Natural Products in Drug Discovery: Approaches and Development

Historically, natural products (NP’s) have played a significant role in drug discovery, not only in cancer and infectious diseases, but also in other therapeutic areas including cardiovascular diseases and multiple sclerosis. Profit and loss, Partnerships and averages, natural products also present certain challenges for drug discovery, such as technical obstacles to screening, isolation, characterization and optimization, which added to decline in their search by the pharmaceutical industry from the 1990s onwards. In recent days the applications of molecular biological techniques have increased the availability of novel compounds that can be conveniently produced in bacteria or yeast or plant sources. In addition to this, combinational chemistry approaches are being based on natural product scaffolds to create screening libraries that closely resemble drug-like compounds. Employing these technologies gives us a chance to execute research in screening new molecules by means of a software and data base to ascertain natural products as a major source for drug discovery. It lastly directs to lead structure discovery. This review discusses plant based natural product drug discovery and how innovative technologies play a role in next generation drug discovery and highlights from the published literature on plants as sources of antiinflammatory agents. GRAPHICAL ABSTRACT

Plants and Plant Constituents with Analgesic and Anti-inflammatory Activities: A Systematic Review

Medicinal plants with potential therapeutic activities are a tremendous resources of prospective drug candidates. NSAIDs, opiates, and other anti-inflammatory & analgesic agents exhibit several unwanted side-effects. Thus, the development of new active compounds with minimum adverse effects necessitates an emergence. This study aims to provide a comprehensive summary of plant species and reported phytoconstituents with analgesic and inti-inflammatory activities. Eighty-seven species from fifty-two plant families with reported constituents and activities have been included in this review. In-depth research in the area of screening novel analgesic and antiinflammatory agents from natural sources followed by the investigation of their pharmacological properties and clinical applications may lead to the generation of new active agents with better therapeutic activity and selectivity in the future. Dhaka Univ. J. Pharm. Sci. 19(2): 207-224, 2020 (December)

Substituted 3-R-2,8-Dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino-[2,3-c]quinazoline-5a(6H)carboxylic Acids and Their Salts – a Promising Class of Anti-inflammatory Agents

Background: Computer aided drug design is among the most effective methods of medicinal chemistry. Abovementioned approaches were used for purposeful search of antiinflammatory agents among quinazoline condensed derivatives. Objective: Purposeful synthesis of novel 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)carboxylic acids and their salts as promising antiinflammatory agents, evaluation of their structure by physicochemical methods and establishing of their anti-inflammatory activity. Methods: The structures of target compounds were proposed due to their structure similarity to existing drugs and experimental agents with anti-inflammatory activity. The features of the synthesized compounds structures were evaluated by IR-, NMR spectroscopy and chromatographymass spectrometry and were discussed in detail. Probable molecular mechanisms of activity were predicted by molecular docking. The anti-inflammatory activity was determined by their ability to reduce the formalin- and carrageenan-induced paw edema in rats. Results: It was found, that condensation of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)ones with 2- oxoglutaric acid yielded 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3- c]quinazoline-5a(6H)carboxylic acids which may be considered as a promising anti-inflammatory agents. In silico study showed, that obtained compounds revealed affinity to the molecular targets and corresponded to the «drug-like» criteria. Additionally docking study allowed to estimate the nature of interactions between synthesized compounds and molecular targets. The in vivo experiments showed that obtained compounds demonstrated the significant anti-inflammatory activity comparable or higher than activity of the reference drug «Diclofenac». Conclusion: The developed and implemented search strategy of the anti-inflammatory agents was justified. 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline5a(6H)carboxylic acids possessed the mentioned activity and additional introduction of fluorine atoms in position 11 or 12 of the heterocyclic system led to amplification of anti-inflammatory activity.

Prediction of the Antiinflammatory Activity of New S-alkyl Derivatives of 1,2,4-triazol-3-thiones Using the PASS Computer Program and Molecular Docking

The strategy of rational approaches to the search for selective COX-2 inhibitors as potential antiinflammatory agents has been proposed and elaborated. It is based on the use of PASS-prediction and molecular docking. The choice of the basic structure of 4-amino-3-thio-1,2,4-triazole as a promising object of chemical modification has been substantiated. Using a modification of the primary molecule, a virtual library of S-derivatives of 5-substituted 4-amino(pyrrol)3-thio-4H-1,2,4-triazoles in the amount of 100 compounds (ten groups) has been obtained by introducing various pharmacophore fragments. Based on the analysis of the results of the PASS-prediction and molecular docking, six of the ten planned groups of compounds have been selected for the synthesis as promising selective COX-2 inhibitors. The reliability of the prediction results has already been confirmed for one of the promising group 4-amino-5-(pyridine-4-yl)-1,2,4-triazole (4?)-3-yl-thioacetamides.