Novel arylalkylamine compounds exhibits potent selective antiparasitic activity against Leishmania major

Abstract

Leishmania major (L. major) is a protozoan parasite causal agent of Leishmaniasis. It is estimated that 12 million people are currently infected and around 2 million infections occur each year. Current treatments suffer of high toxicity for the patient, low efficacy toward the parasite, high cost, and are losing effectiveness due to parasite resistance. Discovering novel small molecule with high specificity/selectivity and drug-like properties for anti-leishmanial activity remains a significant challenge. The purpose of this study is to communicate the design and synthesis strategies of novel chemical compounds based of the arylalkylamine scaffold with selective toxicity towards L. major and less toxicity to human cells in vitro. Here, we have developed a structure activity relationship (SAR) study of arylalkylamine AA1 in order to study their anti-parasitic effect in L. major. Overall, 27 arylalkylamine compounds derived from AA1 were synthesized and purified by silica gel column chromatography. The purity of each analog was confirmed by spectroscopic methods (1H, 13C NMR and LC/MS). Among these analogs, the compound AA9 showed the best toxic activity on L. major (LD50 = 3.34 μM), which represents a 9 fold higher lethality as compared with its parental AA1 (Fer-1) compound (LD50 = 28.75 μM). In addition, AA9 showed no significant toxicity at 80 μM on U20S Human Osteoblasts, Raw 264.7 Macrophages or intraperitoneal macrophages. In summary, our combined SAR study and biological evaluation data of AA1-AA27 compounds allow the identification of novel arylalkylamine compound AA9 that exhibits potent cytotoxicity against L. major promastigote with minimum toxic effect on human cells.

Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major

“…Even though amphotericin B presented similar activity as 5D against promastigotes and amastigotes, this result further supports the application of 5D and 5E as anti-leishmanial agents. Furthermore, the selectivity presented by 5D was remarkably higher than the parent compound 5A (10-fold higher), demonstrating the success to increase the anti-leishmanial activity and reduced cytotoxicity effects when compared to our previously reported arylalkylamine type-compound [ 12 ].…”

“…Based on our previous study [ 12 ], it was hypothesized that 5D may induce parasite death through the production of ROS. Thus, 2 × 10 6 L. major promastigotes per mL were incubated with 5D (EC 50 0.09 ± 0.02 µM).…”

“…Briefly, the 2,2,6,6-tetramethylpiperidine ketone ( 1 , 1 equivalent) was mixed with 2-cyanoacetate esters ( 2 , 1 equivalent) and elemental sulfur (1 equivalent) in the presence of diethylamine (3 equivalents) in ethanol (ETOH) at 60 °C for 17 h. The crude was precipitated by adding water and filtered to provide the desired known 2-aminothiophene intermediate ( 3 ) [ 12 ]. The latter was reacted with 4-trifluomethy benzoyl chloride in the presence of diisopropylethylamine in dry dichloromethane at 0 °C for 1 h and then at room temperature for 4 h. The solvent was evaporated then the crude mixture was purified by flash-column chromatography on silica gel, using a mixture of solvent of dichloromethane: methanol (DCM: MeOH) at ratios from 100:1 to 50:1, to provide the desired ethyl 5,5,7,7-tetramethyl-2-(4-(trifluoromethyl)benzamido)-4,5,6,7-tetrahydrothieno [2,3-c]pyridine-3-carboxylate ( 5A ) as a light brown solid.…”

“…Considering the current interest in the search of antileishmanial agents, we previously reported for the first time that arylalkylamine type-compounds exhibit anti- Leishmania activity with no toxicity to mammalian cells [ 12 , 13 ]. Toward our medicinal chemistry effort in developing novel compounds with anti-parasitic activity and drug like properties (e.g., improved solubility, potency, stability and less or low toxicity), we assessed the antileishmanial activity of a series of novel compounds based on the thiophene scaffold with pharmaceutical properties: low toxicity, improved potency and solubility [ 13 ].…”

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

“…Throughout the years, quinoline scaffold has been used as the core structure for developing promising antileishmanial agents. There is a long way to go until the discovery of an effective treatment against this disease [ 13 , 14 , 15 ]. Thus, this paper intends to provide a structural perspective of the use of the quinoline scaffold in the development of novel antileishmanial agents, emphasizing not only the structural modifications crucial for increasing the antileishmanial properties but also the functionalizations performed to improve their pharmacological properties.…”