Abstract
Leishmaniases are neglected diseases that are endemic in many tropical and sub-tropical Countries. Therapy is based on different classes of drugs which are burdened by severe side effects, occurrence of resistance and high costs, thereby creating the need for more efficacious, safer and inexpensive drugs. Herein, sixteen 9-thioxanthenone derivatives (lucanthone analogues) and four compounds embodying the diarylethene substructure of amitriptyline (amitriptyline analogues) were tested in vitro for activity against Leishmania tropica and L. infantum promastigotes. All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety. All compounds displayed activity against both species of Leishmania with IC50 values in the low micromolar range, resulting in several fold more potency than miltefosine, comparable to that of lucanthone, and endowed with substantially lower cytotoxicity to Vero-76 cells, for the best of them. Thus, 4-amino-1-(quinolizidinylethyl)aminothioxanthen-9-one (14) and 9-(quinolizidinylmethylidene)fluorene (17), with selectivity index (SI) in the range 16–24, represent promising leads for the development of improved antileishmanial agents. These two compounds also exhibited comparable activity against intramacrophagic amastigotes of L. infantum. Docking studies have suggested that the inhibition of trypanothione reductase (TryR) may be at the basis (eventually besides other mechanisms) of the observed antileishmanial activity. Therefore, these investigated derivatives may deserve further structural improvements and more in-depth biological studies of their mechanisms of action in order to develop more efficient antiparasitic agents.
Highlights
All compounds were characterized by the presence of a bulky quinolizidinylalkyl moiety
The studied compounds were characterized by the presence of the bulky quinolizidinylalkyl moieties, which were shown to improve the antiplasmodial and/or antileishmanial activity in the corresponding chloroquine and clofazimine analogs [30] and in the set of 1-basic substituted 2-phenyl/benzyl benzimidazoles [31]
Cmoimltemfoosninlye, aalcltcivoimtypowuansdhsiwgheerre sfoevr eLr.alt–rfooplidcamthoraenpLo.teinnfta,nutpumto. 1In7-fcoolmd pagaariisnosnt Lt.otrmopiilctaefaonsidnue,patlol c9o-fmolpdoaugnadinsswt Le.rienfsaenvtuerma.l–Tfhoeldsemreosrueltpsointednict,atuepthtoat1th7-efoinldtroadguacintisotnLo. ftraoqpuicianoalnizdiduipnytloa9lk-fyollmd oaigeatyinosnt L. infantum. These results indicate that the introduction of a quinolizidinyl alkyl moiety on all the considered tricyclic systems is consistent with the expression of valuable antileishmanial activity, provided that, in the case of thioxanthenone, suitable substituents are present on position 4 and 7
Summary
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