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Background and purpose: Isatin derivatives have excited attention due to their biological attractions, especially, anticancer properties. Isatin analogs such as semaxanib and sunitinib were exposed to tyrosine kinase inhibitory properties. N-substituted isatins were reported to show cytotoxic activity. On the other, the extension of impressive and cost-effective agents against leishmaniasis is necessary in third-world countries. The capability of isatin derivatives to create novel anticancer and anti-leishmanial compounds has been identified in medicinal chemistry research. The current study aimed to synthesize N-alkyl-isatin-3-imino aromatic amine compounds and evaluate their biological effects. Experimental approach: Synthesis started with the formation of 2-chloro-N-phenylacetamide derivatives by the reaction of aniline derivatives with chloroacetyl chloride. N-alkylation of isatin was performed in the presence of K2CO3 in N, N-dimethylformamide. Final products were prepared via the condensation of N-alkyl isatin derivatives with aromatic amines. Cell viability was checked out by using the MTT assay against cancer cells. Final compounds were screened for anti-leishmanial activity. The molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to define the possible interactions. Findings/Results: Compounds 5c and 4d with IC50 value of 50 µΜ showed cytotoxic activity on the MCF-7 cell line. Compound 5b presented anti-leishmanial activity against promastigote form after 48 h (IC50:59 µΜ) and 72 h (IC50: 41 µΜ) incubations. The highest docking score was -7.33 kcal/mol for compound 4d. Conclusions and implications: The nature of substitution in the N1 region of isatin seems to be able to influence the cytotoxic activity. Based on the obtained results of docking and cytotoxic tests, compound 4d seems to be a good compound for further investigations.

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The present study aimed to assess the anti-leishmanial effects of curcumin nanoemulsion (CUR-NE) against Leishmania major (MRHO/IR/75/ER) in both in vitro and in vivo experiments. CUR-NE was successfully prepared via the spontaneous emulsification method. The in vitro effect of various concentrations of CUR-NE against L. major promastigotes was assessed using the flow cytometry method. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 106 L. major promastigotes. Mice were treated with topical CUR-NE (2.5 mg/ml), intra-lesion injection of CUR-NE (2.5 mg/ml), topical CUR suspension (CUR-S, 2.5 mg/ml), topical NE without CUR (NE-no CUR), amphotericin B as the positive control group, and infected untreated mice as the negative control group. In vitro exposure of promastigotes to CUR-NE showed a dose-dependent anti-leishmanial effect, with a 67.52 ± 0.35% mortality rate at a concentration of 1250 µg/ml and an IC50 of 643.56 µg/ml. In vivo experiments showed that topical CUR-NE and CUR-S significantly decreased the mean lesion size in mice after four weeks from 4.73 ± 1.28 to 2.78 ± 1.28 mm and 4.45 ± 0.88 to 3.23 ± 0.59 mm, respectively (p = 0.001). Furthermore, CUR-NE significantly decreased the parasite load in treated mice compared with the negative control group (p = 0.001). Results from the current study demonstrated the promising activity of CUR-NE against L. major in both in vitro and in vivo experiments. Moreover, CUR-NE was more efficient than CUR-S in healing and reducing parasite burden in mouse models. Future studies should aim to identify molecular mechanisms as well as the pharmacologic and pharmacokinetic aspects of CUR-NE.

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A new tetramic acid glycoside, aurantoside L (1), was isolated from the sponge Siliquariaspongia japonica collected at Tsushima Is., Nagasaki Prefecture, Japan. The structure of aurantoside L (1) composed of a tetramic acid bearing a chlorinated polyene system and a trisaccharide part was elucidated using spectral analysis. Aurantoside L (1) showed anti-parasitic activity against L. amazonensis with an IC50 value of 0.74 µM.

