Novel Pthalazinyl Derivatives: Synthesis, Antimycobacterial Activities, and Inhibition of Mycobacterium Tuberculosis Isocitrate Lyase Enzyme

D.      Sriram; P.      Yogeeswari; P.      Senthilkumar; S.      Dewakar; N.      Rohit; B.      Debjani; Pritesh      Bhat; B.      Veugopal; V.   V.S.   Pavan; H.   M.   Thimmappa

Abstract

Novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid hydrazones were synthesized from phthalic anhydride by a six step synthesis and evaluated for in vitro, in vivo activities against eight mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among twenty six compounds N1-[(4-nitrophenyl)methylene]-2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-1,2,3,4-tetrahydro-1-phthalazinyl]ethanohydrazide (7j) was found to be the most active compound in-vitro with MICs of 0.18 and < 0.09 μM against log-phase cultures of MTB and multi-drug resistant MTB respectively. Compound 7j inhibited all the eight mycobacterial species with MIC ranging from < 0.09-12.25 μM and was not toxic to Vero cell lines till 122.5 μM. Seven compounds were tested against starved culture of MTB and they inhibited with MICs ranging from 2.88-8.91 μM. Some compounds showed 45- 61% inhibition against MTB ICL enzyme at 10 μM. In the in vivo animal model 7j decreased the bacterial load in lung and spleen tissues with 1.87 and 3.03-log10 protections respectively at 25 mg/kg body weight dose.

Keywords: Phthalazine, Antimycobacterial, Mycobacterium tuberculosis, Isocitrate lyase

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