Abstract
A series of thiazole-derived N-Boc amino acids were synthesized and evaluated as targeted potential antimalarials against plasmepsins II enzyme of malaria parasite Plasmodium falciparum. All the compounds showed moderate to good activity. Compounds 3f and 3g were found to have highest the 50% inhibitory concentration (IC50) values (3.45 μM and 4.89 μM, respectively) against Plasmodium falciparum. The compounds docked to the active site of plasmepsin II. Most of the compounds were found to interact with the catalytic amino acids ASP34 and ASP214 of plasmepsin II. A good correlation was observed between binding energy and antiparasitic activity of the thiazole derivatives.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Asojo OA, Afonina E, Gulnik SV, Yu B, Erickson JW, Randad R, Medjahed D, Silva AM (2002) Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 Å in complex with the inhibitors rs367 and rs370. Acta cryst D 58:2001–2008
Asojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM (2003) Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from plasmodium falciparum. J Mol Biol 327:173–181
Banerjee R, Liu J, Beatty W, Klemba M, Goldberg DE (2002) Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc Natl Acad Sci USA 99:990–995
Berry C, Humphreys J, Matharu P, Granger R, Horrocks P, Moon RP, Certa U, Ridley RG, Bur D, Kay J (1999) A distinct member of the aspartic proteinase gene family from the human malaria parasite Plasmodium falciparum. FEBS Lett 447:149–154
Borstnik K, Paik IH, Posner GH (2002) Malaria: New chemotherapeutic peroxide drugs. Mini-Rev Med Chem 2:573–583
Coombs GH, Goldberg DE, Klemba M, Berry C, Kay J, Mottram JC (2001) Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol 17:532–537
Eggleson KK, Duffin KL, Goldberg DE (1999) Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum J Biol Chem 274:32411–32417
Ersmark K, Feierberg I, Bjelic S, Hamelink E, Hackett F, Blackman MJ, Hulten J, Samuelsson B, Aqvist J, Hallberg A (2004) Potent inhibitors of the Plasmodium falciparum enzymes Plasmepsin I and II devoid of Capepsin D inhibitory activity. J Med Chem 47:110–122
Fink BA, Mortensen DS, Stauffer SR, Aron ZD, Katzenellenbogen JA (1999) Novel structural templates for estrogen-receptor ligands and prospects for combinatorial synthesis of estrogens. Chem Biol 6:205–219
Francis SE, Gluzman IY, Oksman A, Knickerbocker A, Mueller R, Bryant M, Sherman DR, Russell DG, Goldberg DE (1994) Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. EMBO J 13:306–317
Guerin PJ, Olliaro P, Nosten F, Druilhe P, Laxminarayan R, Binka F, Kilama WL, Ford N, White NJ (2002) Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development. Lancet Infect Dis 2:564–573
Hamze A, Rubi E, Arnal P, Boisbrun M, Carcel C, Salom-Roig X, Maynadier M, Wein S, Vial H, Calas M (2005) Mono- and bis-thiazolium salts have potent antimalarial activity. J Med Chem 48:3639–3643
Haque TS, Skillman AG, Lee CE, Habashita H, Gluzman IY, Ewing TJA,Goldberg DE, Kuntz ID, Ellman JA (1999) Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II. J Med Chem 42:1428–1440
Hargrave KD, Hess FK, Oliver JT (1983) N-(4-Substituted-thiazolyl)oxamic acid derivatives, a new series of potent, orally active antiallergy agents. J Med Chem 26:1158–1163
Haviv F, Ratajczyk JD, DeNet RW, Kerdesky FA, Walters RL, Schmidt SP, Holms JH, Young PR, Carter GW (1988) 3-[ I-(2-Benzoxazolyl) hydrazinolpropanenitrile derivatives: Inhibitors of immune complex induced inflammation. J Med Chem 31:1719–1728
Haynes RK (2001) Artemisinin and derivatives: the future for malaria treatment? Curr Opin Infec Dis 14:719–721
