title: Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline derivatives.
abstract: Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-c]quinolines, which are although considerably active (MIC 0.39-0.78 μg/mL) suffered from intense solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly esters of the "Lead" indeno[2,1-c]quinolines 1, 15 and 27 derivatives were synthesized and their prodrug nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold improved anti-TB activities, increased aqueous solubility and superior selectivity index over their respective parent compounds. MIC of these prodrugs was in the range of <0.20-6.0 μg/mL, and in general, no cytotoxicity was observed in VERO cells.
authors.affiliation: Institute of Molecular Medicine, Pune 411 057, India.
authors.forename: Ram Shankar
authors.initials: RS
authors.lastname: Upadhayaya
authors.forename: Popat D
authors.initials: PD
authors.lastname: Shinde
authors.forename: Sandip A
authors.initials: SA
authors.lastname: Kadam
authors.forename: Amit N
authors.initials: AN
authors.lastname: Bawane
authors.forename: Aftab Y
authors.initials: AY
authors.lastname: Sayyed
authors.forename: Ramakant A
authors.initials: RA
authors.lastname: Kardile
authors.forename: Pallavi N
authors.initials: PN
authors.lastname: Gitay
authors.forename: Santosh V
authors.initials: SV
authors.lastname: Lahore
authors.forename: Shailesh S
authors.initials: SS
authors.lastname: Dixit
authors.forename: András
authors.initials: A
authors.lastname: Földesi
authors.forename: Jyoti
authors.initials: J
authors.lastname: Chattopadhyaya
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011804:Quinolines / Q000378:metabolism*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D011355:Prodrugs; D011804:Quinolines; D014867:Water