title: Small molecule hydrazide agents to inhibit growth and proliferation of mycobacterium tuberculosis.
abstract: Four novel drug designs for the treatment of Mycobacterium tuberculosis are analyzed and shown to prevent the growth and proliferation of this dangerous bacteria. All four agents, designated A, B, C, and D, are hydrazide type compounds, where D has three hydrazide functional groups. Agents B and C have a halogenated aromatic ring substituent, while A contains a pyridine ring. Pharmaceutical properties such as Log P, polar surface area, and violations of the Rule of 5 are determined for all agents. The Polar surface area for these four agents ranged from 55.121 A2 to 165.363 A2 and Log P values for A, B, C, and D were determined at -0.916, 0.95, 0.974, and -4.921, respectively. Drug designs A, B, and C show zero violations of the Rule of 5, where D exhibits only one violation, which are outcomes describing favorable bioavailability. Values of polar surface area for A, B, and C affirm an intestinal absorption of greater than 60% as well as the potential for crossing the blood brain barrier for targeting bacterial meningitis of the central nervous system. Interaction with Mycobacterium tuberculosis was monitored over a 14 day interval with agents at known concentration. Agents A, B, C, and D elicited more than 60% inhibition of bacterial growth by day 14 at concentrations of as little as 30 micrograms/ milliliter. All agents reduced bacteria survival to less than 60% by day 7 of culture. The inhibition of bacterial growth induced by agents A, B, C, and D was comparable to that of isoniazid. K-means cluster analysis of descriptors determined isoniazid most similar to agents A, B, and C. Other characteristics of these small hydrazide compounds render supportive evidence for an efficacious clinical application.
authors.affiliation: University of Nebraska, College of Arts & Sciences, Durham Science Center, Chemistry Department, Omaha, NE 68182, USA. rbartzatt@unomaha.edu
authors.forename: Ronald
authors.initials: R
authors.lastname: Bartzatt
authors.forename: Suat L G
authors.initials: SL
authors.lastname: Cirillo
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cirillo
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000995:Antitubercular Agents; D006834:Hydrazines