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@#Leishmaniasis causes significant morbidity and mortality worldwide. In our country, there has been a significant increase in the number of cases of leishmaniasis in the last decade. In our study, the effects of Hypericum thymbrifolium, Hypericum scabrum and Eryngium creticum plant extracts were tested on Leishmania major, Leishmania tropica and Leishmania infantum/donovani, which were clinically resistant by not responding to Glucantime® therapy. Cytotoxicity of these extracts were evaluated by XTT method in the human fibroblast cell line. Possible active ingredients were detected by GC-MS analysis from plant extracts. Glucantime® resistance was detected at concentrations of 50 µg/mL and lower in 4 of the 7 strains tested. No living leishmania parasites were found in leishmania strains treated with plant extracts at concentrations of 100 µg/mL or higher. The concentrations of plant extracts included in the study on the WI-38 human fibroblast cell line were not cytotoxic. According to the GC-MS analysis, several active substances with biological activities and anti-parasitic effects, such as Thiophene, Germacrene-D, trans-Geranylgeraniol, Pyridine, and Maleimides, were identified. Based on the findings of the study, it is believed that these identified active substances when supported by in-vivo studies, will pave the way for future research and have the potential to be developed as anti-leishmania drugs.

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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.

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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.

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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.

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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.

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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.

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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.

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This study reports the synthesis and characterization of zinc derivatized 3,5-dihydroxy 4', 7- dimethoxyflavone (DHDM-Zn) compound for the development of new antileishmanial agents. The interaction studies of DHDM with zinc were carried out by UV spectra and fluorescence spectra analysis. Characterization of the complex was further accomplished by multi-spectroscopic techniques such as FTIR, Raman, HRMS, NMR, FESEM-EDX. The morphological and topographical studies of synthesized DHDM-Zn were carried out using FESEM with EDX. Further, it was demonstrated that DHDM-Zn exhibited an excellent in vitro antagonistic effect against the promastigote form of L. donovani. In addition, the possible mechanisms of promastigote L. donovani cell death, by involvement of derivatized compound in arrest of the cell cycle in the G1 phase and residual cell count reduction were investigated. Promastigote growth kinetics performed in the presence of the derivatized compound revealed a slow growth rate. The combination of growth kinetics and cell cycle analysis, made it possible to interpret and classify the cause of leishmanial cell death accurately. These results support that zinc derivatized complex (DHDM-Zn) might work as a lead compound for designing and developing a new antileishmanial drug.

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BACKGROUND: Leishmaniasis is a vector-borne disease that is endemic in the tropical and sub-tropical areas of the world. Low efficacy and high cytotoxicity of the current treatment regimens for leishmaniasis is one of the most important health problems. In this experimental study, anti-leishmanial effects of different concentrations of resveratrol and resveratrol nano-emulsion (RNE) were assessed. METHODS: RNE was prepared using the probe ultra-sonication method. The cytotoxicity was evaluated using the MTT technique on the L929 cell line. The anti-leishmanial activities on promastigotes of leishmania were assessed using vital staining and infected BALB/c mice were used to assess the in vivo anti-leishmanial effects. RESULTS: In vitro and in vivo assays revealed that all concentrations of resveratrol and RNE had valuable inhibitory effects against Leishmania major in comparison to the control group (P < 0.05). The half maximal inhibitory concentration (IC50) values were calculated as 16.23 and 35.71 µg/mL for resveratrol and RNE, respectively. Resveratrol and RNE showed no cytotoxicity against the L929 cell line. CONCLUSIONS: According to the potent in vitro and in vivo anti-leishmanial activity of RNE at low concentration against L. major, we suggest that it could be a promising anti-leishmanial therapeutic against L. major in the future.

