2.7.7.60 (1R,3S)-1-(2,3,4-trifluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254249 2.7.7.60 (1R,3S)-1-(2,4-dibromophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254250 2.7.7.60 (1R,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide - 254251 2.7.7.60 (1R,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254252 2.7.7.60 (1R,3S)-1-(2,4-dichlorophenyl)-N,N-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide about 5% inhibition at 0.001 mM 254253 2.7.7.60 (1R,3S)-1-(2,4-dichlorophenyl)-N-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide - 254254 2.7.7.60 (1R,3S)-1-(2,4-dichlorophenyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide - 254255 2.7.7.60 (1R,3S)-1-(2,4-difluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254256 2.7.7.60 (1R,3S)-1-(2-bromo-4,5-difluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254257 2.7.7.60 (1R,3S)-1-(2-bromo-4-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254258 2.7.7.60 (1R,3S)-1-(2-bromo-4-chlorophenyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide - 254259 2.7.7.60 (1R,3S)-1-(2-bromo-4-iodophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254260 2.7.7.60 (1R,3S)-1-(2-chloro-4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254261 2.7.7.60 (1R,3S)-1-(2-chloro-4-fluorophenyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide - 254262 2.7.7.60 (1R,3S)-1-(2-chloro-4-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254263 2.7.7.60 (1R,3S)-1-(2-chloro-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254264 2.7.7.60 (1R,3S)-1-(2-chloro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254265 2.7.7.60 (1R,3S)-1-(2-chloro-4-methylphenyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide - 254266 2.7.7.60 (1R,3S)-1-(2-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254267 2.7.7.60 (1R,3S)-1-(2-fluoro-4-iodophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254268 2.7.7.60 (1R,3S)-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254270 2.7.7.60 (1R,3S)-1-(3-chloropyridin-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254271 2.7.7.60 (1R,3S)-1-(4-bromo-2-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254272 2.7.7.60 (1R,3S)-1-(4-bromo-2-chlorophenyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide - 254273 2.7.7.60 (1R,3S)-1-(4-carboxy-2-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254274 2.7.7.60 (1R,3S)-1-(4-chloro-2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254275 2.7.7.60 (1R,3S)-1-(4-chloro-2-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254276 2.7.7.60 (1R,3S)-1-(4-chloro-2-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254277 2.7.7.60 (1R,3S)-1-(4-chloro-2-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254278 2.7.7.60 (1R,3S)-1-(4-chlorophenyl)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254279 2.7.7.60 (1R,3S)-1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254280 2.7.7.60 (1R,3S)-1-(4-fluoro-2-iodophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254281 2.7.7.60 (1R,3S)-1-methyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254282 2.7.7.60 (1R,3S)-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254283 2.7.7.60 (1R,3S)-1-[(2,4-dichlorophenyl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254284 2.7.7.60 (1R,3S)-1-[2,4-bis(dimethoxymethyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254285 2.7.7.60 (1R,3S)-1-[2,4-bis(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254286 2.7.7.60 (1R,3S)-1-[2,4-di(propan-2-yl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254287 2.7.7.60 (1R,3S)-MMV008138 (1R,3S)-MMV008138 targets the enzyme 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway. The Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. The compound inhibits Plasmodium falciparum Dd2 strain growth with an IC50 value of 250 nM 256899 2.7.7.60 (1S,3S)-1-(5-chlorothiophen-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid - 254293 2.7.7.60 (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate MMV008138, PfIspD is the sole intracellular target of MMV008138, target-based resistance. IspD binding mode analysis, overview. 1R,3S-MMV008138 directly inhibits purified recombinant Plasmodium falciparum IspD (PfIspD), competitively with its CTP substrate. The metabolic effects of 1R,3S-MMV008138 are specific to MEP pathway inhibition, 1R,3S-MMV008138 inhibits malaria parasite growth as a consequence of MEP pathway inhibition. 1R,3S-MMV008138 is also active against Plasmodium vivax but not against bacterial IspD homologues 256892 2.7.7.60 (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate MMV008138, Plasmodium vivax IspD (PvIspD) is potently inhibited by 1R,3S-MMV008138. IspD binding mode analysis, overview 256892 2.7.7.60 (3-(acetylhydroxyamino)propyl)phosphonic acid FR900098 256904 2.7.7.60 1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole about 7% inhibition at 0.001 mM 254763 2.7.7.60 1-[(1R,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl]-2-hydroxyethan-1-one - 254873 2.7.7.60 1H-pyrrolo(2,3-b)quinoxaline - 256893 2.7.7.60 6-hydroxy-DL-DOPA - 27129 2.7.7.60 7-hydroxy-[1,2,4] triazolo[1,5-a] pyrimidine azolopyrimidine, docking reveals strong hydrogen bonds with CTP-specific (T326, K406, R431, and K548) and MEP-specific (D428, R431, T525, and K548) amino acid residues of PvIspD protein. A