Synthesis, characterization, and in vivo pharmacological evaluation of novel mannich bases derived from 1,2,4-triazole containing a naproxen moiety


AVCI A., Taşci H., KANDEMİR Ü., CAN Ö. D., Gökhan-Kelekçi N., Tozkoparan B.

Bioorganic Chemistry, vol.100, 2020 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 100
  • Publication Date: 2020
  • Doi Number: 10.1016/j.bioorg.2020.103892
  • Journal Name: Bioorganic Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Keywords: 1,2,4-Triazole-5-thione N-Mannich derivatives, Anti-inflammatory activity, Antinociceptive activity, Gastric toxicity, Mannich reaction, Naproxen analogs
  • Bilecik Şeyh Edebali University Affiliated: No

Abstract

A new series of 1,2,4-triazole-5-thione Mannich derivatives containing a naproxen moiety (1a-o) was designed and synthesized to create naproxen analogs, with the aim of developing novel anti-inflammatory/analgesic agents with improved safety profiles. Target compounds were synthesized using classical Mannich reaction (i.e. one-pot three component condensation reaction), by reacting triazole molecule (1), formaldehyde, and diverse secondary amines in ethanol. The synthesized compounds were investigated using FT-IR, 1H NMR, 13C NMR and mass spectroscopies, as well as elemental analysis. Compounds were then evaluated for their potential antinociceptive and anti-inflammatory activities using some validated in vivo methods. Data obtained from acetic acid induced-writhing and carrageenan-induced paw edema tests revealed that all compounds induced peripherally-mediated antinociceptive activities, as well as notable anti-inflammatory effects. The results of hot-plate and tail-clip tests indicated that compounds 1a, 1b, 1c, 1d, 1g, and 1j have also centrally-mediated antinociceptive activities in addition to their peripherally-mediated effects. Molecular docking studies were performed to investigate the putative binding modes of the interactions between all compounds and COX-1/COX-2 enzymes using AutoDock Vina software. Docking of the compounds into the COX-2 active site produced binding interactions that are essential for COX-2 inhibitory activity. None of the compounds in the serial, except for 1m and 1j, induced significant gastrointestinal irritation. Overall, the results indicated that triazol Mannich bases bearing a naproxen moiety potentially represent a novel class of antinociceptive and anti-inflammatory agent with an improved gastric safety profile.