title: Synthesis, COX-1/2 inhibition activities and molecular docking study of isothiazolopyridine derivatives.
abstract: One of the main challenges for nowadays medicine is drugs selectivity. In COX-1 and COX-2, the active sites are composed of the same group of amino acids with the exception of the only one residue in position 523, in COX-1 is an isoleucine, while in COX-2 is a valine. Here, we presented a series of isothiazolopyridine/benzisothiazole derivatives substituted differently into an isothiazole ring, which were synthesized and investigated for their potencies to inhibit COX-1 and COX-2 enzymes by colorimetric inhibitor screening assay. All the tested compounds inhibited the activity of COX-1, the effect on COX-2 activity was differential. The mode of binding was characterized by a molecular docking study. Comparing biological activity of the investigated compounds, it was observed that compounds sharing the most similar position to flurbiprofen and meloxicam, representing the two main enzyme subdomains, achieved higher biological activity than others. It is directly related to the fit to the enzyme's active site, which prevents too early dissociation of the compounds.
authors.affiliation: Department of Chemistry of Drugs, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland. Electronic address: piotr.swiatek@umed.wroc.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Świątek
authors.affiliation: Department of Chemistry of Drugs, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Strzelecka
authors.affiliation: Department of Medicine, Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Addenbrooke's Hospital, Hills Rd, CB2 0SP Cambridge, UK.
authors.forename: Rafal
authors.initials: R
authors.lastname: Urniaz
authors.affiliation: Department of Basic Medical Science, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gębczak
authors.affiliation: Department of Basic Medical Science, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gębarowski
authors.affiliation: Department of Basic Medical Science, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Gąsiorowski
authors.affiliation: Department of Chemistry of Drugs, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Malinka
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D005480:Flurbiprofen / Q000737:chemistry; D000077239:Meloxicam; D051379:Mice; D062105:Molecular Docking Simulation; D010894:Piroxicam / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D016861:Cyclooxygenase Inhibitors; D011725:Pyridines; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; D005480:Flurbiprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000077239:Meloxicam
keywords: Cyclooxygenase inhibition; Isothiazolopyridine; Molecular docking