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The Science Journal of the Lander College of Arts and Sciences

Abstract

Isoniazid (INH), one of two first-line drugs used to treat tuberculosis (TB), has been shown to be a potent inhibitor of InhA, the mycobacterial enoyl reductase. However, the increasing resistance to INH makes it imperative to find alternative drugs that are as effective as the first-line drugs, yet active against INH-resistant strains. Since InhA has been validated as an excellent target of TB, there have been attempts to find novel inhibitors of InhA. Through rational drug design, a variety of high affinity InhA inhibitors were synthesized. Triclosan itself was observed to be a suboptimal inhibitor of InhA with a K of .22 µM, but with modifications to the 5-position of the A ring, the new diphenyl ether compounds demonstrated higher affinities with nanomolar constants. A particularly potent triclosan derivative, compound PT70, showed slow, tight-binding inhibition with a K value of 22 pM. In addition, arylamides showed moderate to high inhibition of InhA. They did not show sufficient anti-tubercular activity, and therefore future modifications are needed before they can be considered seriously for use against TB. Lastly, pyridomycin, a natural anti-tubercular drug was rediscovered and confirmed to have high activity against TB. It was found to be the first compound ever published to bind to both binding sites of InhA simultaneously. Current research is ongoing in the synthesis and testing of pyridomycin analogs to further increase their anti-tubercular properties.

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