Rational Design and Synthesis of Biologically Active Disubstituted 2(3H) Furanones and Pyrrolone Derivatives as Potent and Safer Non Steroidal Anti-inflammatory Agents.
BACKGROUND
Furanone and pyrrolone heterocyclic ring system represent important and interesting classes of bioactive compounds. Medicinal chemists use these heterocycyclic moieties as scaffolds in drug design and discovery.


METHODS
A series of 3-arylidene-5-(naphthalene-2-yl)-furan-2(3H)-ones (2a-j) were synthesized by incorporating pharmacophore of COX-2 inhibitor rofecoxib and naphthyl ring of naproxen as potential non steroidal anti-inflammatory agents. These furanone derivatives were subsequently reacted with dry ammonia gas and benzylamine to furnish corresponding 3-arylidene-5-(naphthlen-2-yl)-1H-pyrrol-2(3H)-ones (3a-e) and 3-arylidene-1-benzyl-5- (naphthalene-2-yl)-1H-pyrrol-2(3H)-ones (4a-e), respectively. The newly prepared heterocyclics were screened for their expected in-vivo biological activities including anti-inflammatory, analgesic and ulcerogenic actions in rodents. The COX-2 inhibitory behavior of synthesized compounds was also assessed via automated docking studies.


RESULTS
The chemical structure of the synthesized compounds was characterized by using modern spectroscopic techniques. Result of in-vivo pharmacological studies demonstrated that almost all N-Benzyl-pyrrol-2(3H)-ones (4a-e) showed better anti-inflammatory and analgesic activities in comparison with the other two series of furan-2(3H)-ones and pyrrol- 2(3H)-ones. The moldock score value of the tested compounds was found in the range of -116.66 to -170.328 and was better than the standard drug.


CONCLUSIONS
Among all the synthesized compounds, only nine compounds (2d, 2g, 2h, 3d, 4a, 4b, 4c, 4d and 4e) exhibited potent anti-inflammatory and analgesic activities with significantly reduced gastrointestinal toxicity in various animal models in comparison to standard drug, diclofenac. Therefore, it is recommended to explore the potential of the synthesized compounds as lead candidates for the development of new therapeutic agents.
S L
SL
Khokra
S A
SA
Khan
D
D
Choudhary
S M
SM
Hasan
A
A
Ahmad
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, 110062, India.
Asif
A
Husain
D019342:Acetic Acid; D000700:Analgesics / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D005663:Furans / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D011758:Pyrroles / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D005663:Furans; D011758:Pyrroles; D002351:Carrageenan; D019342:Acetic Acid