Quinolizidine-Derived Lucanthone and Amitriptyline Analogues Endowed with Potent Antileishmanial Activity

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.

Multitarget Biological Profiling of New Naphthoquinone and Anthraquinone-Based Derivatives for the Treatment of Alzheimer’s Disease

“…In order to investigate the molecular determinants for the potency and selectivity of 2 toward MAO B and AChE, molecular modeling studies were next performed. Accordingly, the putative binding sites and modes for 2 were first identified on both human enzymes (Figure ) and then molecular dynamics (MD) simulations of the resulting inhibitor/protein complexes were carried out to evaluate the corresponding free energy of binding (Δ G bind ) following our consolidated approach. − A per-residue binding free energy deconvolution (PRBFED) of the enthalpic (Δ H bind,res ) terms , was finally performed to define and describe the intermolecular interactions between compound 2 and the two proteins (Figure ). The simulation results clearly show that 2 has a substantially higher affinity for MAO B (Δ G bind = −10.98 ± 0.16 kcal/mol) than for AChE (Δ G bind = −7.93 ± 0.13 kcal/mol), in agreement with the relevant experimental findings.…”

“…Each intermolecular complex was then solvated by a cubic box of TIP3P water molecules and energy minimized using a combination of molecular dynamics (MD) techniques. , 20 ns molecular dynamics (MD) simulations at 298 K were then employed for system equilibration, and further, 50 ns MD simulations were run for data production. The binding free energies of the 2 /MAO B and 2 /AChE complexes were calculated following the MM/PBSA methodology as previously described. − The PRBFED analysis was carried out using the molecular mechanics/generalized Boltzmann surface area (MM/GBSA) approach, as already detailed, , and was based on the same snapshots used in the binding free energy calculation.…”

(-)-5-Demethoxygrandisin B a New Lignan from Virola surinamensis (Rol.) Warb. Leaves: Evaluation of the Leishmanicidal Activity by In Vitro and In Silico Approaches

“…The TryR enzyme plays a crucial role in the antioxidant defense of trypanosomatids and has been widely used in molecular modeling studies in the literature [ 73 , 74 ]. Tetrahydrofuran lignans isolated from V. surinamensis showed potent trypanocidal activity against the trypomastigote form of T. cruzi [ 11 ].…”

2-Aminofluorene based triazole cocktailed with organosilane as UV-visible and fluorescence sensor for the highly selective detection of Fe(iii) ion and its anti-leishmanial activity

“…Also, they are used in biomedical research for photodynamic treatment, medical generics, dye-sensitized solar cells, and bioimaging. [21][22][23][24][25][26][27]…”