title: 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 ((1)H, (13)C 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.
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA.
authors.forename: Eva A
authors.initials: EA
authors.lastname: Iniguez
authors.affiliation: Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Perez
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA; Border Biomedical Research Center, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA. Electronic address: ramaldonado@utep.edu.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Maldonado
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA; Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA; Border Biomedical Research Center, University of Texas at El Paso, 500 W. University Ave., El Paso, TX 79902, USA. Electronic address: rskouta@utep.edu.
authors.forename: Rachid
authors.initials: R
authors.lastname: Skouta
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D047068:Arylalkylamine N-Acetyltransferase / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D018320:Leishmania major / Q000187:drug effects*; D015394:Molecular Structure; D010006:Osteoblasts / Q000187:drug effects
chemical_list: C000612900:AA9 compound; D000588:Amines; D000977:Antiparasitic Agents; D047068:Arylalkylamine N-Acetyltransferase
keywords: Amphotericin B; Arylalkylamine compounds; Leishmania major; Mammalian cells