New pentasubstituted pyrrole hybrid atorvastatin-quinoline derivatives with antiplasmodial activity

Rita C C Carvalho; Wagner A Martins; Tayara P Silva; Carlos R Kaiser; Mônica M Bastos; Luiz C S Pinheiro; Antoniana U Krettli; Núbia Boechat

doi:10.1016/j.bmcl.2016.03.027

New pentasubstituted pyrrole hybrid atorvastatin-quinoline derivatives with antiplasmodial activity

Bioorg Med Chem Lett. 2016 Apr 15;26(8):1881-4. doi: 10.1016/j.bmcl.2016.03.027. Epub 2016 Mar 9.

Authors

Rita C C Carvalho¹, Wagner A Martins², Tayara P Silva³, Carlos R Kaiser⁴, Mônica M Bastos², Luiz C S Pinheiro², Antoniana U Krettli³, Núbia Boechat⁵

Affiliations

¹ Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos-FIOCRUZ, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil; Programa de Pós Graduação em Química, PGQu Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
² Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos-FIOCRUZ, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil.
³ Laboratório de Malária, Centro de Pesquisas René Rachou, CPqRR-FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil.
⁴ Programa de Pós Graduação em Química, PGQu Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
⁵ Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos-FIOCRUZ, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil. Electronic address: [email protected].

PMID: 26988303
DOI: 10.1016/j.bmcl.2016.03.027

Abstract

Cerebral malaria is caused by Plasmodium falciparum. Atorvastatin (AVA) is a pentasubstituted pyrrole, which has been tested as an adjuvant in the treatment of cerebral malaria. Herein, a new class of hybrids of AVA and aminoquinolines (primaquine and chloroquine derivatives) has been synthesized. The quinolinic moiety was connected to the pentasubstituted pyrrole from AVA by a linker group (CH2)n=2-4 units. The activity of the compounds increased with the size of the carbons chain. Compound with n=4 and 7-chloroquinolinyl has displayed better activity (IC50=0.40 μM) than chloroquine. The primaquine derivative showed IC50=1.41 μM, being less toxic and more active than primaquine.

Keywords: Atorvastatin; Chloroquine; Malaria; Pentasubstituted pyrrole; Primaquine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry*
Antimalarials / pharmacology*
Atorvastatin / chemistry
Atorvastatin / pharmacology*
Dose-Response Relationship, Drug
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Pyrroles / chemistry
Pyrroles / pharmacology*
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship

Substances

Antimalarials
Pyrroles
Quinolines
Atorvastatin
quinoline