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Biology-Oriented Drug Synthesis (BIODS) deals with the simple chemical transformations on the commercially available drugs in order to enhance their new and diversified pharmacological profile. It opens new avenues for the rapid development of drug candidates for neglected tropical diseases (NTDs). Leishmaniasis is one of the NTDs which spread by the bite of sandflies (plebotomine). It ranges from cutaneous self-healing leishmaniasis to life threatening visceral leishmaniasis, known as kala-azar. The current treatment options include the use of pentamidine, miltefosine, and amphotericin B drugs. Unfortunately, all currently available drugs are associated with adverse effects, such as severe nephron- and cardiotoxicity, pancreatitis, and hepatotoxicity. This warrants the development of new drugs against leishmaniasis. Moreover, emergence of resistance against the current medications further worsens the conditions. With this objective, new N, N'-disubstituted benzylamine derivatives of ampyrone (4-aminoantipyrine) were synthesized by using ultrasonication, and microwave assistance. All derivatives were found to be new, except 1, 4, and 11. All the compounds were evaluated for their anti-leishmanial activity, and cellular cytotoxicity. Among them, compounds 4, 5, 8, and 9 showed a significant anti-leishmanial activity in vitro, in comparison to standard drug, miltefosine (IC50 = 25.78 ± 0.2 µM). These compounds were also docked against various metabolic enzymes to predict their interactions and mechanism of action, and were found to act via targeting important enzymes of various metabolic pathways.

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Objective: Natural plant products are considered as a source of novel and effective compounds for the treatment of leishmaniasis. In this study, the in vitro activities of essential oils obtained from Origanum dubium (OD), Origanum majorana (OM), Salvia fruticosa (SF) and Laurus nobilis (LN) plants in Northern Cyprus were investigated against Leishmania tropica. Methods: Leishmania tropica strain (MHOM/TR/2012/CBCL-LT) was obtained. RPMI-1640 was added to 96-well plates in 100 µL aliquots, 100 µg/mL essential oil was added to the first well of each row and serial 2-fold dilutions were performed. A promastigote suspension was pipetted into all wells, and the plates were incubated. The promastigotes were enumerated using a haemocytometer. Results: OD essential oil was effective at killing all promastigotes at a minimum inhibitor height (MIC)=0.2 µg/mL and had high activity at the lowest concentrations. Both SF and LN oils had MIC=1.56 µg/mL and LD50=0.78 µg/mL. SF was observed to impair promastigote morphology at the lowest concentrations, while LN did not exert any effect at concentrations <0.2 µg/mL. OM essential oil was found to have a MIC=3.13 µg/mL and a LD50=1.56 µg/mL. Conclusion: All tested essential oils inhibited promastigotes of Leishmania tropica. OD essential oil demonstrated the highest anti-leishmanial activity. Amaç: Bitkilerden elde edilen dogal ürünlerin leishmaniasis tedavisi için yeni ve etkili bilesiklerin üretilmesine öncülük edecegi düsünülmektedir. Çalismamizda, Kuzey Kibris'ta yetisen Origanum dubium (OD), Origanum majorana (OM), Salvia fruticosa (SF) ve Laurus nobilis (LN) bitkilerinden elde edilen uçucu yaglarin Leishmania tropica'ya karsi in vitro etkinlikleri arastirilmistir. Yöntemler: Çalismamizda, Leishmania tropica susu (MHOM/TR/2012/CBCL-LT) kullanildi. Düz tabanli 96'lik plaklarda, tüm kuyucuklara 100 µL RPMI-1640 ve ilk kuyucuklara 100 µg/mL uçucu yaglar eklenerek, seri dilüsyonlari yapildi. Ardindan tüm kuyucuklara Leishmania tropica promastigot süspansiyonundan pipetlendi ve inkübe edildi. Hemositometre yöntemiyle promastigotlarin sayisi incelendi. Bulgular: OD yaginin minimum inhibitör konsantrasyonu (MIK)=0,2 µg/mL'de tüm promastigotlari öldürürken, en düsük konsantrasyonlarda bile etkili oldugu görülmüstür. SF ve LN uçucu yaglarinin ikisinde de MIK=1,56 µg/mL, LD50=0,78 µg/mL olarak saptanmistir. SF'nin en düsük konsantrasyonlarinin bile promastigot morfolojisini bozdugu görülürken, Laurus nobilis'in ise 0,2 µg/mL'den sonraki konsantrasyonlarda etkisini kaybettigi belirlenmistir. OM uçucu yaginin MIK=3,13 µg/mL, LD50=1,56 µg/mL oldugu görülmüstür. Sonuç: Kullanilan tüm uçucu yaglarin Leishmania tropica promastigotlarini inhibe ettigi görülürken, en yüksek anti-leishmanial etkinlik Origanum dubium uçucu yaginda bulunmustur.

