Current Developments in the Synthesis and Biological Activity of HIV-1 Double-Drug Inhibitors

Abstract

A combination of different HIV inhibitors into a single molecular entity is a strategy that is growing in popularity in HIV-chemotherapy research. The high levels of resistance elicited by both nucleoside and non-nucleoside reverse transcriptase inhibitors has prompted the design of double-drugs combining these two entities with the aim of addressing the emergence of resistance. The strategy involves combining two different inhibitors into a single chemical entity via a linker, with the aim of improving the physicochemical characteristics of the individual compounds. Linkers may be sub-divided into cleavable and non-cleavable. While the former result in regeneration of the parent drugs of the double-drug once in the cell cytoplasm, the latter type is designed to allow the double-drug to target two active sites in a simultaneous or bifunctional fashion, which are located in close proximity. The linkers have been attached at the C-5', C-5 or N-3 positions of the nucleoside, and in some of the substrates synthesized, a synergistic anti-HIV activity has been observed. This review focuses on the design and synthesis of anti-HIV double-drugs reported to date.

Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One

“…This resulted in a hybrid (22) that demonstrated potent growth inhibition of P. falciparum in culture and promising early results in mice (89). Application of drug hybrids in the field of HIV treatment was reviewed recently (90). …”

Structural Characterization, Biological Effects, and Synthetic Studies on Xanthones from Mangosteen (Garcinia mangostana), a Popular Botanical Dietary Supplement

“…The drugs used in current anti-HIV-1 combination chemotherapy, referred to as “highly active antiretroviral therapy” (HAART), inhibit both HIV-1 protease, responsible for the processing of viral structural proteins, and HIV-1 reverse transcriptase, which copies the genomic RNA to integrate into the host’s DNA. These two enzymes are essential for viral replication [53]. Activity-guided fractionation of G. mangostana using a HIV-1 protease inhibition assay led to two active compounds, α-mangostin ( 1 ) and γ-mangostin ( 3 ), which demonstrated IC 50 values of 5.1 and 4.8 μM, respectively, in a non-competitive manner [54].…”

[d4U]-Spacer-[HI-236] double-drug inhibitors of HIV-1 reverse-transcriptase

“…In the following ten years or so, reports on both cleavable,12 in which the spacer is designed to be hydrolytically labile in order to release the individual drugs, as well as other non-cleavable double-drugs,13 also known as mixed site inhibitors,13b appeared in the literature but similarly without evidence of true synergy between the two inhibitors. For the cleavable type, systems have become extended to different drug targets14 other than RT, whereas for the non-cleavable type, RT remains to date as the only target15 studied for HIV in view of the uniqueness of having the NRTI and NNRTI sites in close proximity. Challenges regarding the successful realization of a truly synergistic double-drug RTI in the non-cleavable class have been primarily twofold as: i) where on the drugs to attach the linker – this has suffered from a lack of modeling data, and, ii) the lack of phosphorylation of the NRTI nucleoside prodrug contained within the double-drug in vitro.…”