01802nas a2200193 4500008004100000022001400041245010800055210006900163260000800232490000700240520109100247100002401338700002401362700002501386700002401411700002101435700002801456856012401484 2018 eng d a2045-232200aEvaluating antimalarial efficacy by tracking glycolysis in Plasmodium falciparum using NMR spectroscopy0 aEvaluating antimalarial efficacy by tracking glycolysis in Plasm cDEC0 v 83 aGlucose is an essential nutrient for Plasmodium falciparum and robust glycolytic activity is indicative of viable parasites. Using NMR spectroscopy, we show that P. falciparum infected erythrocytes consume similar to 20 times more glucose, and trophozoites metabolize similar to 6 times more glucose than ring stage parasites. The glycolytic activity, and hence parasite viability, can be measured within a period of 2 h to 5 h, using this method. This facilitates antimalarial bioactivity screening on ring and trophozoite stage parasites, exclusively. We demonstrate this using potent and mechanistically distinct antimalarial compounds such as chloroquine, atovaquone, cladosporin, DDD107498 and artemisinin. Our findings indicate that ring stage parasites are inherently more tolerant to antimalarial inhibitors, a feature which may facilitate emergence of drug resistance. Thus, there is a need to discover novel antimalarial compounds, which are potent and fast acting against ring stage parasites. The NMR method reported here can facilitate the identification of such molecules.1 aShivapurkar, Rupali1 aHingamire, Tejashri1 aKulkarni, Akshay, S.1 aRajamohanan, P., R.1 aReddy, Srinivasa1 aShanmugam, Dhanasekaran uhttps://library.ncl.res.in/content/evaluating-antimalarial-efficacy-tracking-glycolysis-plasmodium-falciparum-using-nmr02270nas a2200241 4500008004100000245007000041210006900111260000900180300001600189490000700205520148900212100002201701700002301723700002401746700001601770700002001786700002801806700002501834700002301859700002101882700002301903856010201926 2020 eng d00aApproach to nigericin derivatives and their therapeutic potential0 aApproach to nigericin derivatives and their therapeutic potentia cNOV  a43085-430910 v103 a

A new nigericin analogue that has been chemically modified was synthesized through a fluorination process from the parent nigericin, produced from a novel Streptomyces strain DASNCL-29. Fermentation strategies were designed for the optimised production of nigericin molecule and subjected for purification and structural analysis. The fermentation process resulted in the highest yield of nigericin (33% (w/w)). Initially, nigericin produced from the strain DASNCL-29 demonstrated polymorphism in its crystal structure, i.e., monoclinic and orthorhombic crystal lattices when crystallised with methanol and hexane, respectively. Furthermore, nigericin produced has been subjected to chemical modification by fluorination to enhance its efficacy. Two fluorinated analogues revealed that they possess a very potent antibacterial activity against Gram positive and Gram negative bacteria. To date, the nigericin molecule has not been reported for any reaction against Gram-negative bacteria, which are increasingly becoming resistant to antibiotics. For the first time, fluorinated analogues of nigericin have shown promising activity. In vitro cytotoxicity analysis of fluorinated analogues demonstrated tenfold lesser toxicity than the parent nigericin. This is the first type of study where the fluorinated analogues of nigericin showed very encouraging activity against Gram-negative organisms; moreover, they can be used as a candidate for treating many serious infections.

1 aSahu, Amit, Kumar1 aSaid, Madhukar, S.1 aHingamire, Tejashri1 aGaur, Megha1 aKhan, Abujunaid1 aShanmugam, Dhanasekaran1 aBarvkar, Vitthal, T.1 aDharne, Mahesh, S.1 aBharde, Atul, A.1 aDastager, Syed, G. uhttps://library.ncl.res.in/content/approach-nigericin-derivatives-and-their-therapeutic-potential02901nas a2200349 4500008004100000022001400041245017200055210006900227260000800296300001400304490000700318520169700325653002202022653001102044653003402055653000802089653001702097653002502114653002602139653001402165653003002179100002402209700002402233700002702257700001602284700002502300700002002325700001902345700002802364700002902392856013002421 2020 eng d a0066-480400aWhole-cell phenotypic screening of medicines for malaria venture pathogen box identifies specific inhibitors of plasmodium falciparum late-stage development and egress0 aWholecell phenotypic screening of medicines for malaria venture  cMAY ae01802-190 v643 a

We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC50] <= 10 mu M), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC50 of <= 1 mu M, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizontring transition (with >= 50% parasites failing to proceed to the next stage) at 1 mu M. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.

