In vitro anti-Leishmania activity of new isomeric cobalt(II)complexes and in silico insights: Mitochondria impairment and apoptosis-like cell death of the parasite

Samuel M Rocha; Adolfo Horn Jr; Aline R de M L Terra; Lara M Rezende; Felipe F Moreira; Renato A DaMatta; Fernando R Xavier; Rodrigo Cervo; Roberta Cargnelutti; Sreerag N Moorkkannur; Graysen Owenby; Rajeev Prabhakar; Sérgio H Seabra; Christiane Fernandes

doi:10.1016/j.jinorgbio.2022.112088

In vitro anti-Leishmania activity of new isomeric cobalt(II)complexes and in silico insights: Mitochondria impairment and apoptosis-like cell death of the parasite

J Inorg Biochem. 2023 Mar:240:112088. doi: 10.1016/j.jinorgbio.2022.112088. Epub 2022 Dec 9.

Affiliations

¹ Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
² Laboratório de Biologia Celular e Tecidual, Universidade Estadual do Norte Fluminense Darcy Ribeiro, 28013-602 Campos dos Goytacazes, RJ, Brazil.
³ Departamento de Química, Universidade do Estado de Santa Catarina, 89219-710 Joinville, SC, Brazil.
⁴ Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil.
⁵ Department of Chemistry, University of Miami, Coral Gables, FL 33146, USA.
⁶ Laboratório de Biologia Celular e Tecidual, Universidade Estadual do Norte Fluminense Darcy Ribeiro, 28013-602 Campos dos Goytacazes, RJ, Brazil. Electronic address: seabrash@uenf.br.
⁷ Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil. Electronic address: christiane.horn@ufsc.br.

PMID: 36630792
DOI: 10.1016/j.jinorgbio.2022.112088

Abstract

The synthesis, physico-chemical characterization and in vitro antiproliferative activity against the promastigote form of Leishmania amazonensis of two new cobalt(II) coordination compounds (i.e. [Co(HL1)Cl₂]0.4,2H₂O (1) and [Co(HL2)(Cl)(CH₃OH)](ClO₄).2H₂O (2)) are reported, where HL1 = 4-{3-[bis(pyridin-2-ylmethyl)amino]-2-hydroxypropoxy}-2H-chromen-2-one and HL2 = 7-{3-[bis(pyridin-2-ylmethyl)amino]-2-hydroxypropoxy}-2H-chromen-2-one. X-ray diffraction studies were performed for complex (2) and the structure of complex (1) was built through Density Functional Theory (DFT) calculations. Complex (1) presented no cytotoxicity to LLC-MK2, but complex (2) was toxic. IC₅₀ against promastigotes of L. amazonensis for complex (1) were 4.90 (24 h), 3.50 (48 h) and 3. 80 μmol L^-1 (72 h), and for complex (2) were 2.09, 4.20 and 2.80 μmol L^-1, respectively. Due to the high toxicity presented by complex (2) against LLC-MK2 host cells, mechanistic studies, to shed light on the probable mode of leishmanicidal activity, were carried out only for the non-cytotoxic complex. Complex (1) was able to elevate mitochondrial membrane potential of the parasites after treatment. Transmission electron microscopy revealed typical apoptotic condensation of chromatin, altered kinetoplast and mitochondria structures, suggesting that apoptosis-like cell death of the protozoa is probably mediated by an apoptotic mechanism associated with mitochondrial dysfunction (intrinsic pathway). Molecular docking studies with complex (1) upon protein tyrosine phosphatase (LmPRL-1) suggests a plausible positive complex anchoring mainly by hydrophobic and hydrogen bond forces close to the enzyme's catalytic site. These promising results for complex 1 will prompt future investigations against amastigote form of L. amazonensis.

Keywords: Apoptotic mechanism; Cobalt(II) complexes; Leishmania amazonensis; Leishmanicidal activity; Molecular docking; X-ray.

Publication types

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

MeSH terms

Animals
Antiprotozoal Agents* / chemistry
Apoptosis
Cobalt / pharmacology
Leishmania*
Mitochondria
Molecular Docking Simulation
Parasites*

Substances

Cobalt
Antiprotozoal Agents