ABSTRACT
The F1 FO -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Bacterial Proton-Translocating ATPases/antagonists & inhibitors , Diarylquinolines/pharmacology , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Benzamides/chemistry , Benzamides/pharmacology , Benzamides/toxicity , Drug Synergism , Embryonic Stem Cells/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/toxicity , Humans , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium tuberculosis/enzymology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/toxicity , Structure-Activity RelationshipABSTRACT
Scandium triflate is an effective pre-catalyst for the deoxygenative allylation of benzylic alcohols with a narrow substrate window. The reaction is shown to proceed through a "hidden Brønsted acid" mechanism. The reaction is efficient provided that the aryl group is neither too electron rich nor too electron poor. It is shown that this allows useful selectivity. The reaction also works for benzyhydryl alcohols with broader scope. The reaction may also be catalysed by Nafion.
