Browsing by Subject "membrane-bound pyrophosphatase"
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(2024)New drugs against malaria are required, as millions of people are still affected yearly by this deadly disease. The development of drug resistance to current antimalarials is an ongoing process. Membrane-bound pyrophosphatases (mPPases) are potential new drug targets against malaria and other protozoan diseases. mPPases play a crucial role in the survival of the malaria parasite, they couple the energy released from the hydrolysis of pyrophosphate into the transport of protons or ions against an electrochemical gradient. The aim of this study was to identify potential mPPase inhibitors through a docking-based virtual screen of the Tres Cantos Antimalarial Compound Set, which consists of over 13500 malaria-active compounds. The virtual screen against a Thermotoga maritima mPPase protein structure identified a 2,4-diamino-1,6-dihydrotriazine among the top-ranking scaffolds. Four compounds found among the docking results containing this scaffold were synthesised: three with a halophenyl substituent, and one with a hydroxyl substituent. The compounds in their hydrochloride salt forms were synthesised using a three-component method for the synthesis of 2,4-diamino-1,6-dihydrotriazines. The compounds were also freed from the hydrochloride salts into their corresponding molecular forms. The structural characterisation of the compounds, especially the molecular forms, presented challenges. The docking results were also searched to identify compounds containing previously identified mPPase-active substructures. From the docking results, several other interesting compounds were identified in addition to the synthesised compounds. The knowledge and results obtained from this study can be used as openings for potential future docking and synthesis projects in the development of mPPase inhibitors. The activity of the compounds synthesised in the project remains to be evaluated in subsequent investigations.
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(2016)Membrane-bound pyrophosphatases (mPPases) are a potential target for drugs against many neglected protozoan diseases, such as malaria, leishmaniasis, toxoplasmosis and trypanosomiasis. New drugs against these diseases are urgently needed, as the clinically used ones are either not effective, suffer from side effects, or resistance against them is developing. The mPPases of these protozoans are genetically conserved, while mammalian DNA does not encode them. A drug development project to find mPPase inhibitors was started, based on mPPase structures solved through X-Ray crystallography. Four hit compounds were identified. The aim of this study was to investigate the binding of these hit compounds at the mPPase binding site, and based on these results, to develop and synthesize novel compounds with higher affinity. A hit compound with an isoxazole ring was chosen as the model compound to be developed further. These novel compounds were evaluated by docking them into the binding site. Eight compounds were chosen to be synthesized and four to be purchased. The Suzuki-Miyaura cross-coupling reaction was used to couple the isoxazole core to different aromatic substituents, producing 3,5-disubstituted isoxazoles. The reactions mostly succeeded, but the yields were uniformly low. Developing the reaction using different solvents and reaction conditions did not produce clear results. Thirteen compounds were tested for activity, including an intermediate product of the synthesis. Two of the compounds showed increased inhibition activity compared to the hit compound, with approximated IC50 values of 10 and 40 μM, respectively. The knowledge gained from these studies can be used to further develop more efficient inhibitors.
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