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Pistacia chinensis subsp. integerrima is a valuable medicinal plant as its parts and extracts found application for treating diarrhea, fever, liver disorders, asthma, and inflammation. In this study, we report the leishmanicidal activity of sakuranetin, spinacetin, and patuletin extracted from P. chinensis. The tested compounds revealed a strong anti-leishmanial activity in vitro against Leishmania major showing IC50 values of 7.98 ± 0.16 µM, 9.23 ± 0.23 µM 11.09 ± 0.87 µM for sakuranetin, spinacetin, and patuletin, respectively. Moreover, to explore the potential mechanism(s) by which the compounds may act, computational docking studies were performed against dihydrofolate reductase and pteridine reductase, showing that the flavonoids could target these two key enzymes to exploit their leishmanicidal activity. In accordance with in vitro results, patuletin was highlighted as the most promising compound of the set, and binding energy values of −6.72 and −6.74 kcal/mol were computed for the two proteins, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Leishmaniasis, a neglected tropical parasitic disease, is regarded as a major public health problem worldwide. The first-line drugs for leishmaniasis suffer from limitations related to toxicity and the development of resistance in certain parasitic strains. Therefore, the discovery of alternative treatments for leishmaniasis is imperative, and natural products represent a valuable source of potential therapeutic agents. Methods: The present study aimed at finding new potential antileishmanial agents from the aerial parts of the medicinal plant Momordica charantia. This study was based on bioassay-guided fractionation of the M. charantia extract against promastigotes and amastigotes of Leishmania (Leishmania) amazonensis. The cytotoxicity of the extract, fractions, and isolated compounds were evaluated against peritoneal murine macrophages by employing the MTT assay for assessing cell metabolic activity. Results: Antileishmanial assay-guided fractionation of the M. charantia extract led to the bioactive cucurbitacin-enriched fraction and the isolation of four bioactive cucurbitacin-type triterpenoids, which exhibited significant antileishmanial activity, with IC50 values between 2.11 and 3.25 μg.mL−1 against promastigote and amastigote forms, low toxicity and selectivity indexes ranging from 8.5 to 17.2. Conclusion: Our findings demonstrate that the fractions and cucurbitacin-type triterpenoids obtained from the aerial parts of M. charantia are promising natural leishmanicidal candidates. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the leishmanicidal potential of the essential oil (EO) of Micromeria (M.) nervosa and to investigate its molecular mechanism of action by qPCR. Furthermore, in silicointeraction study of the major M. nervosa EO compounds with the enzyme cytochrome P450 sterol 14α-demethylase (CYP51) was also performed. M. nervosa EO was analyzed by gas chromatography-mass spectrometry (GC-MS). Results showed that α-pinene (26.44%), t-cadinol (26.27%), caryophyllene Oxide (7.73 ± 1.04%), and α-Cadinene (3.79 ± 0.12%) are the major compounds of M. nervosa EO. However, limited antioxidant activity was observed, as this EO was ineffective in neutralizing DPPH free radicals and in inhibiting β-carotene bleaching. Interestingly, it displayed effective leishmanicidal potential against promastigote (IC50 of 6.79 and 5.25 μg/mL) and amastigote (IC50 of 8.04 and 7.32 μg/mL) forms of leishmania (L.) infantum and L. major, respectively. Molecular mechanism investigation showed that M. nervosa EO displayed potent inhibition on the thiol regulatory pathway. Furthermore, a docking study of the main components of the EO with cytochrome P450 sterol 14α-demethylase (CYP51) enzyme revealed that t-cadinol exhibited the best binding energy values (−7.5 kcal/mol), followed by α-cadinene (−7.3 kcal/mol) and caryophyllene oxide (−7 kcal/mol). These values were notably higher than that of the conventional drug fluconazole showing weaker binding energy (−6.9 kcal/mol). These results suggest that M. nervosa EO could serve as a potent and promising candidate for the development of alternative antileishmanial agent in the treatment of leishmaniasis. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from MI metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HLR) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with AgI and AuI, leading to the formation of complexes of composition [M(HLR)2]X (M = Ag or Au; X = NO3− or Cl−). All compounds were characterized by FTIR, 1H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets. [ABSTRACT FROM AUTHOR]

Leishmaniasis encompasses a cluster of neglected tropical diseases triggered by kinetoplastid phatogens belonging to the genus Leishmania. Current therapeutic approaches are toxic, expensive, and require long-term treatment. Nanoparticles are emerging as a new alternative for the treatment of neglected tropical diseases. Silk Fibroin is a biocompatible and amphiphilic protein that can be used for formulating nanoemulsions, while kojic acid is a secondary metabolite with antileishmanial actions. Thus, this study evaluated the efficacy of a nanoemulsion, formulated with silk fibroin as the surfactant and containing kojic acid (NanoFKA), against promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. The NanoFKA had an average particle size of 176 nm, Polydispersity Index (PDI) of 0.370, and a Zeta Potential of -32.3 mV. It presented inhibitory concentration (IC50) values of >56 μg/mL and >7 μg/mL for the promastigote and amastigote forms, respectively. Ultrastructural analysis, cell cycle distribution and phosphatidylserine exposure showed that NanoFKA treatment induces apoptosis-like cell death and cell cycle arrest in L. (L.) amazonensis. In addition, NanoFKA exhibited no cytotoxicity against macrophages. Given these results, NanoFKA present leishmanicidal activity against L. (L.) amazonensis. [ABSTRACT FROM AUTHOR]

IntroductionLeishmaniasis, a neglected tropical parasitic disease, is regarded as a major public health problem worldwide. The first-line drugs for leishmaniasis suffer from limitations related to toxicity and the development of resistance in certain parasitic strains. Therefore, the discovery of alternative treatments for leishmaniasis is imperative, and natural products represent a valuable source of potential therapeutic agents.MethodsThe present study aimed at finding new potential antileishmanial agents from the aerial parts of the medicinal plant Momordica charantia. This study was based on bioassay-guided fractionation of the M. charantia extract against promastigotes and amastigotes of Leishmania (Leishmania) amazonensis. The cytotoxicity of the extract, fractions, and isolated compounds were evaluated against peritoneal murine macrophages by employing the MTT assay for assessing cell metabolic activity.ResultsAntileishmanial assay-guided fractionation of the M. charantia extract led to the bioactive cucurbitacin-enriched fraction and the isolation of four bioactive cucurbitacin-type triterpenoids, which exhibited significant antileishmanial activity, with IC50 values between 2.11 and 3.25 μg.mL−1 against promastigote and amastigote forms, low toxicity and selectivity indexes ranging from 8.5 to 17.2.ConclusionOur findings demonstrate that the fractions and cucurbitacin-type triterpenoids obtained from the aerial parts of M. charantia are promising natural leishmanicidal candidates.

