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Structure-Activity relationship of 5‑butyl‑4,6-dimethyl-2-{[4-(o-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-pyrrolo[3,4-c]pyrrole-1,3(2H,5H)‑dione: An experimental and theoretical study
Autorzy
Rok wydania
2025
Czasopismo
Journal of Molecular Structure
Numer woluminu
1322
Strony
140027/1-140027/17
DOI
10.1016/j.molstruc.2024.140027
Kolekcja
Język
Angielski
Typ publikacji
Artykuł
Synthesis of 5‑butyl‑4,6-dimethyl-2-{[4-(o-fluorophenyl)-1-piperazinyl]-2-oxoethyl}-pyrrolo[3,4-c]pyrrole-1,3(2H,5H)‑dione 3 is reported. The compound was obtained by direct alkylation of 3,4-pyrrolodicarboximide 1 with (1-chloroacetyl-4-(o-fluorophenyl)piperazine) 2 in DMF. Its physico-chemical features were characterized by 1H NMR, 13C NMR, FT-IR, MS spectra, and elemental analysis. Single-crystal X-ray diffraction was also recorded. A colorimetric inhibitor screening assay was used to determine its inhibitory potency towards COX-1 and COX-2. It was found that the compound exhibits anti-inflammatory activity higher than the reference structure – Meloxicam (MXM). According to the experimental results, the tested compound inhibited the activity of COX-1 and COX-2 respectively. In the next step, molecular docking was performed to estimate the binding affinity of compound 3 and commercially available reference compounds for COX-1/COX-2 enzymes. It was found that the binding affinity of 3 is higher than for the reference compounds. Quantum Theory of Atoms In Molecules (QTAIM) and Reduced Density Gradient (RDG) methods were used to reveal non-covalent interactions present in the COX-1/COX-2 binding pocket. Finally, Born-Oppenheimer molecular dynamics (BOMD) based on semiempirical forces was carried out to gain insight into the dynamic features of the studied complexes and confirmed the fact that the weak hydrogen bonds play the most important role in stabilizing the ligand conformation for the studied COX-2 complexes with compound 3 and Rofecoxib.
Słowa kluczowe
Anti-inflammatory activity, COX-1/COX-2 activity, Cyclic imides, Pyrrolopyrroles, Non-covalent interactions, Molecular docking, DFT, QTAIM, RDG, BOMD
Adres publiczny
http://dx.doi.org/10.1016/j.molstruc.2024.140027
Strona internetowa wydawcy
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