Abstract
This work describes the synthesis of a series of quaternary ammonium salts and the assessment of their in vitro antileishmanial activity and cytotoxicity. A preliminary discussion on a structure-activity relationship of the compounds is also included. Three series of quaternary ammonium salts were prepared: (i) halomethylated quaternary ammonium salts (series I); (ii) non-halogenated quaternary ammonium salts (series II) and (iii) halomethylated choline analogs (series III). Assessments of their in vitro cytotoxicity in human promonocytic cells U-937 and antileishmanial activity in axenic amastigotes of L. (Viannia) panamensis (M/HOM/87/UA140-pIR-eGFP) were carried out using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) micromethod. Antileishmanial activity was also tested in intracellular amastigotes of L. (V) panamensis using flow cytometry. High toxicity for human U937 cells was found with most of the compounds, which exhibited Lethal Concentration 50 (LC50) values in the range of 9 to 46 μg/mL. Most of the compounds evidenced antileishmanial activity. In axenic amastigotes, the antileishmanial activity varied from 14 to 57 μg/mL, while in intracellular amastigotes their activity varied from 17 to 50 μg/mL. N-Chloromethyl-N,N-dimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (1a), N-iodomethyl-N,N-dimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (2a), N,N,N-trimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (3a) and N,N,N-trimethyl-N-(5,5-diphenylpent-4-en-1-yl)ammonium iodide (3b) turned out to be the most active compounds against intracellular amastigotes of L. (V) panamensis, with EC50 values varying between 24.7 for compound 3b and 38.4 μg/mL for compound 1a. Thus, these compounds represents new “hits” in the development of leishmanicidal drugs.
Highlights
Leishmaniasis is an infectious disease caused by trypanosomatid parasites of the Leishmania genus
At least 20 Leishmania species are known to cause different clinical forms of leishmaniasis in humans and they are present in different locations worldwide [1]
Based on the facts that: (i) choline is important to the biosynthesis of phosphatidylcholine in Leishmania parasites [15]; (ii) some quaternary ammonium salts such as edelfosine, ilmofosine and miltefosine have antileishmanial activity [17] and; (iii) some quaternary ammonium compounds may efficiently inhibit choline transport in other intracellular parasites such as P. falciparum [19], this work reports the synthesis of a series of new quaternary ammonium salts and their in vitro effectiveness against the human pathogen Leishmania (V.) panamensis, which causes cutaneous and mucocutaneous leishmaniasis
Summary
Leishmaniasis is an infectious disease caused by trypanosomatid parasites of the Leishmania genus. At least 20 Leishmania species are known to cause different clinical forms of leishmaniasis in humans and they are present in different locations worldwide [1]. Molecules 2016, 21, 381 manifestations: visceral (VL), mucocutaneous (ML), and cutaneous leishmaniasis (CL), respectively. These vary according to the Leishmania species, the geographical region, and the hosts immune response. Leishmaniases are endemic in 98 countries over five continents, with CL being the most prevalent around the world. It is estimated that 12 million people are infected, with 0.7 to
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