Determination of Molecular Properties Effectuating the Growth Inhibition of Mycobacterium Tuberculosis by Various Small Molecule Hydrazides

Ronald      Bartzatt; Suat   L.G.   Cirillo; Jeffrey   D.   Cirillo

Abstract

A significant percentage of the worlds population has been exposed to Mycobacterium tuberculosis. Four novel hydrazide compounds are presented in this work to discern molecular properties that effectuate bacterial inhibition. The four compounds are hydrazide derivatives of ibuprofen (A), aspirin (B), lauric acid (C), and itaconic acid (D). Of these four hydrazide compounds tested in vitro against Mycobacterium tuberculosis, drug C showed greatest inhibition of bacterial growth, followed in activity by drug A and drug B. The itaconic acid hydrazide derivative showed the least activity, but revealed striking molecular properties that affirms specific criteria for effective bacterial inhibition. Isoniazid was utilized for comparing relative efficacy in reducing proliferation. The lauric acid hydrazide showed high lipophilicity (Log P = 3.449) with low polar surface area (PSA = 55.121 A2). In contrast the itaconic acid hydrazide derivative has low lipophilicity (Log P = -3.52), high water solubility, one violation of the Rule of 5, and the highest value in PSA. Partitioning into the central nervous system via blood-brain barrier penetration, indicated by values of Log BB, is substantially lower for drug D compared to the remaining three hydrazide derivatives and isoniazid. Very high correlation (r > 0.9000) was observed among molecular properties of drugs A, B, C, D, and isoniazid. Multiple regression analysis utilizing formula weight, Log P, polar surface area, and number of atoms accounted for 99.55% of all variance. K-means nonhierarchical cluster analysis indicated isoniazid is most similar to drug D. Results of this study elucidates the influence of various molecular properties that affect inhibitory efficiency.

Keywords: Mycobacterium tuberculosis, Bacteria, Isoniazid, TB

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