Cocrystals of a coumarin derivative: an efficient approach towards anti-leishmanial cocrystals against MIL-resistant Leishmania tropica.

Leishmaniasis is a neglected parasitic tropical disease with numerous clinical manifestations. One of the causative agents of cutaneous leishmaniasis (CL) is Leishmania tropica (L. tropica) known for causing ulcerative lesions on the skin. The adverse effects of the recommended available drugs, such as amphotericin B and pentavalent antimonial, and the emergence of drug resistance in parasites, mean the search for new safe and effective anti-leishmanial agents is crucial. Miltefosine (MIL) was the first recommended oral medication, but its use is now limited because of the rapid emergence of resistance. Pharmaceutical cocrystallization is an effective method to improve the physicochemical and biological properties of active pharmaceutical ingredients (APIs). Herein, we describe the cocrystallization of coumarin-3-carboxylic acid (CU, 1a; 2-oxobenzopyrane-3-carboxylic acid, C10H6O4) with five coformers [2-amino-3-bromopyridine (1b), 2-amino-5-(trifluoromethyl)-pyridine (1c), 2-amino-6-methylpyridine (1d), p-aminobenzoic acid (1e) and amitrole (1f)] in a 1:1 stoichiometric ratio via the neat grinding method. The cocrystals 2-6 obtained were characterized via single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis, as well as Fourier transform infrared spectroscopy. Non-covalent interactions, such as van der Waals, hydrogen bonding, C-H...π and π...π interactions contribute significantly towards the packing of a crystal structure and alter the physicochemical and biological activity of CU. In this research, newly synthesized cocrystals were evaluated for their anti-leishmanial activity against the MIL-resistant L. tropica and cytotoxicity against the 3T3 (normal fibroblast) cell line. Among the non-cytotoxic cocrystals synthesized (2-6), CU:1b (2, IC50 = 61.83 ± 0.59 µM), CU:1c (3, 125.7 ± 1.15 µM) and CU:1d (4, 48.71 ± 0.75 µM) appeared to be potent anti-leishmanial agents and showed several-fold more anti-leishmanial potential than the tested standard drug (MIL, IC50 = 169.55 ± 0.078 µM). The results indicate that cocrystals 2-4 are promising anti-leishmanial agents which require further exploration.

Interleukin-7 potentiates MAPK10-elicited host-protective vaccine against Leishmania donovani.

Leishmania donovani causes the potentially fatal disease visceral leishmaniasis for which neither a vaccine nor an adjuvant for human use exists. Although interleukin-7 (IL-7) is implicated in CD4+ T-cell response stabilization, its anti-leishmanial function is uncertain. Therefore, we examined whether IL-7 would potentiate the efficacy of Leishmania major-expressed MAPK10 (LmjMAPK10; M10)-elicited anti-leishmanial host-protective response. We observed that aligning with IL-7R expression, IL-7 increased IFN-γ-secreting TH1 cell but reduced IL-4-producing TH2 cells and production of IL-10 and TGF-ß effectuating anti-leishmanial functions in susceptible BALB/c mouse-derived macrophages. Co-culturing IL-7-pre-treated L. donovani-infected macrophages with L. donovani-infected BALB/c-derived T cells induced IFN-γ-dominated TH1 type anti-leishmanial function. IL-7 treatment of L. donovani-infected BALB/c mice significantly reduced splenic and hepatic parasite loads. Co-culturing CD4+ T cells from IL to 7-treated mice with L. donovani-infected macrophages reduced amastigote numbers suggesting IL-7-elicited host-protective effector T cells. Priming BALB/c with M10 + IL-7 reduced the splenic parasite burden more effectively than that was observed in M10-primed mice. An enhanced protection against L. donovani infection was accompanied by enhanced IL-12 and IFN-γ, but suppressed IL-10 and IL-4, response and host-protective TH1 and memory T cells. These results indicate IL-7-induced leishmanial antigen-specific memory T cell response that protects a susceptible host against L. donovani infection.

Synergistic combination of Cinnamomum verum and Syzygium aromaticum treatment for cutaneous leishmaniasis and investigation of their molecular mechanism of action.

