SYNTHESIS OF 4,5,6,7-TETRAHYDROBENZO[b]THIOPHENES AS NOVEL ANTI-INFLAMMATORY AGENTS

Abstract

Inflammation involves a complex molecular pathway and plays a pivotal role in the etiology of complications arise from many diseases. Yet, the discovery of effective anti-inflammatory drugs is still an unmet need and poses a challenge to medicinal chemists. The advancement in understanding the inflammatory pathways lead to the identification of novel druggable targets, one of which is the activation of nuclear factor (erythroid-derived 2)-like 2 (nrf2) pathway. The prototype compound reported to activate nrf2 pathway is sulforaphane, a constituent of broccoli. However, sulforaphane causes side effects attributed to the flexibility of the molecule. The main objectives of this work are to synthesise tetrahydrobenzo[b]thiophenes (THBTs) which are analogous to sulforaphane and to investigate their anti-inflammatory mechanisms. Eighteen (18) THBTs of purity ≥ 90% were synthesised in good yields. The compounds were tested for their anti-inflammatory activity and molecular mechanisms using LPSEc induced inflammation in RAW 264.7 cells. The compounds showed significant anti-inflammatory activity through the down-regulation of pro-inflammatory cytokines (IL-1, IL-6 and TNF-) and inflammatory mediators (PGE2, COX-2 and NF-B); inhibition of PI3K (, ,  and  isoforms); activation of nrf2 and up-regulation of HO-1 levels. It is postulated that anti-inflammatory activity of THBTs is mediated through PI3K/ Nrf2/HO-1/NF-B pathway. To gain insights on the molecular interactions of THBTs with proteins (PI3K, nrf2-keap1 complex, NF-B and COX-2), molecular docking studies were performed. The results are congruent with the activities. ADMET properties of the compounds were predicted in-silico and were found to be within the range of those reported for 95% of the drugs.