title: Design, synthesis, and pharmacological evaluation of some 2-[4-morpholino]-3-aryl-5-substituted thiophenes as novel anti-inflammatory agents: generation of a novel anti-inflammatory pharmacophore.
abstract: Compounds incorporating a thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest owing to the therapeutic utility of the template as useful drug molecular scaffolding. Recently we reported the anti-inflammatory activity profile exhibited by two thiophene analogs, AP84 and AP82 in acute and chronic models of inflammation. The good activity profile exhibited by AP84, a 3-(substituted aryl)-2-(4-morpholino)-5-heteroaryl substituted analog of thiophene, in the formalin induced rat paw edema chronic model as compared to a weak activity in acute carrageenin induced rat paw edema, and the slightly better protection exhibited in the acute model by AP82 (27%), the 5-aroyl analog provided an impetus for a proper exploration of their structural types. In this paper we report the synthesis and pharmacological evaluation of some novel, 2-(4-morpholino)-3-(substituted aryl)-5-substituted thiophenes, as possible anti-inflammatory leads. The 3-(4-chlorophenyl)-2-(4-morpholino) thiophene analogs AP49, AP158, and AP88 provided a protection of 20%, 23%, and 20%, respectively, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, comparable to that of AP82, at a dose level of 100mg/kg body weight p.o. compared to ibuprofen as standard. The replacement of the 3-(4-chlorophenyl) moiety with the 3-phenyl moiety gave rise to AP50 (30%), AP159 (38%), AP27 (0%), and AP92 (38%), with three analogs being more active in the acute model. Alteration of the group para to the phenyl ring at third position, from chloro, to methyl mercapto gave rise to the 3-(4-methylmercapto-phenyl) analogs AP54 (20%), AP160 (0%), and AP73 (52%), with only one analog appearing to be better than AP82. These results indicate that 4-methane sulfonyl aroyl group at 5-position and other substituents of different quadrants of Craig plot on the phenyl moiety at the third position could lead to more potent candidates. However, alteration of aroyl to substituted pyridyl at 5-position with a phenyl group at the third position as in AP26 gave rise to much better protection (66%) again reinforcing the importance of the heteroaryl ring at the fifth position and implying its utility in the composition of a novel pharmacophore for designing better trisubstituted thiophenes as anti-inflammatory agents.
authors.affiliation: Department of Pharmaceutical Chemistry, M.S. Ramaiah College of Pharmacy, M.S. Ramaiah Nagar, Mathikere, Bangalore 560 054, Karnataka, India.
authors.forename: Ajay D
authors.initials: AD
authors.lastname: Pillai
authors.forename: Parendu D
authors.initials: PD
authors.lastname: Rathod
authors.forename: Franklin P
authors.initials: FP
authors.lastname: Xavier
authors.forename: Kamala K
authors.initials: KK
authors.lastname: Vasu
authors.forename: Harish
authors.initials: H
authors.lastname: Padh
authors.forename: Vasudevan
authors.initials: V
authors.lastname: Sudarsanam
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000627:therapeutic use; D002351:Carrageenan / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D007052:Ibuprofen / Q000494:pharmacology; D009025:Morpholines / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry; D013876:Thiophenes / Q000138:chemical synthesis* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D009025:Morpholines; D011725:Pyridines; D013438:Sulfhydryl Compounds; D013450:Sulfones; D013876:Thiophenes; C005231:methylmercaptan; D002351:Carrageenan; D007052:Ibuprofen