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

• Published in: Bioorganic & medicinal chemistry 2000-05, Vol.8 (5), p.985-993
• Main Authors: Ryabinin, V A, Zakharova, O D, Yurchenko, E Y, Timofeeva, O A, Martyanov, I V, Tokarev, A A, Belanov, E F, Bormotov, N I, Tarrago-Litvak, L, Andreola, M L, Litvak, S, Nevinsky, G A, Sinyakov, A N
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; HIV Reverse Transcriptase - drug effects; Magnetic Resonance Spectroscopy; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacology; Thiazoles - chemical synthesis; Thiazoles - pharmacology
• ISSN: 0968-0896
• DOI: 10.1016/S0968-0896(00)00029-8

A set of oligo-1,3-thiazolecarboxamide derivatives able to interact with the minor groove of nucleic acids was synthesized. These oligopeptides contained different numbers of thiazole units presenting dimethylaminopropyl or EDTA moieties on the C-terminus, and aminohexanoyl or EDTA moieties on the N-terminus. The inhibition of such compounds on HIV-1 reverse transcriptase activity was evaluated using different model template primer duplexes: DNA x DNA, RNA x DNA, DNA x RNA and RNA x RNA. The biological properties of the thiazolecarboxamide derivatives were compared to those of distamycin, another minor groove binder which contains three pyrrole rings. Similar to distamycin, the thiazole containing oligopeptides were good inhibitors of the reverse transcription reaction in the presence of DNA x DNA. But in contrast to distamycin, the oligothiazolide derivatives were able to inhibit reverse transcription in the presence of RNA x DNA or DNA x RNA template primers. Both distamycin and oligothiazolecarboxamides had low affinity for RNA x 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.