Abstract In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N’-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N’-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.

Chemotherapy currently available for leishmaniasis treatment has many adverse side effects and drug resistance. Therefore, the identification of new targets and the development of new drugs are urgently needed. Previously, we reported the synthesis of a N-(2-methoxyphenyl)-1-methyl-1H-benzimidazol-2-amine, named compound 8, with an IC50 value in the micromolar range against L. mexicana, it also inhibited 68.27% the activity of recombinant L. mexicana arginase. Herein, we report studies carried out to characterize the mechanism of action of compound 8, as well as its in vivo leishmanicidal activity. It was shown in our ultrastructural studies that compound 8 induces several changes, such as membrane blebbing, the presence of autophagosomes, membrane detachment and mitochondrial and kinetoplast disorganization, among others. Compound 8 triggers the production of ROS and parasite apoptosis. It reduced 71% of the parasite load of L. mexicana in an experimental model of cutaneous leishmaniasis in comparison with a control. Altogether, the data obtained suggest the potential use of compound 8 in the treatment of cutaneous leishmaniasis. [ABSTRACT FROM AUTHOR]

Pinene is a major monoterpene described in various plant essential oils. It has two isomers, α- and β-pinene, that differ in the position of their double bond. Each isomer has two enantiomers, which have diverse pharmacological properties. Human tegumentary leishmaniasis (HTL) is a parasitic disease that significantly affects the morbidity, disability, and social stigmatization of poor and marginalized populations. This study aimed to investigate the activity of pinene enantiomers against the HTL causative agent, Leishmania amazonensis. The parasite viability was determined using the resazurin assay and transmission electron microscopy. The most active enantiomers against promastigotes and amastigotes were (+)-α-pinene and (+)-β-pinene with IC50 ranging from 14 to 110 µg/mL. Furthermore, the positive enantiomers exhibited moderate cytotoxicity against the RAW 264.7 cell line and sheep erythrocytes and desirable selectivity indexes exceeding 10. In addition, in silico toxicological analysis revealed a pinene enantiomer profile similar to miltefosine. Parasites treated with (+)-α-pinene exhibited significant ultrastructural alterations suggestive of apoptosis, including mitochondrial swelling, myelin-like figures, and autophagosome-like structures. Additionally, (+)-α-pinene enhanced autophagic activity and increased ROS production in treated parasites, as assessed through monodansylcadaverine and H2DCFDA labeling, respectively. Our results demonstrated that (+)-α-pinene and (+)-β-pinene are the primary enantiomers responsible for the antileishmanial activity. These results provide an important point of view for the therapeutic use of enantiomers. [ABSTRACT FROM AUTHOR]

In this work, in vitro antibacterial and Leishmanicidal activities of a ligand and phthalocyanine derivatives (2, 3, 3a–3c and 4) were tested for six selected standard bacteria and one Leishmania species. The synthesis of fluorinated pyrazoline compound (2) was first carried out from a chalcone precursor (1). Then, peripherally tetra-substituted metallophthalocyanines (zinc(II) (3a), cobalt(II) (3b) and iron(II) (3c)) and axially di-substituted silicon(IV) (4) containing fluorinated pyrazoline groups were obtained. The characterizations of 2, 3, 3a–3c and 4 were performed by IR,1H and 13C NMR, MALDI-TOF-MS and UV-Vis spectra and elemental analyses. The antibacterial and Leishmanicidal activities of the pyrazoline and phthalocyanine compounds were investigated. [ABSTRACT FROM AUTHOR]

Leishmaniasis encompasses a cluster of neglected tropical diseases triggered by kinetoplastid phatogens belonging to the genus Leishmania. Current therapeutic approaches are toxic, expensive, and require long-term treatment. Nanoparticles are emerging as a new alternative for the treatment of neglected tropical diseases. Silk Fibroin is a biocompatible and amphiphilic protein that can be used for formulating nanoemulsions, while kojic acid is a secondary metabolite with antileishmanial actions. Thus, this study evaluated the efficacy of a nanoemulsion, formulated with silk fibroin as the surfactant and containing kojic acid (NanoFKA), against promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. The NanoFKA had an average particle size of 176 nm, Polydispersity Index (PDI) of 0.370, and a Zeta Potential of −32.3 mV. It presented inhibitory concentration (IC50) values of >56 μg/mL and >7 μg/mL for the promastigote and amastigote forms, respectively. Ultrastructural analysis, cell cycle distribution and phosphatidylserine exposure showed that NanoFKA treatment induces apoptosis-like cell death and cell cycle arrest in L. (L.) amazonensis. In addition, NanoFKA exhibited no cytotoxicity against macrophages. Given these results, NanoFKA present leishmanicidal activity against L. (L.) amazonensis.

Leishmaniasis is caused by protozoans of the genus Leishmania, and its treatment is highly toxic, leading to treatment discontinuation and the emergence of resistant strains. In this study, we assessed the leishmanicidal activity and chemical composition of red propolis collected from the Amazon-dominated region of northern Tocantins State, Brazil. The MTT assay was employed to determine the samples' activity against Leishmania amazonensis promastigotes and their cytotoxicity against RAW macrophages. Spectrophotometric assays were utilised to measure the concentrations of total phenolics and flavonoids, while high-performance liquid chromatography coupled to a mass spectrometer (LC-MS/MS) was used to determine the chemical composition. An in silico study was conducted to evaluate which compounds from Brazilian Amazon red propolis may correlate with this biological activity. Brazilian Amazon red propolis exhibited a high concentration of phenolic compounds and an inhibitory activity against L. amazonensis, with an IC50 ranging from 23.37 to 36.10 µg/mL. Moreover, fractionation of the propolis yielded a fraction with enhanced bioactivity (16.11 µg/mL). Interestingly, neither the propolis nor its most active fraction showed cytotoxicity towards macrophages at concentrations up to 200 µg/mL. The red colour and the presence of isoflavonoid components (isoflavones, isoflavans, and pterocarpans) confirm that the substance is Brazilian red propolis. However, the absence of polyprenylated benzophenones suggests that this is a new variety of Brazilian red propolis. The in silico study performed with two of the main leishmanicidal drug targets using all compounds identified in Amazon red propolis reported that liquiritigenin was the compound that exhibited the best electronic interaction parameters, which was confirmed in an assay with promastigotes using a standard. The findings indicate that Amazon red propolis possesses leishmanicidal activity, low toxicity, and significant biotechnological potential. [ABSTRACT FROM AUTHOR]

Propolis is a natural product of great economic and pharmacological importance. The flora surrounding the bee communities is a determining factor in the composition of propolis and therefore in its biological and medicinal properties. Brown propolis is one of the most important types of propolis in Brazil, produced in the southeastern region. The ethanolic extract of a brown propolis sample from Minas Gerais state was chemically characterized for the subsequent development of a RP‐HPLC method, validated according to the standards of regulatory agencies. The leishmanicidal activity of this extract was assessed. The brown propolis was characterized by the presence of chemical markers reported on green propolis such as ferulic acid, coumaric acid, caffeic acid, cinnamic acid, baccharin, artepillin and drupanin, indicating a probable origin on Baccharis dracunculifolia. The developed method agreed with the parameters established by the validation guidelines, then proved to be reliable for the analysis of this type of propolis. The brown propolis displayed significant activity against Leishmania amazonensis with IC50 values of 1.8 and 2.4 μg/ml against the promastigote and amastigote forms, respectively. The studied propolis exhibited promising evidence for use as a natural source against L. amazonensis. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the leishmanicidal potential of the essential oil (EO) of Micromeria (M.) nervosa and to investigate its molecular mechanism of action by qPCR. Furthermore, in silicointeraction study of the major M. nervosa EO compounds with the enzyme cytochrome P450 sterol 14α-demethylase (CYP51) was also performed. M. nervosa EO was analyzed by gas chromatography-mass spectrometry (GC-MS). Results showed that α-pinene (26.44%), t-cadinol (26.27%), caryophyllene Oxide (7.73 ± 1.04%), and α-Cadinene (3.79 ± 0.12%) are the major compounds of M. nervosa EO. However, limited antioxidant activity was observed, as this EO was ineffective in neutralizing DPPH free radicals and in inhibiting β-carotene bleaching. Interestingly, it displayed effective leishmanicidal potential against promastigote (IC50 of 6.79 and 5.25 μg/mL) and amastigote (IC50 of 8.04 and 7.32 μg/mL) forms of leishmania (L.) infantum and L. major, respectively. Molecular mechanism investigation showed that M. nervosa EO displayed potent inhibition on the thiol regulatory pathway. Furthermore, a docking study of the main components of the EO with cytochrome P450 sterol 14α-demethylase (CYP51) enzyme revealed that t-cadinol exhibited the best binding energy values (−7.5 kcal/mol), followed by α-cadinene (−7.3 kcal/mol) and caryophyllene oxide (−7 kcal/mol). These values were notably higher than that of the conventional drug fluconazole showing weaker binding energy (−6.9 kcal/mol). These results suggest that M. nervosa EO could serve as a potent and promising candidate for the development of alternative antileishmanial agent in the treatment of leishmaniasis.

Leishmaniasis is a group of parasitic diseases with the potential to infect more than 1 billion people; however, its treatment is still old and inadequate. In order to contribute to changing this view, this work consisted of the development of complexes derived from MI metal ions with thioureas, aiming to obtain potential leishmanicidal agents. The thiourea ligands (HLR) were obtained by reactions of p-toluenesulfohydrazide with R-isothiocyanates and were used in complexation reactions with AgI and AuI, leading to the formation of complexes of composition [M(HLR)2]X (M = Ag or Au; X = NO3− or Cl−). All compounds were characterized by FTIR, 1H NMR, UV-vis, emission spectroscopy and elemental analysis. Some representatives were additionally studied by ESI-MS and single-crystal XRD. Their properties were further analyzed by DFT calculations. Their cytotoxicity on Vero cells and the extracellular leishmanicidal activity on Leishmania infantum and Leishmania braziliensis cells were evaluated. Additionally, the interaction of the complexes with the Old Yellow enzyme of the L. braziliensis (LbOYE) was examined. The biological tests showed that some compounds present remarkable leishmanicidal activity, even higher than that of the standard drug Glucantime, with different selectivity for the two species of Leishmania. Finally, the interaction studies with LbOYE revealed that this enzyme could be one of their biological targets.

In this study, the synthesis of Schiff bases containing substituted thiophene was carried out. The compounds were characterized by Fourier transform infrared (FTIR), 1H and 13C NMR spectroscopy methods. In the study, it was aimed to determine in vitro leishmanicidal activities of five different newly synthesized compounds against standard L. infantum promastigotes by microdilution method. In silico analysis was used to examine the probable interactions between the synthesized compound and the target proteins. [ABSTRACT FROM AUTHOR]

Chemotherapy currently available for leishmaniasis treatment has many adverse side effects and drug resistance. Therefore, the identification of new targets and the development of new drugs are urgently needed. Previously, we reported the synthesis of a N-(2-methoxyphenyl)-1-methyl-1H-benzimidazol-2-amine, named compound 8, with an IC50 value in the micromolar range against L. mexicana, it also inhibited 68.27% the activity of recombinant L. mexicana arginase. Herein, we report studies carried out to characterize the mechanism of action of compound 8, as well as its in vivo leishmanicidal activity. It was shown in our ultrastructural studies that compound 8 induces several changes, such as membrane blebbing, the presence of autophagosomes, membrane detachment and mitochondrial and kinetoplast disorganization, among others. Compound 8 triggers the production of ROS and parasite apoptosis. It reduced 71% of the parasite load of L. mexicana in an experimental model of cutaneous leishmaniasis in comparison with a control. Altogether, the data obtained suggest the potential use of compound 8 in the treatment of cutaneous leishmaniasis.

