New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors

Author(s)

Feitosa, Livia M. ^{[1, 2]} ; da Silva, Edson R. ^[3] ; Hoelz, Lucas V. B. ^[1] ; Souza, Danielle L. ^[1] ; Come, Julio A. A. S. S. ^[4] ; Cardoso-Santos, Camila ^[5] ; Batista, Marcos M. ^[5] ; Soeiro, Maria de Nazare C. ^[5] ; Boechat, Nubia ^[1] ; Pinheiro, Luiz C. S. ^[1]

Affiliation

^[1] Fundacao Oswaldo Cruz, Farmanguinhos FIOCRUZ, Inst Tecnol Farmacos, Dept Sintese Farmacos, Rua Sizenando Nabuco 100, BR-21041250 Rio De Janeiro, RJ - Brazil

^[2] Univ Fed Rio de Janeiro, PGQu Inst Quim, Programa Posgrad Quim, Rio De Janeiro, RJ - Brazil

^[3] Univ Sao Paulo, Dept Vet Med, Fac Zootecnia & Engn Alimentos, Pirassununga, SP - Brazil

^[4] Univ Sao Paulo, Programa Posgrad Biociencia Anim, Fac Zootecnia & Engn Alimentos, Pirassununga, SP - Brazil

^[5] Fundacao Oswaldo Cruz, FIOCRUZ, Lab Biol Celular, Inst Oswaldo Cruz, Ave Brasil 4365, Rio De Janeiro, RJ - Brazil

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry; v. 27, n. 14, p. 3061-3069, JUL 15 2019.
• Web of Science Citations: 0

Abstract

Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo{[} 3,4-d] pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 mu M concentration against Leishmania amazonensis ARG (LaARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R=H) and 6 (R=CF3), showed arginase inhibition > 70% and IC50 values of 12 mu M and 47 mu M, respectively. Thus, the kinetics of LaARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing K-is values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 +/- 0.9 mu M and 29 +/- 5 mu M, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different LaARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 mu M. The maximum growth inhibition reached was between 20 and 30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds. (AU)

• FAPESP's process: 17/06917-4 - Study of the polyamine synthesis pathway and trypanothione synthesis for the development of new drugs for the treatment of leishmaniasis
• Grantee: Edson Roberto da Silva
• Support Opportunities: Regular Research Grants