Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors.

A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73µM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5µM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36µM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.

Metabolism of Nucleosides and Nucleotides Prodrugs.

BACKGROUND: Modified nucleoside and nucleotide analogs are now the cornerstone of antiviral and anticancer chemotherapies. However, these compounds are not active on their own and need, after entering the cell, to be metabolized to their active 5'-triphosphate form. METHOD: Limitations of these metabolic processes led to development of nucleoside/nucleotide prodrugs in which nucleosides are masked with different groups that can be intracellularly cleaved either chemically or enzymatically. RESULTS: Several prodrug approaches have been successfully developed in order to increase the efficacy, bioavailability, penetration in target organ, and selectivity of nucleoside/nucleotide analogs. CONCLUSION: The concept of nucleoside/nucleotide prodrug is now a well-established approach that led to the approval of numerous drugs for the treatment of HIV, HBV, HCV, HSV and cancer.