title: Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template.
abstract: Compounds incorporating 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. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100 mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic in vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore.
authors.affiliation: Department of Medicinal Chemistry, B.V. Patel Pharmaceutical Education and Research Development Centre, Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India.
authors.forename: Ajay D
authors.initials: AD
authors.lastname: Pillai
authors.forename: Parendu D
authors.initials: PD
authors.lastname: Rathod
authors.forename: Franklin
authors.initials: F
authors.lastname: P X
authors.forename: Manoj
authors.initials: M
authors.lastname: Patel
authors.forename: Manish
authors.initials: M
authors.lastname: Nivsarkar
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; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D005557:Formaldehyde / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D011725:Pyridines; D013876:Thiophenes; D005557:Formaldehyde