title: Hydrazide drugs that inhibit growth and proliferation of tuberculosis bacteria.
abstract: Four hydrazide drugs are shown to effectively and strongly inhibit the growth of Mycobacterium bovis BCG. The four compounds were found to be comparable to isoniazid for extent of growth inhibition. Similar to isoniazid, the four drug designs have a hydrazide functional group (-C(O)NHNH2) that replaces a former carboxyl group (-C(O)OH). Important pharmaceutical properties were determined for all drugs including Log P, polar surface area, water solubility, and violations of the Rule of 5. Values of Log P for A, B, C, D, and isoniazid were determined to be 1.08, 1.26, 1.26, 1.06, and -0.70, respectively. The polar surface area for drugs A, B, and C were calculated to be 55.12 Angstroms2, which is a value that suggests these drugs will effectively penetrate the central nervous system for targeting tuberculosis that infects that anatomical region. All drug designs and isoniazid show zero violations of the Rule of 5 indicating favorable drug bioavailability. Water solubility for all drugs varies from 1074 milligrams/liter to 16690 milligrams/liter. Growth inhibition of tuberculosis bacteria was greater than 50% for all novel drugs at concentrations of 62.5 micrograms/milliliter and higher. Cluster analysis determined that isoniazid is distinct from all new drug designs. For molecular descriptors, molecular volume is directly correlated to formula weight and polar surface area (Pearson r > 0.8800). The four novel drug designs show substantial efficacy for the clinical treatment of tuberculosis.
authors.affiliation: University of Nebraska, Department of Chemistry, Durham Science Center Omaha, Nebraska 68182, USA. rbartzatt@mail.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
authors.initials: J
authors.lastname: Cirillo
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000254:growth & development*; D014376:Tuberculosis / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D006834:Hydrazines; C029424:hydrazine