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BACKGROUND: Leishmaniasis is a major parasitic disease worldwide, except in Australia and Antarctica, and it poses a significant public health problem. Due to the absence of safe and effective vaccines and drugs, researchers have begun an extensive search for new drugs. The aim of the current study was to investigate the in vitro leishmanicidal activity of larval saliva and hemolymph of Lucilia sericata on Leishmania tropica. METHODS: The effects of different concentrations of larval products on promastigotes and intracellular amastigotes of L. tropica were investigated using the mouse cell line J774A.1 and peritoneal macrophages as host cells. The 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and direct observation and counting method were used to assess the inhibitory effects and cell cytotoxicity of the larval products. The effects of larval products on the amastigote form of L. tropica were quantitatively estimated by calculating the rate of macrophage infection, number of amastigotes per infected macrophage cell, parasite load and survival index. RESULTS: The 50% cytotoxicity concentration (CC50) value of both larval saliva and hemolymph was 750 µg/ml, and the 50% inhibitory concentration (IC50) values were 134 µg/ml and 60 µg/ml for larval saliva and larval hemolymph, respectively. The IC50 for Glucantime, used a positive control, was (11.65 µg/ml). Statistically significant differences in viability percentages of promastigotes were observed for different doses of both larval saliva and hemolymph when compared with the negative control (p ≤ 0.0001). Microscopic evaluation of the amastigote forms revealed that treatment with 150 µg/ml larval hemolymph and 450 µg/ml larval saliva significantly decreased the rate of macrophage infection and the number of amastigotes per infected macrophage cell. CONCLUSION: Larval saliva and hemolymph of L. sericata have acceptable leishmanicidal properties against L. tropica.

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The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4'-bipiperidin]-1'-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (IIc) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of L. major cells to IIa and IIc led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of IIa and IIc is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.

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The aims of this study were to produce biogenic antimony sulfide nanoparticles (NPs) using Serratia marcescens (S. marcescens) and investigate the potential anti-leishmanial effects of these NPs on Leishmania major (L. major) (MRHO/IR/75/ER) in both in vitro and in vivo experiments. Biogenic antimony sulfide NPs were synthesized through intracellular biological methods using S. marcescens. The efficiency of various concentrations of antimony sulfide NPs was assessed using in vitro experiments on amastigotes of L. major at various times post-infection. In vivo experiments were carried out in BALB/c mice inoculated subcutaneously with 2 × 106L. major promastigotes (MHROM/IR/75/ER) and treated with antimony sulfide NPs (70 µg/mL, tropically), meglumine antimoniate (glucantime) as positive control and sterile phosphate-buffered saline (PBS, pH 7.4) as vehicle control. Results of in vitro experiments revealed that the anti-leishmanial activity increased when the antimony sulfide NPs concentration increased. The IC50 (50% inhibitory concentration) of antimony sulfide NPs against amastigotes was calculated as 62.5 µg/mL. In in vivo experiments, the average size of lesions significantly decreased to 8.6 ± 2.7 mm2 in mice inoculated with L. major promastigotes and treated with antimony sulfide NPs, compared with that in the negative control group (P = 0.015). Furthermore, results showed that antimony sulfide NPs significantly decreased the parasite load in the test group, compared with the negative control group (P = 0.001). Various concentrations of antimony sulfide NPs showed a great anti-leishmanial efficiency against L. major (MRHO/IR/75/ER), with the greatest efficiency shown by a concentration of 62.5 µg/mL in in vitro and in vivo experiments.

