Affiliation: University of Nebraska, Durham Science Center, Chemistry Department, 6001 Dodge Street, Omaha Nebraska 68182 USA.
Tuberculosis infections of the central nervous system are a serious and often fatal disease predominantly impacting young children. Having a success rate of approximately 10%, an in silico data mining search generated 23 analogs to isoniazid, which is a first-line tuberculostatic. All analogs retained the hydrazide functional group in addition to configurations including: quinoline, pyridine, indole, quinolin-4-ol, quinoline-2,4-diol, and pyridine-2-one. Studies have shown that brain penetration is optimal when polar surface area is less than 90 A2. Sixteen of generated analogs have polar surface area less than 70 A2 (drugs 1, 2, 3, 4, 5, 6, 8, 11, 13, 14, 15, 16, 18, 19, 22, and 23) and six analogs have values between 70 A2 to 90 A2 (drugs 7, 9, 10, 12, 17, 21). All agents showed zero violations of the Rule of 5 which indicates favorable druglikeness. The aqueous solubility, formula weight, molecular volume, polar surface area, and Log P properties are determined. Pattern recognition analysis such as hierarchical cluster analysis, discriminate analysis, and ANOSIM identified underlying relationships among these 24 drugs that is based upon important pharmaceutical properties. Global resurgence of tuberculosis and the rapid emergence of multidrug resistant tuberculosis underscore the importance of the development of new tuberculostatic drugs.