Combination therapy at appropriately suitable doses presents a promising alternative to monotherapeutic drugs. In this study, Cinnamomum verum and Syzygium aromaticum essential oils and their major compounds have exhibited substantial leishmaniacidal potential against both promastigote and amastigote forms of Leishmania (L.) major. However, they displayed high cytotoxicity against Raw264.7 macrophage cells. Interestingly, when combined with each other or with amphotericin B, they demonstrated a synergistic effect (FIC<0.5) with low cytotoxicity. These combinations are able to modulate the production of nitric oxide (NO) by macrophages. Notably, the combination of S. aromaticum Essential oil with amphotericin B stimulates macrophage cells by increasing NO production to eliminate leishmanial parasites. Furthermore, investigation of the molecular mechanism of action of these synergistic combinations reveals potent inhibition of the sterol pathway through the inhibition of the CYP51 gene expression. The findings suggest that combination therapy may offer significant therapeutic benefits in both food and pharmaceutical fields.

Anti-leishmanial, immunomodulatory and additive potential effect of Piperine on Leishmania major: The in silico and in vitro study of Piperine and its combination.

BACKGROUND: Piperine (Pn), an indole alkaloid compound found in pepper, is an effective compound with anti-leishmanial medications that administered alone or in combination. This study aimed to use Pn for possible biochemical targets and to assess mechanisms of anti-leishmanial action and immunomodulatory roles. METHODS: The ability of Pn to bind to interleukin-12P40 (IL-12P40) and interferon-γ (IFN-γ) was investigated using molecular docking. The leishmanicidal effect of Pn, meglumine antimoniate (Glucantime®; MA), and Pn plus MA was assessed on Leishmania major promastigotes and amastigotes. A real-time PCR was applied to quantify cytokines gene expression in drug-treated murine macrophages. RESULTS: The molecular docking findings indicated that Pn could bind to IL-12P40/IFN-γ. In silico analyses showed an affinity of Pn to IL-12P40/IFN-γ, with the MolDock score of -236.91 and -64.87 kcal/mol, respectively. Pn plus MA reduced the proliferation rate of promastigote and amastigote forms of L. major compared to each drug alone (IC50 = 43.22 and 19.41 µg/mL, respectively). Moreover, the combination drug demonstrated no cytotoxicity as the selectivity index (SI) was 14.81. Also, Th1-related cytokines were upregulated, while Th2-related cytokines were downregulated in Pn combination-treated murine macrophages. CONCLUSIONS: The superior effectiveness of combination therapy on L. major warrants further investigations on the clinical potential of this combination in the treatment of leishmaniasis.

Anti-leishmanial and cytotoxic compounds isolated from marine sponge Hemimycale sp.

The methanolic extract of the marine sponge Hemimycale sp. yielded two new compounds; 1-(2'-methyl heptadecyl) phenol (1) and a new pyrazole derivative; 4-(hydroxymethyl)-1H-pyrazol-3-ol (2), together with previously isolated (2'R)-2'-hydroxy-N-((2S,3S,4R)-1,3,4-trihydroxy-16-methylpentadecan-2-yl)docosanamide (3), cholesterol (4), 5, 8-epi-dioxycholest-6-en-3-ol (5) and 3-acetylsesterstatin 3 (6), which were firstly reported from family Hymedesmiidae. Their structure elucidation was based on extensive nuclear magnetic resonance spectroscopy and high resolution-electrospray ionization-mass spectrometry. The isolated compounds were evaluated for their anti-leishmanial and cytotoxic activities. Compound 5 showed remarkable anti-leishmanial activity with IC50 value of 15.8 ± 0.92 µg/mL comparable with the standard miltefosine (IC50 = 3.2 ± 0.07 µg/mL), while compound 3 exhibited noteworthy cytotoxicity against A594 cell line with IC50 value of 29.6 ± 1.68 µg/mL compared to etoposide (IC50 = 10.9 ± 1.30 µg/mL).

4',7-dihydroxyflavone conjugated carbon nanotube formulation demonstrates improved efficacy against Leishmania parasite.