Objective: Medicinal plants are the mainstay of various chemical constituents responsible for curing or mitigating different pathological and non-pathological health issues. In this regard, the current research work was subjected to finding the best effective, new and safe leishmanicidal molecules. Pistacia integerrima is an important medicinal plant growing in Asia with various ethnopharmacological uses such as skin, respiratory and hepatic disorders. The folklore of this plant in skin problems encouraged us to evaluate the isolated compounds for leishmanicidal activity. Methods: In the current study, whole ethyl acetate extract was subjected to chromatographic analysis affording two flavonoid constituents, namely naringenin (1) and 3,5,4′-trihydroxy-7-methoxy-flavanone (2). The extract and isolated constituents were tested for leishmanicidal activity. Both compounds were docked into the target binding site (PDB ID: 5HJ9) using MOE 2016. Arginase was taken as the targeted enzyme which is an important enzyme for leishmania species’ survival. Arginase up-regulates amastin that impacts amastigote replication and survival. This approach aimed to explore the binding modes of the two isolated flavonoids and to predict their inhibitory activity against arginase. Results: The two flavonoid compounds isolated from P. integerrima were evaluated for their anti-leishmanial activity. Compounds 1 and 2 were tested at a concentration of 5 µg/mL against the selected Leishmanial species. The percent inhibition was 70.43 and 74.76 regarding compounds 1 and 2, respectively with IC50 of 29.43 and 16.43 μM. The reference standard drug used, amphotericin-B, displayed the highest leishmanicidal effect (IC50 of 0.22 μM) with 84.09 % inhibition at half concentration compared to compounds 1 and 2. The molecular docking studies of these two compounds and the standard drug were performed in MOE software. According to the findings, compound 1, naringenin, docked well in the binding site, with a docking score of −9.28 followed by compound 2, 3,5,4′-trihydroxy-7-methoxy-flavanone with a docking score of −8.37. Conclusion: Both of the tested samples demonstrated excellent leishmanicidal effects. This pharmacological inhibitory profile provides a strong scientific profile to the folklore of Pistacia integerrima in the treatment of skin disorders especially leishmanial. A further mechanistic study is recommended to find the extract target responsible for the said activity.

In this study we explored the previously established leishmanicidal activity of a complementary set of 24 imidazolium salts (IS), 1-hexadecylimidazole (C16Im) and 1-hexadecylpyridinium chloride (C16PyrCl) against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum chagasi. Promastigotes of L. amazonensis and L. infantum chagasi were incubated with 0.1 to 100 mM of the compounds and eight of them demonstrated leishmanicidal activity after 48 h – C10MImMeS (IC50 L. amazonensis = 11.6), C16MImPF6(IC50 L. amazonensis = 6.9), C16MImBr (IC50 L. amazonensis = 6), C16M2ImCl (IC50 L. amazonensis = 4.1), C16M4ImCl (IC50 L. amazonensis = 1.8), (C10)2MImCl (IC50 L. amazonensis = 1.9), C16Im (IC50 L. amazonensis = 14.6), and C16PyrCl (IC50 L. amazonensis = 4).The effect of IS on reactive oxygen species production, mitochondrial membrane potential, membrane integrity and morphological alterations of promastigotes was determined, as well as on L. amazonensis-infected macrophages. Their cytotoxicity against macrophages and human erythrocytes was also evaluated. The IS C10MImMeS, C16MImPF6, C16MImBr, C16M2ImCl, C16M4ImCl and (C10) 2MImCl, and the compounds C16Im and C16PyrCl killed and inhibited the growth of promastigote forms of L. amazonensis and L. infantum chagasi in a concentration-dependent manner, contributing to a better understanding of the structure-activity relationship of IS against Leishmania. These IS induced ROS production, mitochondrial dysfunction, membrane disruption and morphological alterations in infective forms of L. amazonensis and killed intracellular amastigote forms in very low concentrations (IC50 amastigotes ≤ 0.3), being potential drug candidates against L. amazonensis. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N′-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug. [ABSTRACT FROM AUTHOR]

• The new 1,2,4-triazole compounds (3a–3c) was synthesized. • The molecular structures of the compounds were confirm by FTIR and NMR (1H- and 13C-) methods. • The calculations were performed at DFT/B3LYP/6-311++ G (d,p) level. • In vitro antimicrobial activity was determined by microdilution broth method added Alamar blue. • Molecular docking analysis targeting trypanothione reductase (TRe) was conducted for compound 3b. In this study; new 1,2,4-triazole derivatives, (E)-4-(((3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl 4-methoxybenzoate (3a), (E)-4-(((3-benzyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl 4-methoxybenzoate (3b) and (E)-4-(((3-(4-fluorobenzyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl 4‑methoxy benzoate methoxy benzoate (3c) were synthesized and characterized by FTIR and NMR (1H- and 13C-) spectroscopic methods. Structural and spectral parameters were calculated by DFT/B3LYP/6–311++G(d,p) methods. The newly synthesized compounds 3a–3c were evaluated for their antimicrobial activities against eight pathogenic microorganisms. Standard commercial drugs ampicillin and fluconazole were used as references for bacteria and yeast, respectively. The leishmanicidal activity of three different synthesized compounds against Leishmania infantum promastigotes was investigated using the microdilution method. In addition, the study attempted to investigate the interactions crucial for the antileishmanial activity of compound 3b by molecular docking analysis targeting trypanothione reductase (TRe). [ABSTRACT FROM AUTHOR]

Leishmaniasis is a globally prevalent vector-borne disease caused by parasites of the genus Leishmania. The available chemotherapeutic drugs present problems related to efficacy, emergence of parasite resistance, toxicity and high cost, justifying the search for new drugs. Several classes of compounds have demonstrated activity against Leishmania , including icetexane-type diterpenes, previously isolated from Salvia and other Lamiaceae genera. Thus, in this study, compounds of Salvia procurrens were investigated for their leishmanicidal and immunomodulatory activities. The exudate of S. procurrens was obtained by rapidly dipping the aerial parts in dichloromethane. The compounds were isolated by column and centrifugal planar chromatography over silica gel. The effects on L. amazonensis growth, survival, membrane integrity, reactive oxygen species (ROS) generation, mitochondrial membrane potential and cytotoxicity of the compounds towards human erythrocytes, peripheral blood mononuclear cells and macrophages were evaluated. The effects on intracellular amastigote forms, nitric oxide (NO) and TNF-α production were also investigated. The exudate from the leaves afforded the novel icetexane 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2), fruticulin A (3) and demethylfruticulin A (4). The compounds (1–4) were tested against promastigotes of L. amazonensis and showed an effective inhibition of the parasite survival (IC 50 = 4.08–16.26 μM). In addition, they also induced mitochondrial ROS production, plasma membrane permeability and mitochondrial dysfunction in treated parasites, and presented low cytotoxicity against macrophages. Furthermore, all diterpenes tested reduced the number of parasites inside macrophages, by mechanisms involving TNF-α, NO and ROS. The results suggest the potential of 7-hydroxyfruticulin A (1) as well as the known demethylisofruticulin A (2),fruticulin A (3) and demethylfruticulin A (4) as candidates for use in further studies on the design of anti-leishmanial drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

