Anti-HIV activity of aromatic and heterocyclic thiazolyl thiourea compounds.
Several thiazolyl thiourea derivatives were designed and synthesized as non-nucleoside inhibitors (NNRTI) of HIV-1 reverse transcriptase. Six lead compounds were identified that showed subnanomolar IC50 values for the inhibition of HIV replication, were minimally toxic to human peripheral blood mononuclear cells (PBMC) with CC50 values ranging from 28 to >100 microM, and showed remarkably high selectivity indices ranging from 28,000 to >100,000. The most promising compound was N-[1-(1-furoylmethyl)]-N'-[2-(thiazolyl)]thiourea (compound 6), which showed potency against two NNRTI-resistant HIV-1 isolates (A17 and A17 variant) at nanomolar to low micromolar concentrations, exhibited much greater potency against both wild-type as well as NNRTI-resistant HIV-1 than nevirapine, delavirdine, HI-443, and HI-244, was minimally toxic to PBMC, and had a selectivity index of > 100,000. The potency and minimal cytotoxicity of these aromatic/heterocyclic thiourea compounds suggest that they may be potentially useful as anti-AIDS drugs.
Venkatachalam
T K
TK
Drug Discovery Program, Parker Hughes Institute, St. Paul, MN 55113, USA.
Sudbeck
E A
EA
Mao
C
C
Uckun
F M
FM
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D054303:HIV Reverse Transcriptase / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013890:Thiourea / Q000138:chemical synthesis* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D054303:HIV Reverse Transcriptase; D013890:Thiourea