One of the global problems of rising concern is the spread of the neglected tropical disease, leishmaniasis. There are several drugs used for the treatment of the disease but the repertoire of drugs has drawbacks like toxicity and low therapeutic value. Considering the need for new drugs, we studied the synthesis of 4',7-dihydroxyflavone conjugated multi-walled carbon nanotubes (47DHF-MWCNTs) and evaluated their anti-leishmanial activity against Leishmania donovani. The compound 47DHF was conjugated to the acid oxidized MWCTNs by Steglich esterification. The synthesized 47DHF-MWCNTs were characterized by UV spectroscopy, and, from the zeta value of 35 mV, they were found to be stable. 47DHF-MWCNTs possessed 84% drug loading efficiency and 63% cumulative drug release at intra-macrophage pH of 5.8. Moreover, the evaluation of 47DHF-MWCNTs for activity showed an IC50 value of 0.051 ± 0.01 µg/ml and 0.072 ± 0.01 µg/ml against the promastigote and amastigote form, respectively. 47DHF-MWCNTs exhibited an infectivity index of 42 and selectivity index of 95, suggesting the activity of 47DHF-MWCNTs against intracellular amastigotes in the study. The 47DHF-MWCNTs also had low cytotoxicity towards macrophage cells. Fascinatingly, the 47DHF-MWCNTs treatment causes a high accumulation of ROS in the promastigotes suggesting the mechanism of anti-leishmanial activity to be ROS mediated. Summarizing from our results, we propose for the first time a novel 47DHF conjugated MWCNTs capable of anti-leishmanial activity with lower cytotoxicity that has a huge potential to be a formulation against leishmaniasis.

2-Aroyl quinazolinone: Synthesis and in vitro anti-parasitic activity.

Trypanosomes and Leishmania are parasitic protozoans that affect millions of people globally. Herein we report the synthesis of 2-aroyl quinazolinones and their antiprotozoal efficacy against Trypanosoma brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. These compounds were counter-screened against a human cell line for cytotoxicity. Thirteen of the twenty target compounds in this study inhibited the growth of these parasites, with compounds KJ1, and KJ10 exhibiting IC50 values of 4.7 µM (T. b. brucei) and 1.1 µM (T. b. rhodesiense), respectively.

Systems biology of autophagy in leishmanial infection and its diverse role in precision medicine.

Autophagy is a contentious issue in leishmaniasis and is emerging as a promising therapeutic regimen. Published research on the impact of autophagic regulation on Leishmania survival is inconclusive, despite numerous pieces of evidence that Leishmania spp. triggers autophagy in a variety of cell types. The mechanistic approach is poorly understood in the Leishmania parasite as autophagy is significant in both Leishmania and the host. Herein, this review discusses the autophagy proteins that are being investigated as potential therapeutic targets, the connection between autophagy and lipid metabolism, and microRNAs that regulate autophagy and lipid metabolism. It also highlights the use of systems biology to develop novel autophagy-dependent therapeutics for leishmaniasis by utilizing artificial intelligence (AI), machine learning (ML), mathematical modeling, network analysis, and other computational methods. Additionally, we have shown many databases for autophagy and metabolism in Leishmania parasites that suggest potential therapeutic targets for intricate signaling in the autophagy system. In a nutshell, the detailed understanding of the dynamics of autophagy in conjunction with lipids and miRNAs unfolds larger dimensions for future research.

In vitro Anti-Leishmanial Activities of Methanol Extract of Brucea antidysenterica J.F. Mill Seeds and Its Solvent Fractions.

Introduction: Leishmaniasis is one of the neglected tropical diseases, threatening lives of about 350 million people globally. Brucea antidysenterica seeds are used for the treatment of cutaneous leishmaniasis in the traditional medicine in Ethiopia. Objective: This study aimed to evaluate Brucea antidysenterica seeds' anti-leishmanial activity in vitro. Methods: The crude (80% methanol) extract of Brucea antidysenterica seeds and its fractions were evaluated for their anti-leishmanial activities against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania aethiopica, and for their cytotoxic effects against mammalian cells. The quantitative estimations of total phenolic compounds (TPCs), flavonoids (TFCs) and alkaloids (TACs) were determined, spectrophotometrically. Median inhibitory concentration (IC50) and median cytotoxic concentration (CC50) of the extract and its solvent fractions were calculated using GraphPad Prism 9.1.0 computer software. Data was presented as mean ± standard error of the mean (SEM). Results: The crude extract and its hexane, ethyl acetate and butanol fractions showed anti-leishmanial activities, with IC50 values of 4.14-60.12 µg/mL against promastigotes, and 6.16-40.12 µg/mL against amastigotes of both Leishmania species. They showed moderate cytotoxicity against Vero cell lines and peritoneal mice macrophages, with CC50 values of 100-500 µg/mL, but >1600 µg/mL against red blood cells. Selectivity indices ranged from 7.97 to 30.97. The crude extract, and its ethyl acetate and hexane fractions possessed 54.78-127.72 mg of gallic acid equivalent TPC, 18.30-79.21 mg of quercetin equivalent TFC, and 27.62-97.22 mg of atropine equivalent TAC per gram of extracts. Conclusion: The seeds of the plant possessed anti-leishmanial activities against L. aethiopica and L. donovani that might provide a scientific justification for its use in the treatment of leishmaniasis by traditional healers. Future works are recommended to isolate, purify and identify the possible secondary metabolites attributed to the anti-leishmanial activity.