Leishmaniasis is caused by protozoans of the genus Leishmania, and its treatment is highly toxic, leading to treatment discontinuation and the emergence of resistant strains. In this study, we assessed the leishmanicidal activity and chemical composition of red propolis collected from the Amazon-dominated region of northern Tocantins State, Brazil. The MTT assay was employed to determine the samples’ activity against Leishmania amazonensis promastigotes and their cytotoxicity against RAW macrophages. Spectrophotometric assays were utilised to measure the concentrations of total phenolics and flavonoids, while high-performance liquid chromatography coupled to a mass spectrometer (LC-MS/MS) was used to determine the chemical composition. An in silico study was conducted to evaluate which compounds from Brazilian Amazon red propolis may correlate with this biological activity. Brazilian Amazon red propolis exhibited a high concentration of phenolic compounds and an inhibitory activity against L. amazonensis, with an IC50 ranging from 23.37 to 36.10 µg/mL. Moreover, fractionation of the propolis yielded a fraction with enhanced bioactivity (16.11 µg/mL). Interestingly, neither the propolis nor its most active fraction showed cytotoxicity towards macrophages at concentrations up to 200 µg/mL. The red colour and the presence of isoflavonoid components (isoflavones, isoflavans, and pterocarpans) confirm that the substance is Brazilian red propolis. However, the absence of polyprenylated benzophenones suggests that this is a new variety of Brazilian red propolis. The in silico study performed with two of the main leishmanicidal drug targets using all compounds identified in Amazon red propolis reported that liquiritigenin was the compound that exhibited the best electronic interaction parameters, which was confirmed in an assay with promastigotes using a standard. The findings indicate that Amazon red propolis possesses leishmanicidal activity, low toxicity, and significant biotechnological potential.

In this study we explored the previously established leishmanicidal activity of a complementary set of 24 imidazolium salts (IS), 1-hexadecylimidazole (C16Im) and 1-hexadecylpyridinium chloride (C16PyrCl) against Leishmania (Leishmania) amazonensis and Leishmania (Leishmania) infantum chagasi. Promastigotes of L. amazonensis and L. infantum chagasi were incubated with 0.1 to 100 μM of the compounds and eight of them demonstrated leishmanicidal activity after 48 h – C10MImMeS (IC50L. amazonensis = 11.6), C16MImPF6(IC50L. amazonensis = 6.9), C16MImBr (IC50L. amazonensis = 6), C16M2ImCl (IC50L. amazonensis = 4.1), C16M4ImCl (IC50L. amazonensis = 1.8), (C10)2MImCl (IC50L. amazonensis = 1.9), C16Im (IC50L. amazonensis = 14.6), and C16PyrCl (IC50L. amazonensis = 4).The effect of IS on reactive oxygen species production, mitochondrial membrane potential, membrane integrity and morphological alterations of promastigotes was determined, as well as on L. amazonensis-infected macrophages. Their cytotoxicity against macrophages and human erythrocytes was also evaluated. The IS C10MImMeS, C16MImPF6, C16MImBr, C16M2ImCl, C16M4ImCl and (C10)2MImCl, and the compounds C16Im and C16PyrCl killed and inhibited the growth of promastigote forms of L. amazonensis and L. infantum chagasi in a concentration-dependent manner, contributing to a better understanding of the structure-activity relationship of IS against Leishmania. These IS induced ROS production, mitochondrial dysfunction, membrane disruption and morphological alterations in infective forms of L. amazonensis and killed intracellular amastigote forms in very low concentrations (IC50 amastigotes ≤ 0.3), being potential drug candidates against L. amazonensis.

In the present study, molecular interaction fields are applied to a data set of forty 5-(nitroheteroaryl)-1,3,4-thiadiazol derivatives to generate a 3D-QSAR model. The statistical significance of the 3D-QSAR model is built as reported on the literature. External validation indicates that the 3D-QSAR model is robust and that it has predictive capacity. The results show that the model has steric (59.80%) and electrostatic (40.20%) properties that play an important role in leishmanicidal activity. Analyses of contour maps extracted from molecular interaction fields provide insights on the possible structural modifications of 5-(nitroheteroaryl)-1,3,4-thiadiazole derivatives. These modifications can serve to obtain new derivatives to improve their biological activity. In conclusion, the biological activities calculated for training and test sets show a high degree of concordance with experimental values, suggesting that the constructed 3D-QSAR model is useful for designing new 1,3,4-thiadiazoles derivatives with leishmanicidal potential. [ABSTRACT FROM AUTHOR]

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

During last decades, 3,5-disubstituted-tetrahydro- 2H -thiadiazine-2-thione scaffold remains the center of interest due to their ease of preparation, diverse range substituents at N-3 and N-5 positions, and profound biological activities. In the current study, a series of 3,5-disubstituted-tetrahydro- 2H -thiadiazine-2-thiones were synthesized in good to excellent yield, and the structure of the compounds were confirmed by various spectroscopic techniques such as FTIR, 1 H-NMR, 13 C-NMR and Mass spectrometry, and finally evaluated against Leishmania major . Whereas, all the evaluated compounds (1-33), demonstrate potential leishmanicidal activities with IC 50 values in the range of (1.30- 149.98 uM). Among the evaluated compounds such as 3, 4, 6, and 10 exhibited excellent leishmanicidal activities with IC 50 values of (2.17 μM), (2.39 μM), (2.00 μM), and (1.39 μM), respectively even better than the standard amphotericin B (IC 50 = 0.50) and pentamidine (IC 50 = 7.52). In order to investigate binding interaction of the most active compounds, molecular docking study was conducted with Leishmania major . Further molecular dynamic simulation study was also carried out to assess the stability and correct binding of the most active compound 10, within active site of the Leishamania major . Likewise, the physiochemical properties, drug likeness, and ADMET of the most active compounds were investigated, it was found that none of the compounds violate Lipiniski's rule of five, which show that this class of compounds had enough potential to be used as drug candidate in near future.Communicated by Ramaswamy H. Sarma.

