Properties and Potency of Small Molecule Agents for Treatment of Mycobacterium Tuberculosis Infections of the Central Nervous System

Abstract

Tuberculous meningitis is caused by Mycobacterium tuberculosis, which is the bacteria that causes tuberculosis. This bacteria spreads to the brain from another site within the body. If untreated, tuberculous meningitis can be life-threatening. Substantial brain damage can result from infection which results in mental impairment, motor paralysis, seizures, and abnormal behavior. This study presents the analysis of the effectiveness of 13 novel tuberculostatic agents, along with isoniazid (a first-line drug utilized for treatment of Mycobacterium tuberculosis). All 13 agents retain a diverse character of molecular structure effectuating a range of molecular properties such as in polar surface area, Log P, and formula weight. Properties such as polar surface area, formula weight, and Log P were determined for these agents as well as values of BB (Cbrain/Cblood), and Log BB. Values of BB varied from 0.0681 to 1.16. Only three of the novel drug structures showed one violation of the Rule of 5, while the remaining showed zero violations (an outcome favoring bioavailability). Values of polar surface area ranged from 55.121 Angstroms(2) to 110.24 Angstroms(2), and Log P from -3.52 to 4.965. This group of novel tuberculostatic agents reveals examples of three homologous series of tuberculostatic drugs which purposes the likelihood of as many as 20 effective tuberculostatic drugs. Determination of MIC60 disclosed eight novel structures matching the effectiveness of isoniazid, while two showed superior ability to deter Mycobacterium tuberculosis proliferation. These novel drug designs are shown to have substantial potential for the beneficial treatment of patients having infections of Mycobacterium tuberculosis within the central nervous system.