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Fragment-Based Discovery of 2-Aminoquinazolin-4(3H)-ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV.

Rasina D, Otikovs M, Leitans J, Recacha R, Borysov OV, Kanepe-Lapsa I, Domraceva I, Pantelejevs T, Tars K, Blackman MJ, Jaudzems K, Jirgensons A
J Med Chem 59 374-87 (2016)
Related entries: 1miq, 1pfz, 1qs8

Cited: 18 times
EuropePMC logo PMID: 26670264

Abstract

2-Aminoquinazolin-4(3H)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial fragment hit optimization led to a submicromolar inhibitor, which was cocrystallized with Plm II to produce an X-ray structure of the complex. The structure showed that 2-aminoquinazolin-4(3H)-ones bind to the open flap conformation of the enzyme and provided clues to target the flap pocket. Further improvement in potency was achieved via introduction of hydrophobic substituents occupying the flap pocket. Most of the 2-aminoquinazolin-4(3H)-one based inhibitors show a similar activity against digestive Plms I, II, and IV and >10-fold selectivity versus CatD, although varying the flap pocket substituent led to one Plm IV selective inhibitor. In cell-based assays, the compounds show growth inhibition of Plasmodium falciparum 3D7 with IC50 ∼ 1 μM. Together, these results suggest 2-aminoquinazolin-4(3H)-ones as perspective leads for future development of an antimalarial agent.

Reviews - 4z22 mentioned but not cited (1)

  1. Pepsin-like aspartic proteases (PAPs) as model systems for combining biomolecular simulation with biophysical experiments. Bhakat S. RSC Adv 11 11026-11047 (2021)

Articles - 4z22 mentioned but not cited (2)

  1. EU-OPENSCREEN: A Novel Collaborative Approach to Facilitate Chemical Biology. Brennecke P, Rasina D, Aubi O, Herzog K, Landskron J, Cautain B, Vicente F, Quintana J, Mestres J, Stechmann B, Ellinger B, Brea J, Kolanowski JL, Pilarski R, Orzaez M, Pineda-Lucena A, Laraia L, Nami F, Zielenkiewicz P, Paruch K, Hansen E, von Kries JP, Neuenschwander M, Specker E, Bartunek P, Simova S, Leśnikowski Z, Krauss S, Lehtiö L, Bilitewski U, Brönstrup M, Taskén K, Jirgensons A, Lickert H, Clausen MH, Andersen JH, Vicent MJ, Genilloud O, Martinez A, Nazaré M, Fecke W, Gribbon P. SLAS Discov 24 398-413 (2019)
  2. Flap Dynamics in Pepsin-Like Aspartic Proteases: A Computational Perspective Using Plasmepsin-II and BACE-1 as Model Systems. Bhakat S, Söderhjelm P. J Chem Inf Model 62 914-926 (2022)


Reviews citing this publication (3)

  1. Drug target identification in protozoan parasites. Müller J, Hemphill A. Expert Opin Drug Discov 11 815-824 (2016)
  2. NMR-Fragment Based Virtual Screening: A Brief Overview. Singh M, Tam B, Akabayov B. Molecules 23 E233 (2018)
  3. Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination. Mathews ES, Odom John AR. F1000Res 7 F1000 Faculty Rev-1170 (2018)

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  1. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Nasamu AS, Glushakova S, Russo I, Vaupel B, Oksman A, Kim AS, Fremont DH, Tolia N, Beck JR, Meyers MJ, Niles JC, Zimmerberg J, Goldberg DE. Science 358 518-522 (2017)
  2. Scope of 3D Shape-Based Approaches in Predicting the Macromolecular Targets of Structurally Complex Small Molecules Including Natural Products and Macrocyclic Ligands. Chen Y, Mathai N, Kirchmair J. J Chem Inf Model 60 2858-2875 (2020)
  3. Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D. Zogota R, Kinena L, Withers-Martinez C, Blackman MJ, Bobrovs R, Pantelejevs T, Kanepe-Lapsa I, Ozola V, Jaudzems K, Suna E, Jirgensons A. Eur J Med Chem 163 344-352 (2019)
  4. Solution and Gas-Phase Reactivity of Me12 Fe8- and Related Cluster Ions. Parchomyk T, Koszinowski K. Chemistry 23 3213-3219 (2017)
  5. Regioselective synthesis and biological evaluation of N-substituted 2-aminoquinazolin-4-ones. Liao ZY, Yeh WH, Liao PY, Liu YT, Chen YC, Chen YH, Hsieh TH, Lin CC, Lu MH, Chen YS, Hsu MC, Li TK, Chien TC. Org Biomol Chem 16 4482-4494 (2018)
  6. Altered Plasmodium falciparum Sensitivity to the Antiretroviral Protease Inhibitor Lopinavir Associated with Polymorphisms in pfmdr1. Sonoiki E, Nsanzabana C, Legac J, Sindhe KM, DeRisi J, Rosenthal PJ. Antimicrob Agents Chemother 61 e01949-16 (2017)
  7. Formation of Transient Anionic Metal Clusters in Palladium/Diene-Catalyzed Cross-Coupling Reactions. Kolter M, Koszinowski K. Chemistry 25 13376-13384 (2019)
  8. Low-Valent Ate Complexes Formed in Cobalt-Catalyzed Cross-Coupling Reactions with 1,3-Dienes as Additives. Kreyenschmidt F, Koszinowski K. Chemistry 24 1168-1177 (2018)
  9. Click Inspired Synthesis of Novel Cinchonidine Glycoconjugates as Promising Plasmepsin Inhibitors. Mishra N, Agrahari AK, Bose P, Singh SK, Singh AS, Tiwari VK. Sci Rep 10 3586 (2020)
  10. Deciphering the mechanism of potent peptidomimetic inhibitors targeting plasmepsins - biochemical and structural insights. Mishra V, Rathore I, Arekar A, Sthanam LK, Xiao H, Kiso Y, Sen S, Patankar S, Gustchina A, Hidaka K, Wlodawer A, Yada RY, Bhaumik P. FEBS J 285 3077-3096 (2018)
  11. Azole-based non-peptidomimetic plasmepsin inhibitors. Kinena L, Leitis G, Kanepe-Lapsa I, Bobrovs R, Jaudzems K, Ozola V, Suna E, Jirgensons A. Arch Pharm (Weinheim) 351 e1800151 (2018)
  12. Copper-Catalyzed Enantioselective Aerobic Alkene Aminooxygenation and Dioxygenation: Access to 2-Formyl Saturated Heterocycles and Unnatural Proline Derivatives. Carmo RLL, Galster SL, Wdowik T, Song C, Chemler SR. J Am Chem Soc 145 13715-13729 (2023)


Related citations provided by authors (2)

  1. Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum.. Bernstein NK, Cherney MM, Loetscher H, Ridley RG, James MN Nat Struct Biol 6 32-7 (1999)
  2. Structural insights into the activation of P. vivax plasmepsin.. Bernstein NK, Cherney MM, Yowell CA, Dame JB, James MN J Mol Biol 329 505-24 (2003)

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