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

The observation that stilbene 3 (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 3 by an amide function and the quinoline motif by a 2-aminobenzothiazole subunit, as in 12jj (R' = Cl), 12pp (R = NO2), and 12vv (R = CF3). On the basis of the possible CF3 <-> NO2 bioisostere relationship in 12vv and 12pp, compound 23 was prepared and also found to be active. In the final step, the thiazole compounds 28 (GPS488) (EC50 = 1.66 mu M) and 29 (GPS491) (EC50 = 0.47 mu M) were prepared and evaluated. Similar activity and cell viability values (therapeutic index (TI = CC50/EC50) 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 29 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 3.

Automated summary

The study identified a compound that blocks HIV replication by affecting HIV mRNA processing. Through synthesis of related compounds, it was found that one compound showed strong activity against HIV and could inhibit resistance to multiple drugs used in antiretroviral therapy.