title: Four hydrazide compounds that inhibit the growth of mycobacterium tuberculosis.
abstract: Over one-third of the world's population has been exposed to Mycobacterium tuberculosis (TB). New drug designs are necessitated by the appearance of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). This work presents four hydrazide compounds that inhibit Mycobacterium tuberculosis growth at potency comparable to isoniazid. The hydrazide drugs A, B, C, and D were synthesized utilizing microwave excitation methodologies. Hydrazide agents are produced from parent carboxyl compounds. All reactions were accomplished in dry conditions. Using suitable molecular scaffolds the final hydrazides possessed the desired properties in Log P, polar surface area, molecular weight, etc. All four hydrazide compounds induced at least 60% inhibition of TB at concentrations at less than 31.5 microgram/mL. Measured as relative survival, all four hydrazide compounds induced greater than 95% death of TB bacteria at concentrations less than 31.5 microgram/mL. Drugs A, B, C, D exhibited zero violations of the Rule of 5, indicating favorable bioavailability. Although isoniazid, A, B, C, and D were determined to have a polar surface area less than 70 Angstroms2, the values of Log P (a measurement of lipophilicity) showed a broad range of -1.463 (drug C) to 4.46 (drug A). The numerical values of polar surface area suggests that all drugs would have greater than 50% intestinal absorption. For all drugs the number of amine (-NH) and hydroxyl (-OH) groups remains constant at three, with number of oxygens and nitrogens varying only three to four. ANOSIM (analysis of similarity) indicated that isoniazid, A, B, C, and D are highly similar. Correlation of molecular properties for all five drugs is greater than r = 0.9500. Drugs A, B, C, and D are members of two homologous series of anti-tuberculosis agents. All hydrazides effectively inhibited TB at 31.5 micrograms/mL and lower concentrations.
authors.affiliation: University of Nebraska, College of Arts & Sciences, Chemistry Department, 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 D
authors.initials: JD
authors.lastname: Cirillo
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry*; D007538:Isoniazid / Q000737:chemistry; D008872:Microwaves; D008956:Models, Chemical; D008970:Molecular Weight; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology; D017672:Nitrogen Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055095:Optics and Photonics / Q000379:methods; D017601:Oxygen Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000588:Amines; D000995:Antitubercular Agents; D006834:Hydrazines; D017672:Nitrogen Compounds; D017601:Oxygen Compounds; D007538:Isoniazid