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

Abstract

Four double-drug HIV NRTI / NNRTI inhibitors 15a-d of the type [d4U]-spacer- in which the spacer is varied as 1-butynyl (15a), propargyl-1-PEG (15b), propargyl-2-PEG (15c) and propargyl-4-PEG (15d) have been synthesized and biologically evaluated as RT inhibitors against HIV-1. The key step in their synthesis involved a Sonogashira coupling of 5-iodo d4U's benzoate with an alkynylated tethered HI-236 precursor followed by introduction of the HI-236 thiourea functionality. Biological evaluation in both cell-culture (MT-2 cells) as well as using an in vitro RT assay revealed 15a-c to be all more active than d4T. However, overall the results indicate the derivatives are acting as chain-extended NNRTIs in which for 15b-d the nucleoside component is likely situated outside of the pocket but with no evidence for any synergistic double binding between the NRTI and NNRTI sites. This is attributed, in part, to the lack of phosphorylation of the nucleoside component of the double drug as a result of kinase recognition failure, which is not improved upon with the phosphoramidate of 15d incorporating a 4-PEG spacer.

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

“…Previous studies on C-5-substituted d4T derivatives yielded mixed results but mostly resulted in inactive analogues. 24,25,40–43 Moreover, earlier attempts to show efficient HIV replication inhibition of bifunctional compounds all failed. 44,45 We hypothesized that one of the possible reasons for these unsuccessful attempts could be impaired phosphorylation of the nucleoside end of bifunctional analogues catalyzed by cellular kinases.…”

Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

“…This scenario, where the medium chain fatty acid and resveratrol would be playing a role side-by-side, indicates that compound 8 could indeed be a double-drug. Other double-drugs have been reported earlier as antimalarial [58], anti-HIV [59] or as antiproliferative agents [60].…”

Bifunctional inhibition of HIV-1 reverse transcriptase: A first step in designing a bifunctional triphosphate

“…Comparison of these two studies yields significant differences in the linker terminus, further supporting the complexity in addressing linkage position and linker design for an RT bifunctional inhibitor. Work from our lab preparing a bifunctional inhibitor prodrug based on phenylethylthiazolylthiourea (PETT) compounds such as HI-236 as an NNRTI showed antiviral activity in cell culture however structural data with PETT-2 NNRTIs suggested the choice of position for linkage from the NNRTI was not optimal 26,27 .…”