Synthesis and biological evaluation of novel borono-nucleoside analogs as anti- HIV agents

Abstract

The human immunodeficiency virus (HIV) has infected millions of people worldwide. This virus is still a global pandemic due to the continued emergence of viral resistance to current drugs. The nucleoside reverse transcriptase inhibitors (NRTIs) are one of the most used classes of drugs in antiretroviral therapy (ART). These NRTIs analogs can inhibit HIV replication since they are competitive inhibitors of the native nucleotide triphosphate (NTP) substrates of reverse transcriptase (RT). Because of the lack of 3’-hydroxyl group in the nucleoside reverse transcriptase inhibitors, incorporation causes termination of DNA chain elongation. Although these drugs have been proven effective clinically, they have several drawbacks when used in long-term treatment regimes. These drugs have relatively low bioavailability and require phosphorylation by human and/or viral kinases to become activated. Boronic acids and their derivatives have recently emerged as biologically interesting moieties, with increased attention in their use as pharmaceutical agents. It is hypothesized that the incorporation of the boronic acid moiety will improve cellular permeability and pharmacological properties due to their lower negative charge compared to the current nucleoside analogs which incorporate phosphonate moieties, e.g., tenofovir. In this research, we investigate nucleoside boronic acids and their derivatives as potential NRTIs useful for HIV treatment. Herein, we report on the synthesis of a novel borono-nucleoside analogs compounds that are rationally designed analog of Adefovir and tenofovir. Novel borono-nucleoside analogs compounds exhibit an anti- HIV activity when they evaluated against HIV replication. Moreover, structure activity relationship studies indicate that changing boron warhead, increasing carbon chain length, and including ether linker on the alkyl chain backbone, have importance effect on the borononucleoside analogs activity against HIV replication. In addition, cytotoxicity analysis also shows that the borono-nucleoside analogs are not toxic to the mammalian cells. However, the mechanism of action is still unclear although we suggest that borono-nucleoside analogs may act as competitive inhibition, metal chelator, and act as Lewis’s acids and bind to Lewis basic amino acids in the active side. These data will then be utilized in ongoing drug design efforts and allow us to further probe the structure activity relationships of this class compounds.