Synthesis and evaluation of oligo-1,3-thiazolecarboxamide derivatives as HIV-1 reverse transcriptase inhibitors

A set of oligo-1,3-thiazolecarboxamide derivatives able to interact with th e minor groove of nucleic acids was synthesized. These oligopeptides contai ned different numbers of thiazole units presenting dimethylaminopropyl or E DTA moieties on the C-terminus, and aminohexanoyl or EDTA moieties on the N -terminus. The inhibition of such compounds on HIV-I reverse transcriptase activity was evaluated using different model template-primer duplexes: DNA DNA, RNA.DNA, DNA.RNA and RNA RNA. The biological properties of the thiazol ecarboxamide derivatives were compared to those of distamycin, another mino r groove binder which contains three pyrrole rings. Similar to distamycin, the thiazole containing oligopeptides were good inhibitors of the reverse t ranscription reaction in the presence of DNA.DNA. But in contrast to distam ycin, the oligothiazolide derivatives were able to inhibit reverse transcri ption in the presence of RNA.DNA or DNA RNA template-primers. Both distamyc in and oligothiazolecarboxamides had low affinity for RNA RNA duplexes. The inhibition obtained with the newly synthesized thiazolecarboxamides showed that these compounds were more powerful and versatile inhibitors of the RT -dependent polymerization than the natural minor groove binder distamycin. (C) 2000 Elsevier Science Ltd. All rights reserved.