Rational design in the creation of potential NSAIDs – COX and 5-LOX inhibitors

Abstract

The aim of the study was to analyse current literature data on the development of new anti-inflammatory drugs with different selectivity to cyclooxygenase and lipoxygenase isoforms, to demonstrate Drug Design possibilities in their search. The article presents an overview of literature sources on the search for potential targeted biologically active substances based on a target-oriented mono-, di- and multi-target approach. The results are presented regarding selective inhibitors of cyclooxygenase and lipoxygenase isoforms (direct effect – lipoxygenase inhibitors and indirect effect through binding to activating protein, FLAP), dual inhibitors of COX/LOX and COX/LOX/TNF-α, COX/LOX/mPGES. The search for new inhibitors of cyclooxygenase and lipoxygenase isoforms is carried out among biologically active substances of various heterocyclic systems by modifying the structure of known drugs – ketoprofen, rofecoxib, celecoxib, ibuprofen, nimesulide, diclofenac, etc. Approaches to the determination of the selectivity of COX isoenzymes, depending on chemical characteristics of various NSAIDs, are indicated. Currently, a small number of selective COX-1 inhibitors have been developed; in particular, selective COX-1 inhibitors have been found among quinazoline derivatives. The discovery of selective COX-1 inhibitors may start a new direction in the development of anti-inflammatory agents capable of modulating response to chemotherapy and modifying drug resistance. Of primary importance is the discovery of effective molecules with an improved safety profile. Potential lipoxygenase inhibitors are being sought to reduce gastrointestinal toxicity. A directed search for potential LOX inhibitors was carried out among new pyrrolo[1,2-a][1,2,4]triazolo(triazino-)-[c]quinazolines, their compliance with the drug-like criteria was determined, molecular docking and in vitro screening were performed. Structural analogues of ketoprofen and rofecoxib have been studied as potential LOX-5 inhibitors. The importance of a target-oriented approach based on a combination of modern in silico studies with classical rational design, synthesis, and pharmacological screening is noted.