Magnesium oxide-zinc oxide (MgO: ZnO) bimetallic nanoparticles were fabricated, employing Malvastrum coromandelianum root extract, in search of bioactive materials. This is the first ever report of nanocomposites’ synthesis with this plant species, through an environmentally friendly, convenient, cost-effective, and scalable method. The nanocomposites were synthesized with different ratios of metals (Mg: Zn) i.e., 1:1, 1:2, and 2:1, to draw a comparative analysis among their biological potential. The metals gave characteristic bands in the Fourier-Transform Infrared spectrum, indicating successful fabrication of the composites. Highly crystalline nature of the composites was observed through x-ray diffraction studies. Particle sizes were determined to be 29, 30, and 13 nm for the 1:1, 1:2, and 2:1 nanocomposites, respectively, with irregular shapes and aggregates observed during microscopic analysis. Energy dispersive x-ray diffraction confirmed the presence of corresponding metals in all composites, which remained stable up to 400 °C according to the thermogravimetric analysis data. The composites displayed significant anti-bacterial activity against three bacterial strains, with the 1:1 and 1:2 (Mg: Zn) nanocomposites showing higher activity against Bacillus subtilis, with 26 and 21 mm zones of inhibition, respectively. Escherichia coli was significantly inhibited by the 2:1 nanocomposite with a 20 mm zone of inhibition. Anti-fungal activity against Aspergillus niger, Fusarium solani, and Candida albicans, revealed highest inhibitory potential against A. niger, for all the three composites, with zones of inhibition of 18, 19, and 22 mm for 1:1, 1:2, and 2:1 composites, respectively. All samples exhibited a dose-dependent response against the 1,1-Diphenyl-2-picrylhydrazyl radical. The composites also demonstrated significant Leishmanicidal potential, with IC50 values of 40.90 ± 5.8 (2:1), 51.62 ± 3.8 (1:1), and 58.88 ± 3.9 (1:2) µg/mL, indicating promising biological activity. These preliminary biological studies accentuates the potential of these nanoparticles for further in-depth analyses. [ABSTRACT FROM AUTHOR]

We evaluated the leishmanicidal activity of commercially available 5α-cholest-7-en-3β-ol [5α-chol], (+)-4-cholesten-3-one [(+)-4-chol] and the equimolar mixture of the two of them in promastigotes and amastigotes of two different strains of Leishmania mexicana (LCL) and (DCL). The leishmanicidal effectiveness of these sterols was determined by promastigote growth-kinetic experiments and promastigote viability using the propidium iodide staining procedure. The proliferation test was performed using the CFSE (5-Carboxyfluorescein N-succinimidyl ester) staining of parasites at different time points. To determine the leishmanicidal effectiveness of these sterols in amastigotes, we evaluated parasite killing inside of macrophages at different time points. The trypan blue exclusion test was used to determine cytotoxicity of sterols in uninfected macrophages. We included in all experiments a control group of parasites treated with 2% DMSO (Dimethyl Sulfoxide) and another one treated with the reference drug sodium stibogluconate (Sb). Our results showed that the equimolar mixture at 2000 times lower concentration presented similar leishmanicidal activity as Sb. This mixture was similarly effective at 100 times lower concentration than individual sterols tested separately indicating the existence of a synergistic effect against LCL and DCL parasites. The therapeutic index of the equimolar mixture was 10,000—16,000 times higher than the one recorded by Sb and was not cytotoxic to macrophages. Therefore, the equimolar mixture of 5α-Chol and (+)-4-chol may represent a potential alternative for the treatment of cutaneous leishmaniasis. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a tropical disease caused by parasites of the genus Leishmania spp; it presents different clinical manifestations, of which cutaneous leishmaniasis is the most common form, and it is endemic in more than 70 countries worldwide. Only four drugs are registered for the treatment of the disease, all associated with high toxicity. Recently, the in vitro and in vivo leishmanicidal activity of a mixture of the benzoic acid 2-(2,3-dihydro-4H-1-benzopyran-4-ylidene) hydrazide (TC2) and the compounds present in the plant extract Sapindus saponaria L (SS) were reported. In the present study were prepared soft capsules of chitosan incorporating TC2 and SS in 1:1 (CQ) ratio showed low cytotoxicity in U937 macrophages but moderate cytotoxicity in Detroit 551 fibroblast and had high antileishmanial activity against intracellular L. braziliensis amastigotes. The kinetics of TC2 release from CQ was fitted to the Korsmeyer-Peppas model. Finally, CQ was effective in treating experimental cutaneous leishmaniasis induced in the hamster model. In conclusion, the CQ are biocompatible and can help treat cutaneous leishmaniasis.

Introduction: Leishmaniasis, a neglected tropical parasitic disease, is regarded as a major public health problem worldwide. The first-line drugs for leishmaniasis suffer from limitations related to toxicity and the development of resistance in certain parasitic strains. Therefore, the discovery of alternative treatments for leishmaniasis is imperative, and natural products represent a valuable source of potential therapeutic agents., Methods: The present study aimed at finding new potential antileishmanial agents from the aerial parts of the medicinal plant Momordica charantia . This study was based on bioassay-guided fractionation of the M. charantia extract against promastigotes and amastigotes of Leishmania ( Leishmania ) amazonensis . The cytotoxicity of the extract, fractions, and isolated compounds were evaluated against peritoneal murine macrophages by employing the MTT assay for assessing cell metabolic activity., Results: Antileishmanial assay-guided fractionation of the M. charantia extract led to the bioactive cucurbitacin-enriched fraction and the isolation of four bioactive cucurbitacin-type triterpenoids, which exhibited significant antileishmanial activity, with IC 50 values between 2.11 and 3.25 μg.mL -1 against promastigote and amastigote forms, low toxicity and selectivity indexes ranging from 8.5 to 17.2., Conclusion: Our findings demonstrate that the fractions and cucurbitacin-type triterpenoids obtained from the aerial parts of M. charantia are promising natural leishmanicidal candidates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marques, Yoshida, Torres-Santos, Garcez and Garcez.)