Leishmanicidal Activity of Guanidine Derivatives against Leishmania infantum.

Leishmaniasis is a neglected tropical infectious disease with thousands of cases annually; it is of great concern to global health, particularly the most severe form, visceral leishmaniasis. Visceral leishmaniasis treatments are minimal and have severe adverse effects. As guanidine-bearing compounds have shown antimicrobial activity, we analyzed the cytotoxic effects of several guanidine-bearing compounds on Leishmania infantum in their promastigote and amastigote forms in vitro, their cytotoxicity in human cells, and their impact on reactive nitrogen species production. LQOFG-2, LQOFG-6, and LQOFG-7 had IC50 values of 12.7, 24.4, and 23.6 µM, respectively, in promastigotes. These compounds exhibited cytotoxicity in axenic amastigotes at 26.1, 21.1, and 18.6 µM, respectively. The compounds showed no apparent cytotoxicity in cells from healthy donors. To identify mechanisms of action, we evaluated cell death processes by annexin V and propidium iodide staining and nitrite production. Guanidine-containing compounds caused a significant percentage of death by apoptosis in amastigotes. Independent of L. infantum infection, LQOFG-7 increased nitrite production in peripheral blood mononuclear cells, which suggests a potential mechanism of action for this compound. Therefore, these data suggest that guanidine derivatives are potential anti-microbial molecules, and further research is needed to fully understand their mechanism of action, especially in anti-leishmanial studies.

Identification of potential novel inhibitors against glutamine synthetase enzyme of Leishmania major by using computational tools.

Glutamine Synthetase (GS) is functionally important in many pathogens, so its viability as a drug target has been widely investigated. We identified Leishmania major glutamine synthetase (Lm-GS) as an appealing target for developing potential leishmaniasis inhibitors. Comparative modeling, virtual screening, MD simulations along with MM-PBSA analyses were performed and two FDA approved compounds namely Chlortalidone (id ZINC00020253) and Ciprofloxacin (id ZINC00020220) were identified as potential inhibitor among the screened library. These compounds may be used as a lead molecule, although additional in vitro and in vivo testing is required to establish its anti-leishmanial effect. Hence, the goal of this study was to locate and identify certain medications that were previously FDA-approved for definite disorders and that might show anti-leishmanial effect. Due to GS's presence in additional Leishmania species, a novel medication docked with Lm-GS may have broad anti-leishmania efficacy.Communicated by Ramaswamy H. Sarma.

Computer-Aided drug design of new 2-amino-thiophene derivatives as anti-leishmanial agents.

The leishmaniasis is a neglected disease caused by a group of protozoan parasites from the genus Leishmania whose treatment is limited, obsolete, toxic, and ineffective in certain cases. These characteristics motivate researchers worldwide to plan new therapeutic alternatives for the treatment of leishmaniasis, where the use of cheminformatics tools applied to computer-assisted drug design has allowed research to make great advances in the search for new drugs candidates. In this study, a series of 2-amino-thiophene (2-AT) derivatives was screened virtually using QSAR tools, ADMET filters and prediction models, allowing direct the synthesis of compounds, which were evaluated in vitro against promastigotes and axenic amastigotes of Leishmania amazonensis. The combination of different descriptors and machine learning methods led to obtaining robust and predictive QSAR models, which was obtained from a dataset composed of 1862 compounds extracted from the ChEMBL database, with correct classification rates ranging from 0.53 (for amastigotes) to 0.91 (for promastigotes), allowing to select eleven 2-AT derivatives, which do not violate Lipinski's rules, exhibit good druglikeness, and with probability ≤70% of potential activity against the two evolutionary forms of the parasite. All compounds were properly synthesized and 8 of them were shown to be active at least against one of the evolutionary forms of the parasite with IC50 values lower than 10 µM, being more active than the reference drug meglumine antimoniate, and showing low or no citotoxicity against macrophage J774.A1 for the most part. Compounds 8CN and DCN-83, respectively, are the most active against promastigote and amastigote forms, with IC50 values of 1.20 and 0.71 µM, and selectivity indexes (SI) of 36.58 and 119.33. Structure Activity Relationship (SAR) study was carried out and allowed to identify some favorable and/or essential substitution patterns for the leishmanial activity of 2-AT derivatives. Taken together, these findings demonstrate that the use of ligand-based virtual screening proved to be quite effective and saved time, effort, and money in the selection of potential anti-leishmanial agents, and confirm, once again that 2-AT derivatives are promising hit compounds for the development of new anti-leishmanial agents.

