Synthesis,biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide,sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold |
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Authors: | Annalisa Reale Simone Brogi Alessia Chelini Marco Paolino Angela Di Capua Germano Giuliani Andrea Cappelli Gianluca Giorgi Giulia Chemi Alessandro Grillo Massimo Valoti Lidia Sautebin Antonietta Rossi Simona Pace Concettina La Motta Lorenzo Di Cesare Mannelli Elena Lucarini Carla Ghelardini Maurizio Anzini |
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Institution: | 1. Dipartimento di Biotecnologie, Chimica e Farmacia, (Dipartimento d’Eccellenza 2018-2022), Università di Siena, Via A. Moro, I-53100 Siena, Italy;2. Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, I-56126 Pisa, Italy;3. Dipartimento di Scienze della Vita, Università di Siena, Via A. Moro, I-53100 Siena, Italy;4. Dipartimento di Farmacia, (Dipartimento d’Eccellenza 2018-2022), Scuola di Medicina e Chirurgia, Università di Napoli “Federico II”, Via D. Montesano 49, I-80131 Napoli, Italy;5. Dipartimento di Neuroscienze, Area del Farmaco e Salute del Bambino (NEUROFARBA), Università di Firenze, Viale G. Pieraccini 6, I-50139 Firenze, Italy |
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Abstract: | A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10–12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect.Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs. |
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Keywords: | Corresponding author COX-2 inhibitors 1 5-Diarylpyrrole derivatives Anti-inflammatory agents Antinociceptive agents Molecular modeling |
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