New Pyrolle and Pyrazole based compounds active as anti-inflammatory and antimalarial drugs

This thesis addresses the urgent requirement for novel anti-inflammatory drugs and antimalarial interventions: The beneficial effects of carbon monoxide (CO) gained much interest in research and offer new potential treatments of vascular- and inflammatory-related diseases. However, the medical application of this gas has been hampered by the complexity of the administration route. This problem has been overcome with the discovery of CO-releasing molecules (CORMs), which are an effective tool to deliver CO safely and precisely to the target locations. Particularly, metal-based CORMs are emerging for their striking anti- inflammatory properties that are amplified by the transition metal and are being progressively improved in view of novel future applications. We developed novel dual-active metal-based CORMs with the potential to be used as therapeutic agents in tendon-derived diseases. Specifically, we designed and synthesized dicobalt(0)hexacarbonyl (DCH)-CORMs containing structural fragments of COX-2 selective inhibitors and tested them for the CO release kinetic (myoglobin release assay) and anti- inflammatory/cytoprotective effects on hydrogen peroxide-stimulated human primary- derived tenocytes by taking in account the PGE2 secretion as a readout. Malaria drug research and development efforts have recently resurged in the last decade following deceleration rate of mortality and malaria cases in endemic regions. Inefficiency of malaria interventions are largely driven by the spreading resistance of the Plasmodium falciparum parasite to the current drug regimens and from the malaria vector – mosquito Anopheles – to insecticides. In response to the new eradication agenda, the development of drugs that act by breaking the malaria transmission cycle (transmission-blocking drugs) has been recognized as an important and additional target for intervention. These drugs take advantage of the susceptibility of Plasmodium population bottlenecks before transmission (gametocytes) and in the mosquito vector (gametes, zygotes, ookinetes, oocysts, 3 sporozoites). In this context, we sought to address the urgent requirement for novel antimalarial interventions by developing and aiding future discovery of transmission- blocking drugs. We designed and synthesized analogues of the pyrazole MMV1580843, recently discovered in a high-throughput screening as a potent and selective gametocytocidal compound. SAR studies of these compounds hold promise for improved chemical modifications to progress to a hit-to-lead campaign. Particularly, we found that the pyrazole core allows a variety of substitutions that maintain potent activity towards late-stage gametocytes along with favorable physicochemical and safety profiles. In parallel, from a phenotypic screening of compounds belonging to an in-house library, we discovered new pyrazole- and pyrrole-based compounds endowed with selective activity towards ring and trophozoite stages in the P. falciparum asexual cycle and potential activity against sporogonic stages in mosquitoes. The transmission-blocking potential was assessed by performing topical exposure assays on females Anopheles Gambiae mosquitoes of selected hits and found compound 19 and 12 to significantly decrease the parasite development in the mosquito midgut.