Amphotericin B Nano-Assemblies Circumvent Intrinsic Toxicity and Ensure Superior Protection in Experimental Visceral Leishmaniasis with Feeble Toxic Manifestation.

In spite of its high effectiveness in the treatment of both leishmaniasis as well as a range of fungal infections, the free form of the polyene antibiotic amphotericin B (AmB) does not entertain the status of the most preferred drug of choice in clinical settings. The high intrinsic toxicity of the principal drug could be considered the main impedance in the frequent medicinal use of this otherwise very effective antimicrobial agent. Taking into consideration this fact, the pharma industry has introduced many novel dosage forms of AmB to alleviate its toxicity issues. However, the limited production, high cost, requirement for a strict cold chain, and need for parenteral administration are some of the limitations that explicitly compel professionals to look for the development of an alternate dosage form of this important drug. Considering the fact that the nano-size dimensions of drug formulation play an important role in increasing the efficacy of the core drug, we employed a green method for the development of nano-assemblies of AmB (AmB-NA). The as-synthesized AmB-NA manifests desirable pharmacokinetics in the treated animals. The possible mechanistic insight suggested that as-synthesized AmB-NA induces necrosis-mediated cell death and severe mitochondrial dysfunction in L. donovani promastigotes by triggering depolarization of mitochondrial membrane potential. In vivo studies demonstrate a noticeable decline in parasite burden in the spleen, liver, and bone marrow of the experimental BALB/c mice host. In addition to successfully suppressing the Leishmania donovani, the as-formed AmB-NA formulation also modulates the host immune system with predominant Th1 polarization, a key immune defender that facilitates the killing of the intracellular parasite.

Mannosylated imiquimod-terbinafine co-loaded transethosomes for cutaneous leishmaniasis; assessment of its anti-leishmanial potential, in vivo safety and immune response modulation.

Current treatment options for cutaneous leishmaniasis are associated with myriad limiting factors including low penetration, poor efficacy, and drug toxicities. Herein, we reported imiquimod and terbinafine co-loaded mannosylated transethosomes (IMQ-TER-MTES) with enhanced cutaneous retention, macrophage targeting, anti-leishmanial potential, and dermal immunomodulation. IMQ-TER-MTES were optimized using Design Expert® followed by their loading into chitosan gel. Moreover, the antileishmanial response against amastigotes-infected macrophages and Leishmania-infected BALB/c mice was evaluated. Finally, the safety and immunomodulation activity of IMQ-TER-MTES gel was performed using BALB/c mice. Optimized IMQ-TER-MTES showed nano-sized particles with low poly-dispersibility index (PDI) and high drug entrapment. Mannosylation has augmented macrophage targeting and the internalization capability of TES. IMQ-TER-MTES showed significantly reduced IC50 value (19.56 ± 3.62 µg/ml), higher selectivity index (29.24), and synergism against Leishmania major (L. major) amastigotes. In L. major infected BALB/c mice, the cutaneous lesion healing potential of IMQ-TER-MTES was also elevated with reduced lesion size (1.52 ± 0.43 mm). Superior safety of IMQ-TER-MTES was observed in BALB/c mice along with adequate stimulation of dermal immune cells, in contrast to the ALDARA®. Moreover, incremented Nuclear factor Kappa-ß (NF-κß) and nitric oxide (NO) biosynthesis were observed with IMQ-TER-MTES.

Ascaridole exerts the leishmanicidal activity by inhibiting parasite glycolysis.

