2-Trifluoromethylthiazole-5-carboxamides: Analogues of a Stilbene-Based Anti-HIV Agent that Impact HIV mRNA Processing.

The observation that stilbene (5350150) blocks HIV replication through its impact on HIV mRNA processing prompted a program to develop non-cytotoxic analogues that maintain its mechanism of action. This initially involved replacement of the central double bond in by an amide function and the quinoline motif by a 2-aminobenzothiazole subunit, as in (R' = Cl), (R = NO), and (R = CF). On the basis of the possible CF ↔ NO bioisostere relationship in and , compound was prepared and also found to be active. In the final step, the thiazole compounds (GPS488) (EC = 1.66 μM) and (GPS491) (EC = 0.47 μM) were prepared and evaluated. Similar activity and cell viability values (therapeutic index (TI = CC/EC) values of 50-100) were observed in primary peripheral blood mononuclear cells. Furthermore, they remained active against a panel of HIV mutant strains displaying resistance to individual drugs used in antiretroviral therapy. It was determined that compound suppressed expression of the HIV-1 structural protein Gag and altered HIV-1 RNA accumulation, decreasing the abundance of RNAs encoding the structural proteins while increasing levels of viral RNAs encoding the regulatory proteins, a pattern similar to that seen for compound .