In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition

Abstract

Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action. Previously, we reported the discovery of CTN1122, a potent imidazo[1,2-a]pyrazine-based antileishmanial hit compound targeting L-CK1.2 at low micromolar ranges. Here, we described structurally related, safe and selective compounds endowed with antiparasitic properties, better than miltefosine, the reference therapy by oral route. L-CK1.2 homology model gave the first structural explanations of the role of 4-pyridyl (CTN1122) and 2-aminopyrimidin-4-yl (compound 21) moieties, at the position 3 of the central core, in the low micromolar to nanomolar L-CK1.2 inhibition, whereas N-methylpyrazole derivative 11 remained inactive against the parasite kinase. Highlights 13 new imidazo[1,2-a]pyrazines related to CTN1122 were synthesized as antileishmanials The most promising and safe compounds displayed low micromolar range potency against VL L-CK1.2 homology model gave the first structural explanations of inhibitory activity 6 compounds showed low micromolar to nanomolar range L-CK1.2 inhibition

Dangerous Duplicity: The Dual Functions of Casein Kinase 1 in Parasite Biology and Host Subversion

“…The dual functions of some of these kinases both in parasite biology and subversion of the host cell, likely increases the genetic barrier for the development of drug resistant parasites (Lamotte et al, 2017). To date, only Leishmania CK1.2 was used in drug screenings (Allocco et al, 2006;Marhadour et al, 2012;Marchand et al, 2015;Durieu et al, 2016;Bazin et al, 2020).…”

Volatile Nitrogenous Compounds from Bacteria: Source of Novel Bioactive Compounds

“…[89] A potent imidazo [1,2-a]pyrazine-based antileishmanial compound has been reported by Bazin et al to target L-CK1.2 at low micromolar ranges. [90] The authors described a range of structurally related, safe and selective compounds with antiparasitic activity superior than miltefosine, which is the reference oral treatment that requires long-term treatment leading to parasitic resistance. In 2015, a new 7-Szubstituted nitroimidazooxazine compound was tested in vitro and in vivo showing no toxicity and high activity against intramacrophage forms of both L. donovani and L. infantum, [91] reaching clinical trials in 2018.…”

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

“…Although research on the biological activity of cercosporamide has increased in the last decade, few efforts have been carried out in the design of kinase inhibitor deriva-tives. The interest of the collaborators in this field of research [17][18][19][20][21][22] and the results of the literature highlighting cercosporamide as a kinase inhibitor and targeting human PKCα/β [4], Mnk1/2, Jak3, GSK3β, ALK4, and Pim-1 [7,8], from nanomolar to low micromolar ranges, prompted us to develop a new series of heterocyclic compounds inspired from cercosporamide (Figure 1).…”

“…Against L929 normal cells, no cytotoxicity (Table 3, entries 2-4 and 6) or poor cytotoxicity (Table 3, entries 1 and 5) was observed, strengthening the interest in the series in terms of the selectivity index. Complementing this study, the determination of in vivo toxicity, using Galleria mellonella larvae [22], was performed for all the compounds involved in the antitumor assays. Indeed, Galleria mellonella has been demonstrated to be a more robust assessment of the likely toxicity of chemicals in mammals than cell lines [58].…”

“…32.4-34.6 • C) [59]; 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (dt, J = 7.2, 1.7 Hz, 1H), 7.45-7.28 (m, 1H), 7.11-6.88 (m, 2H), 2.21 (s, 3H, CH 3 ); 13 C NMR (100 MHz, CDCl 3 ) δ 168.9 (C=O), 150.9 (C 1 ), 134.9 (C 4 ), 130. 1-(2-Hydroxy-4-iodophenyl)ethanone (22) 3-Iodophenyl acetate 21 (250 mg, 0.95 mmol) was dissolved in boron trifluoride acetic acid complex (4 mL). The mixture was stirred at 180 • C for 12 h. The reaction medium was allowed to cool and then was diluted in dichloromethane (20 mL).…”