Rational design and synthesis of substrate–product analogue inhibitors of α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis

Abstract

2,2-Bis(4-isobutylphenyl)propanoyl-CoA and 2,2-bis(4-t-butylphenyl)propanoyl-CoA are rationally designed, gem-disubstituted substrate–product analogues that competitively inhibit α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis with K_i values of 16.9 ± 0.6 and 21 ± 4 μM, respectively, exceeding the enzyme's affinity for the substrate by approximately 5-fold.