10aDNA fragmentation10aegress10aMedicines for Malaria Venture10aMMV10aPathogen Box10aphenotypic screening10aPlasmodium falciparum10aschizonts10astage-specific inhibition1 aPatra, Alok, Tanala1 aHingamire, Tejashri1 aBelekar, Meenakshi, A.1 aXiong, Aoli1 aSubramanian, Gowtham1 aBozdech, Zbynek1 aPreiser, Peter1 aShanmugam, Dhanasekaran1 aChandramohanadas, Rajesh uhttps://library.ncl.res.in/content/whole-cell-phenotypic-screening-medicines-malaria-venture-pathogen-box-identifies-specific03191nas a2200313 4500008004100000022001400041245011700055210006900172260000800241300001200249490000700261520213700268653002902405653002602434653001202460653002602472653001802498100002302516700002502539700002802564700002402592700002802616700002202644700002402666700001902690700001802709700002202727856012802749 2023 eng d a1230-282100aAntimalarial activity of anacardium occidentale leaf extracts against plasmodium falciparum transketolase (PfTK)0 aAntimalarial activity of anacardium occidentale leaf extracts ag cDEC a832-8410 v683 a

BackgroundAs per estimates by WHO in 2021 almost half of the world's population was at risk of malaria and > 0.6 million deaths were attributed to malaria. Therefore, the present study was aimed to explore the antimalarial activity of extracts derived from the leaves of the plant Anacardium occidentale L., which has been used traditionally for the treatment of malaria. Different extracts of A.occidentale leaves were prepared and tested for their inhibitory activity against recombinant P. falciparum transketolase (rPfTK) enzyme, in vitro. Further, growth inhibitory activity against cultivated blood stage P. falciparum parasites (3D7 strain), was studied using SYBR Green fluorescence-based in vitro assays. Acute toxicity of the hydro alcoholic extracts of leaves of A. occidentale (HELA) at different concentrations was evaluated on mice and Zebra fish embryos. HELA showed 75.45 +/- 0.35% inhibitory activity against the recombinant PfTk and 99.31 +/- 0.08% growth inhibition against intra-erythrocytic stages of P. falciparum at the maximum concentration (50 mu g/ml) with IC50 of 4.17 +/- 0.22 mu g/ml. The toxicity test results showed that the heartbeat, somite formation, tail detachment and hatching of embryos were not affected when Zebra fish embryos were treated with 0.1 to 10 mu g/ml of the extract. However, at higher concentrations of the extract, at 48 h (1000 mu g/ml) and 96 h (100 mu g/ml and 1000 mu g/ml, respectively) there was no heartbeat in the fish embryos. In the acute oral toxicity tests performed on mice, the extract showed no toxicity up to 300 mg/kg body weight in mice.ConclusionThe hydro-alcoholic extract of leaves of A. occidentale L. showed potent antimalarial activity against blood stage P. falciparum. Based on the observed inhibitory activity on the transketolase enzyme of P. falciparum it is likely that this enzyme is the target for the development of bioactive molecules present in the plant extracts. The promising anti-malarial activity of purified compounds from leaves of A. occidentale needs to be further explored for development of new anti-malarial therapy.

10aAnacardium occidentale L10aAntimalarial activity10amalaria10aPlasmodium falciparum10aTransketolase1 aKaushik, Meenakshi1 aHoti, Sugeerappa, L.1 aSaxena, Jitendra, Kumar1 aHingamire, Tejashri1 aShanmugam, Dhanasekaran1 aJoshi, Rajesh, K.1 aMetgud, Sharada, C.1 aUngar, Banappa1 aSingh, Ishwar1 aHegde, Harsha, V. uhttps://library.ncl.res.in/content/antimalarial-activity-anacardium-occidentale-leaf-extracts-against-plasmodium-falciparum01960nas a2200301 4500008004100000022001400041245004800055210004700103260000900150490000700159520111600166653001601282653001601298653002201314653001201336653001501348653001501363653000601378100002401384700002401408700001701432700002601449700002601475700001801501700002801519700002801547856008301575 2023 eng d a1860-717900aHistidinal-based potent antimalarial agents0 aHistidinalbased potent antimalarial agents cMAY 0 v183 a

Herein we report the synthesis and evaluation of peptide-histidinal conjugated drug scaffolds, which have the potential to target the hemoglobin-degrading proteases falcipain-2/3 from the human malaria parasite. Scaffolds with various substitutions were tested for antimalarial activity, and compounds 8 g, 8 h, and 15 exhibited EC50 values of similar to 0.018 mu M, similar to 0.069 mu M, and similar to 0.02 mu M, respectively. Structure-based docking studies on falcipain-2/3 proteases (PDB:2GHU and PDB:3BWK) revealed that compounds 8 g, 8 h, and 15 interact strongly with binding sites of falcipain-2/3 in a substrate-like manner. In silico ADME studies revealed that the molecules of interest showed no or minimal violations of drug-likeness parameters. Further, phenotypic assays revealed that compound 8 g and its biotinylated version inhibit hemoglobin degradation in the parasite food vacuole. The identification of falcipain-2/3 targeting potent inhibitors of the malaria parasite can serve as a starting point for the development of lead compounds as future antimalarial drug candidates.

10aartemisinin10achloroquine10adigestive vacuole10adocking10afalcipains10afalciparum10aP1 aMeena, Chhuttan, L.1 aHingamire, Tejashri1 aGupta, Tanya1 aDeshmukh, Bhagyashree1 aKarmodiya, Krishanpal1 aJoshi, Rakesh1 aShanmugam, Dhanasekaran1 aSanjayan, Gangadhar, J. uhttps://library.ncl.res.in/content/histidinal-based-potent-antimalarial-agents