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Emilio F Merino - One of the best experts on this subject based on the ideXlab platform.
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biological studies and target engagement of the 2 c methyl d erythritol 4 phosphate cytidylyltransferase ispd targeting antimalarial agent 1r 3s mmv008138 and analogs
ACS Infectious Diseases, 2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Morgan Simpson, Maria L Fernandezmurga, Joshua H Butler, Michael A Casasanta, Priscilla KraiAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS)...
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Biological Studies and Target Engagement of the 2‑C‑Methyl‑d‑Erythritol 4‑Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1R,3S)‑MMV008138 and Analogs
2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Joshua H Butler, Michael A Casasanta, Priscilla Krai, Morgan E. Simpson, Maria L. Fernández-murga, Maxim M. TotrovAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents
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determination of the active stereoisomer of the mep pathway targeting antimalarial agent mmv008138 and initial structure activity studies
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Zhongke Yao, Emilio F Merino, Morgan Simpson, Priscilla Krai, María B Cassera, Carla Slebodnick, Paul R CarlierAbstract:Abstract Compounds that target isoprenoid biosynthesis in Plasmodium falciparum could be a welcome addition to malaria chemotherapy, since the methylerythritol phosphate (MEP) pathway used by the parasite is not present in humans. We previously reported that MMV008138 targets the apicoplast of P. falciparum and that its target in the MEP pathway differs from that of Fosmidomycin. In this Letter, we determine that the active stereoisomer of MMV008138 is 4a , which is (1 R ,3 S )-configured. 2′,4′-Disubstitution of the D ring was also found to be crucial for inhibition of the parasite growth. Limited variation of the C3-carboxylic acid substituent was carried out, and methylamide derivative 8a was found to be more potent than 4a ; other amides, acylhydrazines, and esters were less potent. Finally, lead compounds 4a , 4e , 4f , 4h , 8a , and 8e did not inhibit growth of Escherichia coli , suggesting that protozoan-selective inhibition of the MEP pathway of P. falciparum can be achieved.
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Effect of Fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum
Instituto Oswaldo Cruz Ministério da Saúde, 2007Co-Authors: María B Cassera, Emilio F Merino, Valnice J Peres, Emilia A Kimura, Gerhard Wunderlich, Alejandro M KatzinAbstract:In Plasmodium falciparum, the formation of isopentenyl diphosphate and dimethylallyl diphosphate, central intermediates in the biosynthesis of isoprenoids, occurs via the methylerythritol phosphate (MEP) pathway. Fosmidomycin is a specific inhibitor of the second enzyme of the MEP pathway, 1-deoxy-D-xylulose-5-phosphate reductoisomerase. We analyzed the effect of Fosmidomycin on the levels of each intermediate and its metabolic requirement for the isoprenoid biosynthesis, such as dolichols and ubiquinones, throughout the intraerythrocytic cycle of P. falciparum. The steady-state RNA levels of the MEP pathway-associated genes were quantified by real-time polymerase chain reaction and correlated with the related metabolite levels. Our results indicate that MEP pathway metabolite peak precede maximum transcript abundance during the intraerythrocytic cycle. Fosmidomycin-treatment resulted in a decrease of the intermediate levels in the MEP pathway as well as in ubiquinone and dolichol biosynthesis. The MEP pathway associated transcripts were modestly altered by the drug, indicating that the parasite is not strongly responsive at the transcriptional level. This is the first study that compares the effect of Fosmidomycin on the metabolic and transcript profiles in P. falciparum, which has only the MEP pathway for isoprenoid biosynthesis
Priscilla Krai - One of the best experts on this subject based on the ideXlab platform.
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biological studies and target engagement of the 2 c methyl d erythritol 4 phosphate cytidylyltransferase ispd targeting antimalarial agent 1r 3s mmv008138 and analogs
ACS Infectious Diseases, 2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Morgan Simpson, Maria L Fernandezmurga, Joshua H Butler, Michael A Casasanta, Priscilla KraiAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS)...
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Biological Studies and Target Engagement of the 2‑C‑Methyl‑d‑Erythritol 4‑Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1R,3S)‑MMV008138 and Analogs
2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Joshua H Butler, Michael A Casasanta, Priscilla Krai, Morgan E. Simpson, Maria L. Fernández-murga, Maxim M. TotrovAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents
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determination of the active stereoisomer of the mep pathway targeting antimalarial agent mmv008138 and initial structure activity studies
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Zhongke Yao, Emilio F Merino, Morgan Simpson, Priscilla Krai, María B Cassera, Carla Slebodnick, Paul R CarlierAbstract:Abstract Compounds that target isoprenoid biosynthesis in Plasmodium falciparum could be a welcome addition to malaria chemotherapy, since the methylerythritol phosphate (MEP) pathway used by the parasite is not present in humans. We previously reported that MMV008138 targets the apicoplast of P. falciparum and that its target in the MEP pathway differs from that of Fosmidomycin. In this Letter, we determine that the active stereoisomer of MMV008138 is 4a , which is (1 R ,3 S )-configured. 2′,4′-Disubstitution of the D ring was also found to be crucial for inhibition of the parasite growth. Limited variation of the C3-carboxylic acid substituent was carried out, and methylamide derivative 8a was found to be more potent than 4a ; other amides, acylhydrazines, and esters were less potent. Finally, lead compounds 4a , 4e , 4f , 4h , 8a , and 8e did not inhibit growth of Escherichia coli , suggesting that protozoan-selective inhibition of the MEP pathway of P. falciparum can be achieved.
