea NNI ligands were evaluated for (i) anti-HIV activity using the cell-free recombinant RT inhibition assays, (ii) cellular HIV replication assays, (iii) spermicidal activity against human sperm by computer-assisted sperm analysis (CASA), and (iv) cytotoxicity against normal human female genital tract epithelial cell using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye-reduction assays. Similar to thiourea NNIs 1 and 2, the OVT-NNIs 3 and 4, exhibited potent anti-HIV activity with submicromolar IC50[p24] values (0.08 and 0.128 muM, respectively) and submicromolar IC50[RT] values (2.1 and 0.87 muM, respectively). Notably, OVT-NNIs were spermicidal against human sperm at low micromolar concentrations (IC50 = 34 and 55 muM, respectively) and induced rapid sperm immobilization (T-1/2 = 12 and 240 s) when compared with their respective thiourea NNI ligands (EC50 = >400 muM and T-1/2 = >180min). Moreover, OVT-NNIs displayed high selectivity indices against normal female genital tract epithelial cells (IC50 values > 250muM) when compared to the detergent-type spermicide, nonoxynol-9, which was cytotoxic at spermicidal concentrations (IC50 values 32-64 muM). This is the first report on the dual anti-HIV and spermicidal activities of a vanadium/oxovanadium complex. Our discovery of potent anti-HIV and rapid spermicidal activities of OVT-NNIs may be useful for the development of an effective and safe vaginal anti-HIV spermicide for women who are at high risk for acquiring HIV/AIDS by heterosexual transmission. (C) 2003 Elsevier Science (USA). All rights reserved.