title: Evaluation of small molecule tuberculostats for targeting tuberculosis infections of the central nervous system.
abstract: Tuberculosis infection of the central nervous system is a serious and frequently fatal disease. Four drugs have been found to very efficiently inhibit the growth of Mycobacterium tuberculosis and are examined for molecular properties that enable penetration of the blood-brain barrier. Drugs 1, 2, and 3 are aromatic compounds having a single bromine atom in ortho, meta, and para-position, respectively, relative to the hydrazide group (-C(O)NHNH2). A paraposition for bromine enabled the strongest inhibition of Mycobacterium tuberculosis. Drug 4 is a hydrazide derivative of ciprofloxacin. All drugs showed molecular properties suitable for targeting tuberculosis infections of the central nervous system. Drugs 1, 2, 3, 4, and isoniazid showed zero violations of the Rule of 5 and potential capability for oral administration. Values of BB (Cbrain/Cblood) suggested that drugs 1, 2, and 3 will be able to penetrate the brain approximately three times greater than isoniazid. Similarly, the calculated value of BB for drug 4 is comparable to that of isoniazid. Calculated values of polar surface area for drugs 1, 2, 3, and isoniazid indicated a potential rate of intestinal absorption of greater than 75% of drug amount present. The intestinal absorption of drug 4 is predicted to be greater than 50% of total amount present. Drug concentrations necessary for achieving MIC50 for 1, 2, 3, 4, and isoniazid are determined to be 65.9 μg/mL, 29.5 μg/mL, 21.5 μg/mL, 36.4 μg/mL, and 16.7 μg/mL, respectively. The position of the bromine atom within drugs 1, 2, and 3 appears to substantially influence the effectiveness of growth inhibition. These compounds show substantial potential for targeting tuberculosis infections within the central nervous system.
authors.affiliation: University of Nebraska, College OF Arts & Sciences, Durham Science Center, Omaha, Nebraska 68182, USA. rbartzatt@unomaha.edu
authors.forename: Ronald
authors.initials: R
authors.lastname: Bartzatt
mesh_terms: D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D020306:Tuberculosis, Central Nervous System / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents