title: Design, synthesis and characterization of novel 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives as inhibitors of NF-kappaB and AP-1 mediated transcription activation and as potential anti-inflammatory agents.
abstract: A series of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives were designed and synthesized. Synthesized molecules were further evaluated for their inhibitory activity towards transcription factors NF-kappaB and AP-1 mediated transcriptional activation in a cell line based in vitro assay as well as for their anti-inflammatory activity in in vivo model of acute inflammation. This series provides us with selective and dual inhibitors of NF-kappaB and AP-1 mediated transcriptional activation which also exhibit significant efficacy in in vivo model of inflammation. Two of the compounds 9m and 9o turned out to be the most promising dual inhibitors of NF-kappaB and AP-1 mediated transcriptional activation with an IC(50) of 3.3 microM for both. 9n (IC(50)=5.5 microM) and 9p (IC(50)=5.5 microM) emerged as selective inhibitors of NF-kappaB mediated transcriptional activation and 9c (IC(50)=5.5 microM) and 9d (IC(50)=5.5 microM) were found to be more selective inhibitor of AP-1 mediated transcriptional activity. Though the relationship between the activities shown by these compounds in in vivo and in vitro model is still to be established, these results suggest the suitability of the designed molecular framework as a potential anti-inflammatory molecular framework which also exhibits the inhibitory activity towards NF-kappaB and AP-1 mediated transcriptional activation. This will be worth studying further to explore its complete potential particularly in chronic inflammatory conditions. The structure activity relationship (SAR) of this series has been discussed herein.
authors.affiliation: B.V. Patel Pharmaceutical Education and Research Development Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India. [corrected]
authors.forename: Rajan S
authors.initials: RS
authors.lastname: Giri
authors.forename: Hardik M
authors.initials: HM
authors.lastname: Thaker
authors.forename: Tony
authors.initials: T
authors.lastname: Giordano
authors.forename: Jill
authors.initials: J
authors.lastname: Williams
authors.forename: Donna
authors.initials: D
authors.lastname: Rogers
authors.forename: Vasudevan
authors.initials: V
authors.lastname: Sudersanam
authors.forename: Kamala K
authors.initials: KK
authors.lastname: Vasu
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D052999:Quinazolinones; D018808:Transcription Factor AP-1