02816nas a2200301   4500008004100000022001400041245014500055210006900200260000800269300001100277490000800288520178700296653001502083653001902098653001802117653001802135653002502153653003402178653003302212100001902245700001902264700001602283700002002299700002402319700002602343700001802369856012702387       2025                        eng d  a0045-206800aNovel pyrazole derivatives as inhibitors of Leishmania donovani: an integrated approach combining in vitro analysis and mechanistic insights0 aNovel pyrazole derivatives as inhibitors of Leishmania donovani   cSEP  a1088040 v1643 a<p>
	Leishmaniasis is a neglected tropical disease that continues to be a global public health problem, leading to a disastrous impact on poor rural people. The present therapeutic arsenal faces the limitations of drug resistance and toxicity concerns, raising a great need to identify novel chemical scaffolds that are potent, non-toxic, and cost-effective. Heterocycles comprise a distinctive class of molecules exhibiting a wide array of physical, chemical, and biological characteristics and occupy a prominent position in pharmaceutical applications. In the present study, we aimed to investigate three series of pyrazole derivatives synthesized previously by our group for their anti-leishmanial potential against Leishmania donovani parasites. Primarily, 29 compounds were evaluated using an Alamar blue dye-based assay for their inhibitory potency, out of which six molecules (4a, 4b, 4c, 4j, 7a, and 7d) were active with &gt;50 % growth inhibition at a 50 mu M dose. Among them, three molecules (4b, 4j, and 7d) showed remarkable leishmanicidal potency with 50 % inhibitory concentration (IC50) in the range of 5 to 13 mu M. Toxicity analysis revealed that the potential hit (4j) represented a promising cytocompatibility profile along with noteworthy activity against L. donovani intracellular amastigotes. Furthermore, the in-depth mechanistic evaluation using scanning electron microscopy, reactive oxygen species (ROS) generation, mitochondrial membrane potential (Delta Psi m) determination, ATP quantification, cell cycle analysis, and lipid accumulation assay confirms the inhibitory potential of compound 4j. Thus, the present study represents pyrazole derivatives as a potential scaffold for the development of novel chemotherapeutics against leishmaniasis.</p>
10aCell death10adrug discovery10aFACS analysis10aleishmaniasis10aPyrazole derivatives10aReactive Oxygen Species (ROS)10ascanning electron microscopy1 aKumari, Diksha1 aKour, Jaspreet1 aKumar, Anuj1 aSangral, Monica1 aSingh, Shashank, K.1 aSawant, Sanghapal, D.1 aSingh, Kuljit  uhttps://library.ncl.res.in/content/novel-pyrazole-derivatives-inhibitors-leishmania-donovani-integrated-approach-combining