Jiang S, Prigge ST, Wei L, Gao YE, Hudson TH, Gerena L, Dame JB, Kyle DE (2001) New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting Plasmepsins. Antimicrob Agents Chemother 45:2577–2584
Lazzaro A, Vertuani G, Bergamini P, Mantovani N, Marchi A, Marvelli L, Rossi R, Bertolasi V, Ferretti V (2002) Synthesis, charecterization, properties and structures of rhenium-(II),-(III), and -(V) complexes containing amino acids conjugated with a 2-aminothiazole ligand. J Chem Soc Dalton Trans 2843
Lewis JR (1999) Miscellaneous alkaloids: Amaryllidaceae, sceletium, muscarine, imidazole,oxazole, peptide and other miscellaneous alkaloids. Nat Prod Rep 16:389–416
Marcantonio KM, Frey LF, Murry JA, Chen CYi (2002) A practical preparation of 5- (ketoaryl)thiazoles. Tetraherdon Lett 43:8845–8848
Murray MC, Perkins ME (1996) Chemotherapy of malaria. Annu Rep Med Chem 31:141–150
Musso DL, Andersen MW, Andrews RC, Austin R, Beaudet EJ, Becherer JD, Bubacz DG, Bickett DM, Chan JH, Conway JG, Cowan DJ, Gaul MD, Glennon KC, Hedeen KM, Lambert MH, Leesnitzer MA, McDougald DL, Mitchell JL, Moss ML, Rabinowitz MH, Rizzolio MC, Schaller LT, Stanford JB, Tippin TK, Warner JR, Whitesell LG, Wiethe RW (2001) N-Hydroxyformamide peptidomimetics as TACE/Matrix metalloprotease inhibitors: Oral activity via P10 isobutyl substitution. Bioorg Med Chem Lett 11:2147–2151
Patt WC, Hamilton HW, Taylor MD, Ryan MJ, Taylor DGJr, Connolly CJC, Doherty AM, Klutchko SR, Sircar I, Steinbaugh BA, Batley BL, Painchaud CA, Rapundalo ST, Michniewicz BM, Olson SCJ (1992) Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors. J Med Chem 35:2562–2572
Prade L, Jones AF, Boss C, Richard-Bildstein S, Meyer S, Binkert C, Bur D X-ray structure of plasmepsin II complexed with a potent achiral inhibitor. J Biol Chem 280:23837–23843
Quelever G, Burlet S, Garino C, Pietrancosta N, Laras Y, Kraus JL (2004) Simple coupling reaction between amino acids and weakly nucleophilic heteroaromatic amines. J Comb Chem 6:695–698
Rosenthal PJ, McKerrow JH, Aikawa M, Nagasawa H, Leech JH A malarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum. J Clin Invest 82:1560–1566
Salas E, Ramirez A, Otero-Bilbao A, Vazquez R, Reyes O, Mendiola J, Duarte CA, Otero-Gonzalez A, Gutierrez OA, Chavez MA (2004) A heterogeneous enzymatic assay for quantification of plasmepsin II activity and the evaluation of its inhibitors. J Pharm Biomed Anal 34:833–840
Silva AM, Lee AY, Gulnik SV, Majer P, Collins J, Bhat TN, Collins PJ, Cachau RE, Luker KE, Gluzman IY, Francis SE, Oksman A, Goldberg DE, Erickson JW (1996) Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum. Proc Natl Acad Sci USA 93:10034–10039
Trager W, Jensen JB (1976) Human malaria parasites in continuous culture. Science 193:673–675
Tsuji K, Ishikawa H (1994) Synthesis and anti-pseudomonal activity of new 2-isocephems with a dihydroxypyridone moiety at C-7. Bioorg Med Chem Lett 4:1601–1606
White NJ (2004) Antimalarial drug resistance. J Clin Invest 113:1084–1092
WHO Report; World Health Organosation; Geneva, Switzerland, 2005, (http://rbm.who.int/wmr 2005)
Acknowledgements
We thank Dr. R. Vijayaraghavan, Director DRDE, Gwalior for his keen interest and encouragement in the present study. We thank Mr. Asish Srivastava for carrying out ESI-MS analysis and Mr. Basant Lal for NMR analysis. Our special thanks to Accelrys K.K, Bangalore, India for extending facility of Discovery Studio.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Karade, H.N., Acharya, B.N., Sathe, M. et al. Design, synthesis, and antimalarial evaluation of thiazole-derived amino acids. Med Chem Res 17, 19–29 (2008). https://doi.org/10.1007/s00044-008-9089-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-008-9089-0