title: Preclinical comprehensive physicochemical and pharmacokinetic profiling of novel nitroimidazole derivative IIIM-019 - A potential oral treatment for tuberculosis.
abstract: New compounds against tuberculosis are urgently needed to combat the crisis of drug resistance in tuberculosis (TB). We have identified a nitrodihydroimidazooxazole analog, IIIM-019 as a new anti-tubercular agent with a MIC of 0.23 μM against H37Rv. Physicochemical properties, in-vitro pharmacokinetics and in-vivo multiple-doses pharmacokinetics were studied for the compound. In silico physicochemical parameters and Lipinski's violations were determined for drug like properties. Lipophilicity was determined experimentally as Octanol-PBS partition coefficient (log P). Passive and active permeability of the compound was determined by PAMPA and Caco-2 cell permeability analysis, respectively. Plasma protein binding was determined by Rapid equilibrium dialysis. Metabolism by liver microsomes revealed the t1/2 and intrinsic clearance of the compound. Hepatotoxicity of IIIM-019 was determined alone and in combination to first line anti-tubercular drugs. The compound was also estimated for nuclear DNA damage. Single doses of IIIM-019 (2.5, 10, 25 and 100 mg/kg) were administered orally to Balb/c mice and the blood samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). IIIM-019 exhibited very good lipophilicity (log P) of 2.47 which makes it optimal for oral administration. The compound showed low solubility and permeability and high plasma protein binding. However, it was highly stable in rat liver microsomes with t1/2 > 2 h and very low intrinsic clearance. It was found to be non-hepatotoxic and did not induce any significant DNA damage at high concentrations even up to 100 μM. IIIM-019 showed satisfactory in-vivo pharmacokinetic properties. By increasing the dose from 2.5 mg/kg to 10 mg/kg, AUC0-t increased from 14935 ng h/ml to 81,478 ng h/ml. However the exposure of IIIM-019 in plasma suggested that the levels reached saturation at higher concentrations. The compound showed a good oral bioavailability of 58.7%. The results insinuate that IIIM-019 should undergo further development as a potential treatment for tuberculosis.
authors.affiliation: Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India; Academy of Scientific and Innovative Research (AcSIR), India.
authors.forename: Gurleen
authors.initials: G
authors.lastname: Kour
authors.affiliation: Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India; Academy of Scientific and Innovative Research (AcSIR), India.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India.
authors.forename: Parvinder Pal
authors.initials: PP
authors.lastname: Singh
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India.
authors.forename: Asha
authors.initials: A
authors.lastname: Bhagat
authors.affiliation: Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India. Electronic address: zahmed@iiim.ac.in.
authors.forename: Zabeer
authors.initials: Z
authors.lastname: Ahmed
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010080:Oxazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D053719:Tandem Mass Spectrometry; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; C000624145:IIIM-019 compound; D009593:Nitroimidazoles; D010080:Oxazoles
keywords: Hepatotoxicity; IIIM-019; LC-MS/MS (liquid chromatography tandem mass spectrometry); Pharmacokinetics; Physicochemical parameters