03604nas a2200385 4500008004100000022001400041245019700055210006900252260006700321300001200388490000700400520219800407653001002605653001202615653002402627653000902651653002102660653000802681653004902689653002602738653004602764653000902810653002702819653002202846100002302868700002302891700003402914700002502948700002002973700002202993700002403015700002603039700002403065856012903089 2013 eng d a1747-027700aDesign, synthesis, structural characterization by IR, 1H, 13C, 15N, 2D-NMR, X-ray diffraction and evaluation of a new class of phenylaminoacetic acid benzylidene hydrazines as pfENR inhibitors0 aDesign synthesis structural characterization by IR 1H 13C 15N 2D a111 RIVER ST, HOBOKEN 07030-5774, NJ USAbWILEY-BLACKWELLcJUN a715-7290 v813 a

Recent studies have revealed that plasmodial enoyl-ACP reductase (pfENR, FabI), one of the crucial enzymes in the plasmodial type II fatty acid synthesis II (FAS II) pathway, is a promising target for liver stage malaria infections. Hence, pfENR inhibitors have the potential to be used as causal malarial prophylactic agents. In this study, we report the design, synthesis, structural characterization and evaluation of a new class of pfENR inhibitors. The search for inhibitors began with a virtual screen of the iResearch database by molecular docking. Hits obtained from the virtual screen were ranked according to their Glide score. One hit was selected as a lead and modified to improve its binding to pfENR; from this, a series of phenylamino acetic acid benzylidene hydrazides were designed and synthesized. These molecules were thoroughly characterized by IR, 1H, 13C, 15N, 2D-NMR (COSY, NOESY, 1H-13C, 1H-15N HSQC and HMBC), and X-ray diffraction. NMR studies revealed the existence of conformational/configurational isomers around the amide and imine functionalities. The major species in DMSO solution is the E, E form, which is in dynamic equilibrium with the Z, E isomer. In the solid state, the molecule has a completely extended conformation and forms helical structures that are stabilized by strong hydrogen bond interactions, forming a helical structure stabilized by N-H...O interactions, a feature unique to this class of compounds. Furthermore, detailed investigation of the NMR spectra indicated the presence of a minor impurity in most compounds. The structure of this impurity was deduced as an imidazoline-4-one derivative based on 1H-13C and 1H-15H HMBC spectra and was confirmed from the NOESY spectra. The molecules were screened for in vitro activity against recombinant pfENR enzyme by a spectrophotometric assay. Four molecules, viz. 17, 7, 10, and 12 were found to be active at 7, 8, 10, and 12m concentration, respectively, showing promising pfENR inhibitory potential. A classification model was derived based on a binary QSAR approach termed recursive partitioning (RP) to highlight structural characteristics that could be tuned to improve activity.

10aADMET10adocking10aenoyl-ACP reductase10aFabI10ahydrogen bonding10aNMR10aphenylaminoacetic acid benzylidene hydrazine10aPlasmodium falciparum10aPlasmodium falciparum enoyl-ACP reductase10aQSAR10arecursive partitioning10aX-ray diffraction1 aSamal, Ramanuj, P.1 aKhedkar, Vijay, M.1 aPissurlenkar, Raghuvir, R. S.1 aBwalya, Angela, Gono1 aTasdemir, Deniz1 aJoshi, Ramesh, A.1 aRajamohanan, P., R.1 aPuranik, Vedavati, G.1 aCoutinho, Evans, C. uhttps://library.ncl.res.in/content/design-synthesis-structural-characterization-ir-1h-13c-15n-2d-nmr-x-ray-diffraction-and-002207nas a2200229 4500008004100000022001400041245020100055210006900256260005700325300001400382490000800396520130300404653001201707653002001719653002601739653001301765100001901778700001901797700001701816700001901833856012501852 2014 eng d a0932-011300aAntiplasmodial activity-aided isolation and identification of quercetin-4 `-methyl ether in chromolaena odorata leaf fraction with high activity against chloroquine-resistant plasmodium falciparum0 aAntiplasmodial activityaided isolation and identification of que a233 SPRING ST, NEW YORK, NY 10013 USAbSPRINGERcDEC a4415-44220 v1133 a

The present study was undertaken to evaluate the antiplasmodial activity of Chromolaena odorata leaf extract and gradient fractions through in vivo and in vitro tests, aimed at identifying its antiplasmodial constituents. Sub-fractions obtained from the most active gradient fraction were further tested for cytotoxicity against THP-1 cells, chloroquine-sensitive (HB3) and chloroquine-resistant (FCM29) Plasmodium falciparum. Our results showed the dichloromethane gradient fraction was most effective, significantly (P<0.05) suppressing infection by 99.46 % at 100 mg/kg body weight. Amongst its 13 sub-fractions (DF1-DF13), DF11 was highly active, with IC50 of 4.8 and 6.74 mu g/ml against P. falciparum HB3 and FCM29, respectively. Cytotoxicity of DF11 was estimated to be above 50 mu g/ml, and its separation by column chromatography yielded a flavonoid which was characterized as 3, 5, 7, 3' tetrahydroxy-4'-methoxyflavone from its spectroscopic data. It significantly suppressed infection (65.43-81.48 %) in mice at 2.5-5 mg/kg doses and compared favourably with the effects of chloroquine and artemisinin. It may therefore serve as a useful phytochemical and antiplasmodial activity marker of C. odorata leaves, which exhibit potential for development as medicine against malaria.

10amalaria10aMedicinal plant10aPlasmodium falciparum10aToxicity1 aEzenyi, I., C.1 aSalawu, O., A.1 aKulkarni, R.1 aEmeje, Martins uhttps://library.ncl.res.in/content/antiplasmodial-activity-aided-isolation-and-identification-quercetin-4-methyl-ether-002659nas a2200277 4500008004100000022001400041245011000055210006900165260011100234300001200345490000700357520164400364653000902008653001202017653002202029653003602051653002602087653002202113653000902135100002202144700001902166700002902185700002202214700002502236856012002261 2016 eng d a1386-207300aVirtual screening techniques to probe the antimalarial activity of some traditionally used phytochemicals0 aVirtual screening techniques to probe the antimalarial activity  aEXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATESbBENTHAM SCIENCE PUBL LTDcJUL a572-5910 v193 a

Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the `rule of five' criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by `Ligplot' analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.

10aADME10amalaria10aMolecular docking10amolecular operating environment10aPlasmodium falciparum10avirtual screening10aweka1 aShibi, Indira, G.1 aAswathy, Lilly1 aJisha, Radhakrishnan, S.1 aMasand, Vijay, H.1 aGajbhiye, Jayant, M. uhttps://library.ncl.res.in/content/virtual-screening-techniques-probe-antimalarial-activity-some-traditionally-used02901nas 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-falciparum