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N′-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug.

Eight gallic acid alkyl esters (1–8) were synthesized via Fischer esterification and evaluated for their trypanocidal and leishmanicidal activity using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. The general cytotoxicity of the esters was evaluated with human HL-60 cells. The compounds displayed moderate to good trypanocidal but zero to low leishmanicidal activity. Gallic acid esters with alkyl chains of three or four carbon atoms in linear arrangement (propyl (4), butyl (5), and isopentyl (6)) were found to be the most trypanocidal compounds with 50% growth inhibition values of ~3 μM. On the other hand, HL-60 cells were less susceptible to the compounds, thus, resulting in moderate selectivity indices (ratio of cytotoxic to trypanocidal activity) of >20 for the esters 4–6. Modeling studies combining molecular docking and molecular dynamics simulations suggest that the trypanocidal mechanism of action of gallic acid alkyl esters could be related to the inhibition of the T. brucei alternative oxidase. This suggestion is supported by the observation that trypanosomes became immobile within minutes when incubated with the esters in the presence of glycerol as the sole substrate. These results indicate that gallic acid alkyl esters are interesting compounds to be considered for further antitrypanosomal drug development.

Oliveria decumbens Vent. (Apiaceae), a single aromatic species in Iran, is traditionally used for healing inflammation, gastrointestinal disorders, and infections. Regarding the importance of O. decumbens in traditional medicine, we aimed to set out the plant's biological screening and analyze the chemical components of the active fractions. Air-dried O. decumbens aerial parts were macerated by ethanol:water (70:30). Using a liquid-liquid extraction (LLE) technique, n -hexane, dichloromethane (DCM), ethyl acetate (EtOAc), n -butanol (n -BuOH), and water were successively used to fractionate the crude extract into different portions. Various biological activities were performed on the crude extract, fractions, and some experiments on pure compounds. The bioassays were as follows: antibacterial activity against Staphylococcus aureus , Bacillus subtilis , Escherichia coli , Pseudomonas aeruginosa , and Salmonella typhi (using microplate alamar blue assay; MABA), antifungal activity against Aspergillus niger , A. fumigatus , Candida albicans , C. glabarate , Fusarium lini , Microspurum canis , and Trichophyton rubrum (using agar tube dilution method), antileishmanial activity against Leishmania major and L. tropica using a 96-well serial dilution protocol, anti-inflammatory activity using the respiratory burst assay, cytotoxicity against HeLa (cervical cancer) and BJ (normal fibroblast) cells using MTT assay, insecticidal activity against Tribolium castaneum , Sitophilus oryzae , and Rhyzopertha dominica (using the contact toxicity method), larvicidal activity against Aedes aegypti , anti-DPPH• activity, and cytotoxicity against brine shrimp (Artemia salina) in a lethality assay. Eventually, the phytochemicals from the active fractions were studied by gas chromatography coupled with mass spectrometry (GC-MS). Interestingly, the DCM fraction was the most active, followed by the n -hexane fraction in the biological assays, including antibacterial (>80% inhibition), leishmanicidal (IC 50 (L.major) = 29.4 μg/mL, and IC 50 (L.tropica) = 30.0 μg/mL), anti-inflammatory (IC 50 = 15.8 μg/mL), insecticidal (>80% inhibition), and larvicidal (100% inhibition of A. aegypti) assays. Further GC-MS analysis of the DCM and n -hexane fractions resulted in the characterization of 12 and 14 phytoconstituents, respectively, compared with the NIST library. Thymol and carvacrol were abundant in both fractions. To lesser quantities, the presence of monoterpenoids (p -cymen-8-ol, thymoquinone, 3-hydroxy-β-damascone, and 3-hydroxy-7,8-dihydro-β-ionol), phenylpropanoids (methoxyeugenol, elemicin, and 4-[(1 E)-3-hydroxy-1-propenyl]-2-methoxyphanol, simple phenolics (salicylic acid and 4-methoxy-2,3,6-trimethyl-phenol), and a coumarin (6,7-dimethoxy-coumarin) were detected in the DCM fraction. On the other hand, besides a coumarin and monoterpenoids, the fatty acids (tetradecanoid acid, n -hexadecanoic acid, and linolenic acid) and a sesquiterpene (spathulenol) were observed in the n -hexane fraction. The EtOAc fraction scavenged the DPPH• radicals better than other fractions (IC 50 = 41.4 μg/mL), while in brine shrimp lethality assay, the crude extract was more active than n -hexane and DCM fractions with LD 50 = 385.20, 660.28, and 699.74 μg/mL, respectively. Surprisingly, the crude extract and fractions were ineffective against assayed fungal strains and tested cancer and non-cancer cell lines. Our findings showed that O. decumbens deserves to be a multi-bioactive medicinal plant, besides its ability for cereal protection against pests. To understand the principal mechanism of action, in silico , in vitro , and in vivo experiments may clarify the ambiguities and even figure out the synergistic behavior of the minor secondary metabolites. [Display omitted] [ABSTRACT FROM AUTHOR]

This study reports the isolation of CollinLAAO-I, a new L-amino acid oxidase from Crotalus durissus collilineatus snake venom, its biochemical characterization and leishmanicidal potential in Leishmania spp. CollinLAAO-I (63.1 kDa) was successfully isolated with high purity using two chromatographic steps and represents 2.5% of total venom proteins. CollinLAAO-I displayed high enzymatic activity (4262.83 U/mg/min), significantly reducing after 28 days. The enzymatic activity of CollinLAAO-I revealed higher affinity for hydrophobic amino acids such as L-leucine, high enzymatic activity in a wide pH range (6.0–10.0), at temperatures from 0 to 25 °C, and showed complete inhibition in the presence of Na+ and K+. Cytotoxicity assays revealed IC 50 of 18.49 and 11.66 μg/mL for Leishmania (L.) amazonensis and Leishmania (L.) infantum , respectively, and the cytotoxicity was completely suppressed by catalase. CollinLAAO-I significantly increased the intracellular concentration of reactive oxygen species (ROS) and reduced the mitochondrial potential of both Leishmania species. Furthermore, CollinLAAO-I decreased the parasite capacity to infect macrophages by around 70%, indicating that even subtoxic concentrations of CollinLAAO-I can interfere with Leishmania vital processes. Thus, the results obtained for CollinLAAO-I provide important support for developing therapeutic strategies against leishmaniasis. [Display omitted] • CollinLAAO-I increased ROS production and caused mitochondrial damage in Leishmania. • CollinLAAO-I treatment interfered in essential steps of the Leishmania infection. • L. (L.) infantum is more susceptible to the leishmanicidal effect of CollinLAAO-I. [ABSTRACT FROM AUTHOR]