BACKGROUND: The global burden of leishmaniasis is exacerbated by the limited repertoire of drugs, resulting in an urgent need to develop new therapeutic alternatives. Endoperoxides like ascaridole have emerged as promising anti-parasitic candidates, and its effectiveness was established in an animal model of cutaneous leishmaniasis (CL). However, its impact on Leishmania donovani parasites, causative of visceral leishmaniasis (VL) remains to be established. PURPOSE: This study aimed to delineate the underlying mechanisms contributing towards the leishmanicidal effect of ascaridole in terms of its impact on the cellular redox status and metabolic bioenergetics of L. donovani parasites. METHODOLOGY: The anti-promastigote activity of ascaridole was established by a cell viability assay in L. donovani [MHOM/IN/1983/AG83] and anti-amastigote activity by microscopy and ddPCR (droplet digital polymerase chain reaction). The cellular redox status, mitochondrial membrane potential (MMP), annexin V positivity and cell cycle arrest was evaluated by flow cytometry, while cellular and mitochondrial bioenergetics was assessed using Agilent XFp Analyzer, and the levels of ATP was measured by chemiluminescence. RESULTS: Ascaridole demonstrated strong anti-promastigote and anti-amastigote activities in l. donovani, IC50 (half maximal Inhibitory concentration) being 2.47 ± 0.18 µM and 2.00±0.34 µM respectively, while in J774.A1 and murine peritoneal macrophages, the CC50 (half maximal cytotoxic concentration) was 41.47 ± 4.89 µM and 37.58 ± 5.75 µM respectively. Ascaridole disrupted the redox homeostasis via an enhanced generation of reactive oxygen species (ROS), lipid peroxidation and concomitant depletion of thiols. However, it failed to increase the generation of mitochondrial superoxide, which minimally impacted on mitochondrial respiration and was corroborated by energy metabolism studies. Instead, ascaridole inhibited glycolysis of promastigotes, caused a loss in MMP, which translated into ATP depletion. In promastigotes, ascaridole enhanced annexin-V positivity and caused a cell cycle arrest at sub- G0/G1 phase. CONCLUSION: In summary, ascaridole displays its leishmanicidal activity possibly due to its ability to auto-generate free radicals following cleavage of its endoperoxide bridge that led to disruption of the redox homeostasis, inhibition of glycolysis and culminated in an apoptotic like cell death.

Modulating aryl substitution: Does it play a role in the anti-leishmanial activity of a series of tetra-aryl Sb(V) fluorinated carboxylates?

Eight tetra-arylantimony carboxylates of the general formula Ar4SbOC(O)R with Ar = Ph (a), p-Tol (b), R = C6F5 (1), CH2CF3 (2), CF2Br (3), CF2CF2CF3 (4) have been synthesised and characterised. Two of them (2b, 3b) are structurally novel. All structures were analytically characterised by FT-IR, 1H, 13C NMR spectroscopy. Previously synthesised structures were also analysed by X-ray diffraction and their solid-state structures authenticated. The solid-state structures exhibited a typical trigonal-bipyramidal geometry at the antimony centre, with the carboxylic oxygen and one of the aryl group carbons occupying axial positions with the remaining three aryl groups in the equatorial plane. All complexes were screened for their anti-leishmanial activity and cytotoxicity towards mammalian macrophages. No anti-leishmanial testing on tetra-arylantimony carboxylates have been previously performed. It was observed that the tetra-phenylantimony analogues are far more effective in comparison to the tetra-(p-tolyl)antimony complexes, with IC50 values in the ranges of 2.90-7.75 µM and 64.97-124.71 µM, respectively, for the promastigote assay, and 70.87-76.28 µM, 9.08-10.18 µM for the macrophages. Interestingly, the dose-response curve for tetra-phenylantimony carboxylates is a standard sigmoid curve, while for all tetra-(p-tolyl)antimony complexes it has an unusual inverted U-shape, indicating they are effective only at a low dose. All tetra-phenylantimony carboxylates were assessed for their anti-amastigote activity and showed promising results: 1.00% ± 1.44 (1a), 5,25% ± 1.72 (2a), 20.75% ± 8.46 (3a), 5.75% ± 1.62 (4a) at 10 µM.

Gold and silver nanoparticles functionalized with 4',7-dihydroxyflavone exhibit activity against Leishmania donovani.