Zhongke Yao - One of the best experts on this subject based on the ideXlab platform.
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biological studies and target engagement of the 2 c methyl d erythritol 4 phosphate cytidylyltransferase ispd targeting antimalarial agent 1r 3s mmv008138 and analogs
ACS Infectious Diseases, 2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Morgan Simpson, Maria L Fernandezmurga, Joshua H Butler, Michael A Casasanta, Priscilla KraiAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS)...
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Biological Studies and Target Engagement of the 2‑C‑Methyl‑d‑Erythritol 4‑Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1R,3S)‑MMV008138 and Analogs
2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Joshua H Butler, Michael A Casasanta, Priscilla Krai, Morgan E. Simpson, Maria L. Fernández-murga, Maxim M. TotrovAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents
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determination of the active stereoisomer of the mep pathway targeting antimalarial agent mmv008138 and initial structure activity studies
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Zhongke Yao, Emilio F Merino, Morgan Simpson, Priscilla Krai, María B Cassera, Carla Slebodnick, Paul R CarlierAbstract:Abstract Compounds that target isoprenoid biosynthesis in Plasmodium falciparum could be a welcome addition to malaria chemotherapy, since the methylerythritol phosphate (MEP) pathway used by the parasite is not present in humans. We previously reported that MMV008138 targets the apicoplast of P. falciparum and that its target in the MEP pathway differs from that of Fosmidomycin. In this Letter, we determine that the active stereoisomer of MMV008138 is 4a , which is (1 R ,3 S )-configured. 2′,4′-Disubstitution of the D ring was also found to be crucial for inhibition of the parasite growth. Limited variation of the C3-carboxylic acid substituent was carried out, and methylamide derivative 8a was found to be more potent than 4a ; other amides, acylhydrazines, and esters were less potent. Finally, lead compounds 4a , 4e , 4f , 4h , 8a , and 8e did not inhibit growth of Escherichia coli , suggesting that protozoan-selective inhibition of the MEP pathway of P. falciparum can be achieved.
Michel Rohmer - One of the best experts on this subject based on the ideXlab platform.
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The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells [v2; ref status: indexed, http://f1000r.es/2af]
F1000 Research Ltd, 2013Co-Authors: Michael Hartmann, Esther Gerber, Andrea Hemmerlin, Michel Rohmer, Elisabet Gas-pascual, Denis Tritsch, Thomas J BachAbstract:We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL). By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP) pathway with known inhibitors like oxoclomazone and Fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1), shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA) pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL
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isoprenoid biosynthesis via the methylerythritol phosphate pathway structural variations around phosphonate anchor and spacer of Fosmidomycin a potent inhibitor of deoxyxylulose phosphate reductoisomerase
Journal of Organic Chemistry, 2010Co-Authors: Catherine Zingle, Lionel Kuntz, Denis Tritsch, Catherine Grosdemangebilliard, Michel RohmerAbstract:Fosmidomycin and its analogue FR-900098 are potent inhibitors of 1-deoxy-d-xylulose 5-phosphate reducto-isomerase (DXR), the second enzyme of the MEP pathway for the biosynthesis of isoprenoids. This paper describes the synthesis of analogues of the two reverse phosphonohydroxamic acids 3 and 4, in which the length of the carbon spacer is modified, the N-methyl group of 3 is replaced by an ethyl group, and the phosphate group is replaced by potential isosteric moieties, i.e., sulfonate or carboxylate functionalities. The potential of the synthesized analogues to inhibit the E. coli DXR was evaluated.
