Nonacidic thiophene‐based derivatives as potential analgesic and design, synthesis, biological evaluation, and metabolic stability study

Abstract

Nonsteroidal anti‐inflammatory drugs represent one of the most popularly used classes of drugs. However, their long‐term administration is associated with various side effects including gastrointestinal ulceration. One of the major reasons of NSAIDs ulcerogenicity is direct damage of the epithelial lining cells by the acidic moieties present in many drugs. Another drawback for this acidic group is its rapid metabolism and clearance through Phase II conjugation. Three series of thiophene and thienopyrimidine derivatives were designed and synthesized as nonacidic anti‐inflammatory agents. In vivo testing of their analgesic activity indicated that compounds 2b and 7a‐d showed higher PI values than that of the positive control drugs, indomethacin and celecoxib. The latter compounds 2b and 7a‐d were subjected to further anti‐inflammatory activity testing where they showed comparable percentage edema inhibition to that of indomethacin and celecoxib. Compounds 2b, 7a, 7c, and 7d inhibited PGE2 synthesis by 61.10%–74.54% (71.47% for indomethacin, and 80.11% for celecoxib). The same compounds inhibited the expression of rat mPGES‐1 and cPGES3 by 74%–83% (77% for indomethacin, and 82% for celecoxib) and 48%–70% (62% for indomethacin, and 70% for celecoxib), respectively. The stability of the most active compound 2b in Nonenzymatic gastrointestinal fluids and in human plasma was tested. Additionally, studying the metabolic stability of compound 2b in S9 rat liver fraction showed that it displayed a slow in vitro clearance with half‐life time 1.5‐fold longer than indomethacin. The metabolites of 2b were predicted via UPLC‐MS/MS. In silico ADMET profiling study was also included.

Exploring the potential of thiophene derivatives as dual inhibitors of β-tubulin and Wnt/β-catenin pathways for gastrointestinal cancers in vitro

“…Thiophene, a five-membered ring structure containing a sulfur heteroatom, has been synthesized as a key scaffold in medicinal chemistry due to its diverse documented biological activities, including anticancer, antimicrobial, anti-inflammatory, and analgesic effects [ [41] , [42] , [43] , [44] , [45] ]. Thiophene derivatives, have been reported as anticancer agents via different mechanisms.…”

“…Moreover, traditional Chinese medicines and targeted small molecules have been explored as potential therapeutic options for colorectal cancer by modulating this pathway [ 40 ]. Thiophene derivatives, known for their diverse biological activities, including antibacterial and anti-allergic properties, have also shown promising inhibitory effects against various cancers [ [41] , [42] , [43] , [44] , [45] ]. Based on our prior studies, a series of thiophene derivatives were built and their anti-proliferative efficacy was evaluated.…”