ABSTRACT
A series of novel 5-substituted-1-(arylmethyl/alkylmethyl)-1H-indole-2,3-dione-3-(N-hydroxy/methoxy thiosemicarbazone) analogues were synthesized and evaluated for their anti-HIV activity and anti-tubercular activity in both log phase and starved cultures. The compound 2-(1-{[4-(4-chlorophenyl)tetrahydropyrazin-1(2H)-yl]methyl}-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-yliden)-N-(methyloxy)hydrazine-1-carbothioamide (B21) displayed promising activity against the replication of HIV-1 cells (EC(50) 1.69 µM). In anti-mycobacterial screening B21 proved effective in inhibiting the growth of both log phase (MIC 3.30 µM) and starved (MIC 12.11 µM) MTB cultures. Isocitrate lyase enzyme having momentous implication in persistent TB was shown to be inhibited by 1-cyclopropyl-6-fluoro-7-[4-{[5-methyl-3-((Z)-2-{[(methyloxy)amino]carbothioyl}hydrazono)-2-oxo-1H-indol-1(2H)-yl]methyl}tetrahydropyrazin-1(2H)-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (B30) with 63.44% inhibition at 10 mM.
Subject(s)
HIV Infections/drug therapy , HIV/drug effects , Mycobacterium tuberculosis/drug effects , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Tuberculosis/drug therapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Cell Line , HIV/enzymology , HIV/physiology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/metabolism , Isocitrate Lyase/antagonists & inhibitors , Isocitrate Lyase/chemistry , Isocitrate Lyase/metabolism , Models, Molecular , Molecular Conformation , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/physiology , Thiosemicarbazones/metabolism , Thiosemicarbazones/therapeutic useABSTRACT
Various 5-nitro-2-furoic acid hydrazones were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among twenty one compounds, 5-nitro-N'-[(5-nitro-2-furyl)methylidene]-2-furohydrazide (4o) was found to be the most active compound in vitro with MICs of 2.65 and 10.64 microM against log- and starved-phase culture of MTB. Compound 4o also showed good enzyme inhibition of MTB ICL at 10 microM. The docking studies also confirmed the binding potential of the compounds at the ICL active site.
