SYNTHESIS OF 2-AMINOPYRIDOPYRIMIDINONES AND THEIR PLASMEPSIN I, II, IV INHIBITION POTENCY

Авторы

  • Dace Rasina Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia
  • Georgijs Stakanovs Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia
  • Iveta Kanepe-Lapsa Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia
  • Raitis Bobrovs Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia
  • Kristaps Jaudzems Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia
  • Aigars Jirgensons Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia

DOI:

https://doi.org/10.1007/5479

Ключевые слова:

2-aminopyrido[2, 3-d]pyrimidin-4(3H)-ones, 2-aminopyrido[3, 2-d]pyrimidin-4(3H)-ones, 2-aminopyrido[4, malaria, plasmepsins.

Аннотация

Malarial aspartic protease, plasmepsin (Plm), is perspective antimalarial drug target. Following up our previosly identified 2-aminoquinazolin-4(3H)-one-based inhibitors, 2-aminopyrido[2,3-d]-, -[3,2-d]-, and -[4,3-d]pyrimidin-4(3H)-ones bearing subpocket-specific substituents at position 7 were prepared and tested for their Plm I, II, IV inhibition potency. The position of the nitrogen atom in 2-aminopyridopyrimidinones plays significant role in the inhibitory potency against Plms. Pyrido[2,3-d]pyrimidin-4(3H)-one derivatives showed poor inhibitory potency against Plms I, II, IV irrespectively of the substituent at position 7. However, pyrido[4,3-d]pyrimidin-4(3H)-ones and pyrido[3,2-d]pyrimidin-4(3H)-ones were more appropriate scaffolds for Plm inhibitor development. Particularly, 2-amino-7-[4-(3-phenylpropyl)phenyl]-3-[(tetrahydrofuran-2-yl)methyl]pyrido[3,2-d]pyrimidin-4(3H)-one showed very high potency against Plm IV subtype and high selectivity against human aspartic protease, cathepsin D.

Опубликован

2020-07-10