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Leishmaniasis is a poverty-related disease endemic in 98 countries worldwide, with morbidity and mortality increasing daily. All currently used first-line and second-line drugs for the treatment of leishmaniasis exhibit several drawbacks including toxicity, high costs and route of administration. Consequently, the development of new treatments for leishmaniasis is a priority in the field of neglected tropical diseases. The aim of this work is to develop computational models those allow the identification of new chemical compounds with potential anti-leishmanial activity. A data set of 116 organic chemicals, assayed against promastigotes of Leishmania amazonensis, is used to develop the theoretical models. The cutoff value to consider a compound as active one was IC50≤1.5µM. For this study, we employed Dragon software to calculate the molecular descriptors and WEKA to obtain machine learning (ML) models. All ML models showed accuracy values between 82% and 91%, for the training set. The models developed with k-nearest neighbors and classification trees showed sensitivity values of 97% and 100%, respectively; while the models developed with artificial neural networks and support vector machine showed specificity values of 94% and 92%, respectively. In order to validate our models, an external test-set was evaluated with good behavior for all models. A virtual screening was performed and 156 compounds were identified as potential anti-leishmanial by all the ML models. This investigation highlights the merits of ML-based techniques as an alternative to other more traditional methods to find new chemical compounds with anti-leishmanial activity.

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In the present study, 45 maleimides have been synthesized and evaluated for anti-leishmanial activities against L. donovani in vitro and cytotoxicity toward THP1 cells. All compounds exhibited obvious anti-leishmanial activities. Among the tested compounds, there were 10 maleimides with superior anti-leishmanial activities to standard drug amphotericin B, and 32 maleimides with superior anti-leishmanial activities to standard drug pentamidine, especially compounds 16 (IC50 < 0.0128 µg/mL) and 42 (IC50 < 0.0128 µg/mL), which showed extraordinary efficacy in an in vitro test and low cytotoxicities (CC50 > 10 µg/mL). The anti-leishmanial activities of 16 and 42 were 10 times better than that of amphotericin B. The structure and activity relationship (SAR) studies revealed that 3,4-non-substituted maleimides displayed the strongest anti-leishmanial activities compared to those for 3-methyl-maleimides and 3,4-dichloro-maleimides. 3,4-dichloro-maleimides were the least cytotoxic compared to 3-methyl-maleimides and 3,4-non-substituted maleimides. The results show that several of the reported compounds are promising leads for potential anti-leishmanial drug development.

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Cutaneous leishmaniasis is still a health problem worldwide, especially in tropical and subtropical areas. Currently, pentavalent antimony compounds are used to treat leishmaniasis. These compounds cause various side effects in the body. Therefore, there is a need to discover new drugs with less toxicity and more therapeutic effects. In this study, we encapsulated the meglumine antimonate into the albumin as a drug carrier and evaluated the anti-leishmanial effect of the prepared nanoparticles. The precipitation method was used for this purpose by applying different concentrations of glutaraldehyde and N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide hydro chloride Ethyl (DEC) and then, field emission test was performed using Scanning Electron Microscopy for evaluating the morphology and size particles. The cytotoxicity and inhibitory of drugs were evaluated on J774 macrophages and Leishmania major promastigotes, respectively. Nanodrugs prepared using glutaraldehyde (10 µl/ml) and DEC (13 mg/ml) had the smallest and largest size, respectively. The highest anti-leishmanial activity was observed in the drugs prepared with glutaraldehyde (10 µl/ml). Also this nanodrug had the lowest cytotoxicity against macrophages. Given that meglumine antimonate loaded albumin nanoparticles prepared with glutaraldehyde (10 µg/ml), can improve the anti-leishmanial effects of this old drug, it can be a good option as a drug delivery system.