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

Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold / Reale A, Brogi S, Chelini A, Paolino M1, Di Capua A, Giuliani G, Cappelli A, Giorgi G, Chemi G, Grillo A, Valoti M, Sautebin L, Rossi A, Pace S, La Motta C, Di Cesare Mannelli L, Lucarini E, Ghelardini C, Anzini M. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - ELETTRONICO. - (2019), pp. 0-0. [10.1016/j.bmc.2019.115045]

Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold

Pace S;Di Cesare Mannelli L;Lucarini E;Ghelardini C;
2019

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
2019
0
0
Reale A, Brogi S, Chelini A, Paolino M1, Di Capua A, Giuliani G, Cappelli A, Giorgi G, Chemi G, Grillo A, Valoti M, Sautebin L, Rossi A, Pace S, La Mo...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1176521
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