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the plastidial 2 c methyl d erythritol 4 phosphate pathway provides the isoprenyl moiety for protein geranylgeranylation in tobacco by 2 cells
The Plant Cell, 2009Co-Authors: Esther Gerber, Albert Boronat, Manuel Rodriguezconcepcion, Andrea Hemmerlin, Michael Hartmann, Dimitri Heintz, Marieandree Hartmann, Jerome Mutterer, Alain Van Dorsselaer, Michel RohmerAbstract:Protein farnesylation and geranylgeranylation are important posttranslational modifications in eukaryotic cells. We visualized in transformed Nicotiana tabacum Bright Yellow-2 (BY-2) cells the geranylgeranylation and plasma membrane localization of GFP-BD-CVIL, which consists of green fluorescent protein (GFP) fused to the C-terminal polybasic domain (BD) and CVIL isoprenylation motif from the Oryza sativa calmodulin, CaM61. Treatment with Fosmidomycin (Fos) or oxoclomazone (OC), inhibitors of the plastidial 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, caused mislocalization of the protein to the nucleus, whereas treatment with mevinolin, an inhibitor of the cytosolic mevalonate pathway, did not. The nuclear localization of GFP-BD-CVIL in the presence of MEP pathway inhibitors was completely reversed by all-transgeranylgeraniol (GGol). Furthermore, 1-deoxy-D-xylulose (DX) reversed the effects of OC, but not Fos, consistent with the hypothesis that OC blocks 1-deoxy-D-xylulose 5-phosphate synthesis, whereas Fos inhibits its conversion to 2-C-methyl-Derythritol 4-phosphate. By contrast, GGol and DX did not rescue the nuclear mislocalization of GFP-BD-CVIL in the presence of a protein geranylgeranyltransferase type 1 inhibitor. Thus, the MEP pathway has an essential role in geranylgeranyl diphosphate (GGPP) biosynthesis and protein geranylgeranylation in BY-2 cells. GFP-BD-CVIL is a versatile tool for identifying pharmaceuticals and herbicides that interfere either with GGPP biosynthesis or with protein geranylgeranylation.
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isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto isomerase
Biochemical Journal, 2005Co-Authors: Lionel Kuntz, Andrea Hemmerlin, Denis Tritsch, Thomas J Bach, Catherine Grosdemangebilliard, Audrey Willem, Michel RohmerAbstract:Isoprenoid biosynthesis via the methylerythritol phosphate pathway is a target against pathogenic bacteria and the malaria parasite Plasmodium falciparum. 4-(Hydroxyamino)-4-oxobutylphosphonic acid and 4-[hydroxy(methyl)amino]-4-oxobutyl phosphonic acid, two novel inhibitors of DXR (1-deoxy-D-xylulose 5-phosphate reducto-isomerase), the second enzyme of the pathway, have been synthesized and compared with Fosmidomycin, the best known inhibitor of this enzyme. The latter phosphonohydroxamic acid showed a high inhibitory activity towards DXR, much like Fosmidomycin, as well as significant antibacterial activity against Escherichia coli in tests on Petri dishes.
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cross talk between the cytosolic mevalonate and the plastidial methylerythritol phosphate pathways in tobacco bright yellow 2 cells
Journal of Biological Chemistry, 2003Co-Authors: Andrea Hemmerlin, Michel Rohmer, Denis Tritsch, Catherine Grosdemangebilliard, Jeanfrancois Hoeffler, Odile Meyer, Isabelle A Kagan, Thomas J BachAbstract:In plants, two pathways are utilized for the synthesis of isopentenyl diphosphate, the universal precursor for isoprenoid biosynthesis. The key enzyme of the cytoplasmic mevalonic acid (MVA) pathway is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). Treatment of Tobacco Bright Yellow-2 (TBY-2) cells by the HMGR-specific inhibitor mevinolin led to growth reduction and induction of apparent HMGR activity, in parallel to an increase in protein representing two HMGR isozymes. Maximum induction was observed at 24 h. 1-Deoxy-d-xylulose (DX), the dephosphorylated first precursor of the plastidial 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway, complemented growth inhibition by mevinolin in the low millimolar concentration range. Furthermore, DX partially re-established feedback repression of mevinolin-induced HMGR activity. Incorporation studies with [1,1,1,4-2H4]DX showed that sterols, normally derived from MVA, in the presence of mevinolin are synthesized via the MEP pathway. Fosmidomycin, an inhibitor of 1-deoxy-d-xylulose-5-phosphate reductoisomerase, the second enzyme of the MEP pathway, was utilized to study the reverse complementation. Growth inhibition by Fosmidomycin of TBY-2 cells could be partially overcome by MVA. Chemical complementation was further substantiated by incorporation of [2-13C]MVA into plastoquinone, representative of plastidial isoprenoids. Best rates of incorporation of exogenous stably labeled precursors were observed in the presence of both inhibitors, thereby avoiding internal isotope dilution.
Maryam Ghavami - One of the best experts on this subject based on the ideXlab platform.
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biological studies and target engagement of the 2 c methyl d erythritol 4 phosphate cytidylyltransferase ispd targeting antimalarial agent 1r 3s mmv008138 and analogs
ACS Infectious Diseases, 2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Morgan Simpson, Maria L Fernandezmurga, Joshua H Butler, Michael A Casasanta, Priscilla KraiAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS)...
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Biological Studies and Target Engagement of the 2‑C‑Methyl‑d‑Erythritol 4‑Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1R,3S)‑MMV008138 and Analogs
2017Co-Authors: Maryam Ghavami, Emilio F Merino, Zhongke Yao, Rubayet Elahi, Joshua H Butler, Michael A Casasanta, Priscilla Krai, Morgan E. Simpson, Maria L. Fernández-murga, Maxim M. TotrovAbstract:Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit PfIspD recombinant enzyme. Here, we report PfIspD inhibition data for Fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and PfIspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents