| The pathogenesis of many diseases, such as rheumatoid arthritis, inflammatory bowel disease and some cancers is based on chronic inflammation. Although biologic agents are clinically successful, costly, do not have favourable oral bioavailability, they are immunogenic, and thus there is a demand to develop novel small-molecule inhibitors capable of selectively regulating key inflammatory pathways. This preclinical trial assessed a collection of newly made small-molecule compounds in order to target the centrally acting signalling mediators (such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. In vitro screening was done on the macrophage and fibroblast cell lines in presence of pro-inflammatory cytokines (TNF- 2 and IL- 1) stimulant. Lead compounds were shown to have high NF- Kingdom-B nuclear translocation and downstream cytokine production inhibition with half-maximal inhibitory concentration (IC₫) values of between 0.15 and 1.2 1-mM. Follow-up in vivo experiments in murine models of acute and chronic inflammation have shown that there are substantial decreases in serum inflammatory cytokines (C-reactive protein, IL-6, TNF-alpha) and amelioration of the pathology of the affected tissues in comparison with untreated controls. Pharmacokinetic profiling showed good bioavailability and metabolic stability which makes them be suitable in their development into other drugs. The overall implications of these results are the identification of a new group of small-molecule inhibitors which, with great specificity and efficacy, have the ability to regulate numerous inflammatory pathways. Their preclinical data indicate a possibility of providing alternatives or complement to biologic therapies of chronic inflammatory disorders as orally active. Future research will aim at maximizing of molecular structure, long-term safety and therapy effectiveness in advanced animal models and preclinical trials.