Leishmaniasis is a neglected tropical disease that has been burdening the world for over a century. Though there are drugs to treat leishmaniasis, the repertoire suffers several drawbacks like toxicity and low therapeutic value. Therefore, there is a rising concern to develop new anti-leishmanial strategies. In this study, we report, for the first time, the one-pot synthesis method and functionalization of gold and silver nanoparticles with 4',7-dihydroxyflavone (Au-47DHF and Ag-47DHF)) and their anti-leishmanial activity. Oval and spherical-shaped Au-47DHF nanoparticles were obtained with an average size of 5.8 ± 0.1 nm and while synthesized dodecahedron-shaped Ag-47DHF had an average size of 25.1 ± 1 nm. The zeta potential of Au-47DHF and Ag-47DHF were measured to be stable with values of 40 mV and 60 mV, respectively. The functionalization of nanoparticles with 4',7-dihydroxyflavone was confirmed by FTIR spectra. Both Au-47DHF and Ag-47DHF exhibited promising anti-leishmanial activity against the promastigote forms with IC50 values of 0.1226 ± 0.02 µg/ml and 0.8483 ± 0.14 µg/ml, respectively. The nanoparticles were also capable of anti-intracellular amastigote activity with 0.121 ± 0.36 µg/ml and 0.215 ± 0.85 µg/ml for Au-47DHF and Ag-47DHF, respectively. Interestingly, the treatment with Au-47DHF and Ag-47DHF nanoparticles generated high ROS concentrations in the parasites suggesting a ROS-mediated anti-leishmanial activity of Au-47DHF and Ag-47DHF. Concluding from the results, we present here a novel synthesis method of Au-47DHF and Ag-47DHF nanoparticles that have immense potential to be anti-leishmanial agents.

Synthesis, bio-physical and anti-leishmanial studies of some novel indolo[3,2-a]phenanthridine derivatives.

Eight indolo[3,2-a]phenanthridine derivatives have been synthesized in a regioselective manner involving intramolecular Heck-type arylation as a key step. The compounds display interesting photophysical proprties and hence evaluated for their ability to interact with ct-DNA. Preliminary biophysical studies via UV and Fluorescence spectrophotometric titration with ct-DNA, and dye displacement studies with well known intercalator ethidium bromide and the groove binder Hoechst 33,258 reveal that the binding mode is probably minor groove binding. The prepared indolophenanthridine derivatives have also been evaluated as anti-leishmanial agents for the first time. MTT-assays for cell cytotoxicity against Leishmania promastigotes and Leishmania amastigotes were studied with the compounds 10b-f, 12-14 for the determination of their IC50 values. Cytotoxicity was determined using a murine RAW 264.7 cell line and human embryonic kidney cell line HEK 293. In L. donovani amastigote assay, compounds 10e, 10f and 12 showed good activity with relatively low cytotoxicity against RAW 264.7, resulting in acceptable selectivity indices. Selectivity index determination indicated compounds to be potent anti-leishmanial agents while 10b, 10c and 14 showed moderate selectivity index. Moreover, cell-cycle analysis of four different compounds 10b, 12, 13 and 14, representative of each group, was performed by FACS as an attempt to understand the mechanism of actions of these different sub-classes of the compounds on Leishmania.

Aurothiomalate-Based Drugs as Potentially Novel Agents Against Leishmania major: A Mini Review.

PURPOSE: Leishmaniasis is a major public health problem worldwide in many parts of the world. Current anti-leishmanial drugs have only limited clinical efficacy. Aurothiomalate derivatives are useful for treating rheumatoid arthritis, but have emerged as a promising therapeutic candidate for leishmaniasis. This paper gives a review of the literature about the usefulness of aurothiomalate derivatives against leishmaniasis. METHODS: In this study, we reviewed the proposed mechanisms of action of aurothiomalate and related compounds on the metabolism of L. major and collected data by searching relevant articles. RESULTS: Aurothiomalate-based drugs could be effective against leishmaniasis through two direct and indirect mechanisms: first, cytotoxic effects on parasites via thiomalate's false substrate role in the citric acid cycle against malate; and second, immunosuppressive and anti-inflammatory effects of aurothiomalate derivatives with prostaglandin production inhibitory effects. CONCLUSIONS: The current study documented that aurothiomalate-based drugs could be effective against leishmaniasis through two direct and indirect mechanisms of action. Gold thiomalate as a promising hit should be evaluated against L. major in vitro and in vivo conditions in the future.