salt-bridge formation is also observed with K406 and D428 residues similar to CTP 256903 2.7.7.60 9H-pyrrolo[2,3f]quinoxaline - 256894 2.7.7.60 aurintricarboxylic acid - 1818 2.7.7.60 but-3-enyl diphosphate - 16923 2.7.7.60 cefepime interaction with residues T525 and K548 951 2.7.7.60 chelerythrine - 9640 2.7.7.60 CTP substrate inhibition 60 2.7.7.60 D-erythritol 1-phosphate - 113249 2.7.7.60 dequalinium - 156379 2.7.7.60 domiphen bromide interaction with residue Thr 525 256902 2.7.7.60 fosmidomycin about 4% inhibition at 0.01 mM 1364 2.7.7.60 fosmidomycin - 1364 2.7.7.60 fosmidomycin Fos, a well-known inhibitor of DXR/IspC enzyme. Strong interaction of Fos with PvIspD enzyme, where hydrogen bonds are observed between Fos and amino acid residues D428, R431, Q493, T523, D524, T525 and K548 of PvIspD enzyme. residues R431 and K548 which form the salt bridge with CTP are observed to form a bridge with the negatively charged phosphate group of Fos 1364 2.7.7.60 fosmidomycin 3-[formyl(hydroxy)amino]propylphosphonic acid 1364 2.7.7.60 ketoclomazone - 209792 2.7.7.60 methyl hydroxytriazaindolizine - 256897 2.7.7.60 MMV008138 - 256900 2.7.7.60 MMV008138 weak inhibition of Plasmodium vivax IspD, the compound is a competitive inhibitor of PvIspD at lower concentrations of CTP, interaction with residues D428, T525, and K548 256900 2.7.7.60 additional information no inhibition of Mycobacetrium tuberculosis IspD by (2,4-dichloro-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-3-carboxylate, MMV008138 2 2.7.7.60 additional information the PfISPD genetic locus is refractory to disruption in malaria parasites, providing independent genetic validation for efforts targeting this enzyme. Phosphonic acid antibiotic fosmidomycin is a substrate mimic and inhibitor of DXR.13 The inhibition of downstream enzyme IspD is also metabolically apparent in fosmidomycin-treated cells, although IspD homologues are not directly inhibited by fosmidomycin in vitro 2 2.7.7.60 additional information inhibitor design and inhibition structure-activity relationships analysis, overview. In addition to (1R,3S)-configuration, potent growth inhibition requires 2',4'-disubstitution of the D-ring, featuring at least one electron-withdrawing substituent. Neither (1R,3S)-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (bearing an unsubstituted phenyl ring) nor (1R,3S)-1-[2,4-di(propan-2-yl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (bearing 2',4'-dimethyl substitution) inhibit Plasmodium falciparum growth at 0.01 mM. The 2'-chloro substituted analogue (1R,3S)-1-(2-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid shows weak growth inhibition, and (1R,3S)-1-(2-chloro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (2'-chloro-4'-methyl substituted) nearly recapitulates the potency of (1R,3S)-MMV008138. The carboxy substituent at C3 of the C-ring also proves to be essential, replacement with CO2Me (3a) or H (11a) abrogates growth inhibition potency. But weak growth inhibition is restored with the first amide analogue (1R,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide, and methyl amide derivative (1R,3S)-1-(2,4-dichlorophenyl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide proves equipotent to (1R,3S)-MMV008138. Not inhibitory: (1R,3S)-1-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid, methyl (1R,3S)-1-(2,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate. 2 2.7.7.60 additional information high-throughput screening to identify inhibitors of MEP cytidylyltransferase (IspD) 2 2.7.7.60 additional information bench-scale high-throughput screening to identify inhibitors of MEP cytidylyltransferase (IspD) using purified, recombinant IspD, a commercially available 1280 compound molecular library, and a 150 sample, in-house prepared, natural product extract library. The enzyme activity is not affected by 0.01% Triton X-100, but inhibition is attenuated in the presence of Triton X-100 for all inhibitors, except 6-hydroxy-DL-DOPA 2 2.7.7.60 additional information docking study 2 2.7.7.60 additional information inhibitor screening and enzyme-inhibitor molecular docking study using enzyme structure with bound CTP and Mg2+ (PDB ID 3Q7U). The attached CTP and Mg2+ ion are deleted from the structure, followed by refinement of the protein subunit. The crucial active site residues Gly16, Arg83, Thr84, and Thy190 play a vital role in the protein-ligand stabilization process 2 2.7.7.60 additional information inhibitor molecular docking study 2 2.7.7.60 prop-2-yn-1-yl trihydrogen diphosphate schembl1651692 224153 2.7.7.60 propyl trihydrogen diphosphate - 256896 2.7.7.60 pyrrolo[1,2-a]quinoxaline - 256895 2.7.7.60 quercetin quercetin is retained as a lead molecule for inhibition of IspD, 96% inhibition at 0.1 mM 137 2.7.7.60 rifampicin a prokaryotic transcription inhibitor, interaction with residues T326, R431, T525, and K548 3669 2.7.7.60 rosuvastatin RST, significantly interacts at the active site of the enzyme. Active-site residues Gly16, Arg83, Thr84, and Thy190 are potentially contributing to the protein-ligand interaction 8562 2.7.7.60 sulfanilamide - 1096 2.7.7.60 triazolopyrimidine derivative PubChem CID 330031 256898 2.7.7.60 tunicamycin interaction with residues V323, T324, T326, D338, L381, L384, K406, and T491 1659 2.7.7.60 U-74389G maleate - 256901