Lonazolac analogues: molecular modeling, synthesis, and in vivo anti-inflammatory activity |
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Authors: | Mohamed A H Ismail Jochen Lehmann Dalal A Abou El Ella Amgad Albohy Khaled A M Abouzid |
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Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt 2. Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universit?t Jena, Jena, Germany
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Abstract: | A novel series of 1,3-diarylpyrazole derivatives (4–8), analogues to lonazolac, were designed, synthesized, and evaluated for their anti-inflammatory as well as analgesic activities.
To target preferential cyclooxygenase-2 (COX-2) inhibitors, the design of these compounds was based upon two different molecular
modeling studies. The first study included fit-comparison study of conformational models of compounds 4–8 with a novel validated COX-2 inhibitors hypothesis generated from the corresponding leads I–V using Hip-Hop CATALYST software. The second study included docking study of the designed compounds 4–8 with binding site of COX-1 and COX-2 enzymes using internal coordinate mechanics (ICM)-Pro software. The reported Akaho method
was then used to predict the COX-2 preferentiality of the designed compounds. The designed molecules were synthesized and
screened for in vivo anti-inflammatory and analgesic activity. Compounds 4a, 6a, and 8b showed high activity in comparison with indomethacin, consistent with virtual molecular modeling studies. |
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