ARYL PIPERAZINE AND PYRROLIDINE AS ANTIMALARIAL AGENTS. SYNTHESIS AND INVESTIGATION OF STRUCTURE–ACTIVITY RELATIONSHIPS
Miguel Quiliano(1,2,3)*, Adela Mendoza(1), Silvia Pérez-Silanes(1,2), Adriana Pabón(4), Giovanny Garavito(5), Mirko Zimic(3), Antonio Monge(1), Eric Deharo(6), Silvia Galiano(1,2), Ignacio Aldana(1,2)
(1) Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia y Nutrición, Universidad de Navarra, Pamplona 31008, Spain.
(2) Institute of Tropical Health (ISTUN), Universidad de Navarra, Pamplona 31008, Spain.
(3) Laboratorio de Bioinformática, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia (UPCH), Av. Honorio Delgado 430, SMP, Lima, Perú.
(4) Grupo Malaria, Universidad de Antioquia, Medellín, Colombia.
(5) Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia (DFUNC), Carrera 30 45-03, Bogotá DC, Colombia.
(6) UMR 152 PHARMA-DEV, Université Toulouse, IRD, UPS, 31062 Toulouse, France.
*firstname.lastname@example.org, Tel: +34-644583343
Malaria, a major tropical disease, is still a major health problem in developing countries. In 2015 alone, 214 million cases were reported globally resulting in an estimated 438,000 deaths . The emergence of resistance to almost all available treatments leads to an alarming situation in endemic areas. New therapeutic alternatives are thus urgently needed. Synthesis of piperazine and pyrrolidine derivatives followed by structure-activity relationships, in silico druglikeness, and cytotoxicity led to the identification of five compounds (7, 8, 10, 12, and 13) with in vitro antiplasmodial activity against drug sensitive (NF-54 IC50 ≤ 8 μM) and multidrug resistant (FCR-3 IC50 ≤ 10 μM) strains of P. falciparum. The presence of an aromatic and amino alcohol portion linked by a carbon chain of two atoms in length was crucial for antiplasmodial activity. The most active compound (13) was 20–40 times more active for P. falciparum (FCR-3 IC50 = 0.5 μM) over tumorigenic and non-tumorigenic cells. In vivo test of compound 13 showed low parasitemia reduction (35%) at 10 mg/kg/day against Plasmodium berghei infected mice. Additionally, in silico molecular docking study revealed Plasmodium plasmepsin II enzyme as putative target for compound 13. Finally, further optimization of the scaffold is proposed.
 WHO. World Malaria Report 2015; World Health Organization: Geneva, Switzerland, 2015.