Leishmaniasis is an endemic disease caused by obligate intracellular protozoa of the genus Leishmania prevalent in the Americas, Africa, and Asia. Therapeutic options are limited for this disease and serious drawbacks are related to the administration of these drugs. Moreover, currently there is no vaccine against leishmaniasis, reinforcing the need to develop new therapeutic options. In the last decade several organoselenium and indolic compounds were reported for their ability to exert activity against different species of Leishmania , posing as promising scaffolds for the development of new drug candidates. In this study, we designed and synthesized a series of thirteen seleno-indoles and investigated their activity against Leishmania amazonensis promastigotes and amastigotes. The most promising seleno-indoles 2a , 2c , 2f , 2g and 3a show good activity against L. amazonensis promastigote and amastigote forms, presenting low toxicity to mammalian cells and good in silico ADMETox and druglikeness parameters, supporting the hypothesis as they being a promising scaffold for further investigation. Mechanistic studies revealed that seleno-indoles 2a , 2c , 2f , 2g and 3a can act interfering with membrane integrity, 2f , 2g and 3a also lead to mitochondrial dysfunction and ROS production, while compound 2a caused mitochondrial depolarization without alteration in ROS generation. [Display omitted] • The anti- Leishmania activity of thirteen seleno-indoles was evaluated. • Promastigote and intracellular amastigote stages of Leishmania amazonensis are susceptible to seven seleno-indoles. • A low toxicity of seleno-indoles was found in mammalian cells. • The seleno-indoles 2f, 2g and 3a altered the mitochondrial membrane potential of promastigotes and induce ROS production. [ABSTRACT FROM AUTHOR]

Medicinal plants are the mainstay of various chemical constituents responsible for curing or mitigating different pathological and non-pathological health issues. In this regard, the current research work was subjected to finding the best effective, new and safe leishmanicidal molecules. Pistacia integerrima is an important medicinal plant growing in Asia with various ethnopharmacological uses such as skin, respiratory and hepatic disorders. The folklore of this plant in skin problems encouraged us to evaluate the isolated compounds for leishmanicidal activity. In the current study, whole ethyl acetate extract was subjected to chromatographic analysis affording two flavonoid constituents, namely naringenin (1) and 3,5,4′-trihydroxy-7-methoxy-flavanone (2). The extract and isolated constituents were tested for leishmanicidal activity. Both compounds were docked into the target binding site (PDB ID: 5HJ9) using MOE 2016. Arginase was taken as the targeted enzyme which is an important enzyme for leishmania species' survival. Arginase up-regulates amastin that impacts amastigote replication and survival. This approach aimed to explore the binding modes of the two isolated flavonoids and to predict their inhibitory activity against arginase. The two flavonoid compounds isolated from P. integerrima were evaluated for their anti-leishmanial activity. Compounds 1 and 2 were tested at a concentration of 5 µg/mL against the selected Leishmanial species. The percent inhibition was 70.43 and 74.76 regarding compounds 1 and 2 , respectively with IC 50 of 29.43 and 16.43 μM. The reference standard drug used, amphotericin-B, displayed the highest leishmanicidal effect (IC 50 of 0.22 μM) with 84.09 % inhibition at half concentration compared to compounds 1 and 2. The molecular docking studies of these two compounds and the standard drug were performed in MOE software. According to the findings, compound 1 , naringenin, docked well in the binding site, with a docking score of −9.28 followed by compound 2 , 3,5,4′-trihydroxy-7-methoxy-flavanone with a docking score of −8.37. Both of the tested samples demonstrated excellent leishmanicidal effects. This pharmacological inhibitory profile provides a strong scientific profile to the folklore of Pistacia integerrima in the treatment of skin disorders especially leishmanial. A further mechanistic study is recommended to find the extract target responsible for the said activity. [ABSTRACT FROM AUTHOR]

The synthesis, physico-chemical characterization and in vitro antiproliferative activity against the promastigote form of Leishmania amazonensis of two new cobalt(II) coordination compounds (i.e. [Co(HL1)Cl 2 ]0.4,2H 2 O (1) and [Co(HL2)(Cl)(CH 3 OH)](ClO 4).2H 2 O (2)) are reported, where HL1 = 4-{3-[bis(pyridin-2-ylmethyl)amino]-2-hydroxypropoxy}-2 H -chromen-2-one and HL2 = 7-{3-[bis(pyridin-2-ylmethyl)amino]-2-hydroxypropoxy}-2 H -chromen-2-one. X-ray diffraction studies were performed for complex (2) and the structure of complex (1) was built through Density Functional Theory (DFT) calculations. Complex (1) presented no cytotoxicity to LLC-MK2, but complex (2) was toxic. IC 50 against promastigotes of L. amazonensis for complex (1) were 4.90 (24 h), 3.50 (48 h) and 3. 80 μmol L−1 (72 h), and for complex (2) were 2.09, 4.20 and 2.80 μmol L−1, respectively. Due to the high toxicity presented by complex (2) against LLC-MK2 host cells, mechanistic studies, to shed light on the probable mode of leishmanicidal activity, were carried out only for the non-cytotoxic complex. Complex (1) was able to elevate mitochondrial membrane potential of the parasites after treatment. Transmission electron microscopy revealed typical apoptotic condensation of chromatin, altered kinetoplast and mitochondria structures, suggesting that apoptosis-like cell death of the protozoa is probably mediated by an apoptotic mechanism associated with mitochondrial dysfunction (intrinsic pathway). Molecular docking studies with complex (1) upon protein tyrosine phosphatase (LmPRL-1) suggests a plausible positive complex anchoring mainly by hydrophobic and hydrogen bond forces close to the enzyme's catalytic site. These promising results for complex 1 will prompt future investigations against amastigote form of L. amazonensis. The anti -Leishmania activity of new Co(II) complex containing coumarin group involves mitochondrial dysfunction of parasite, suggesting apoptosis-like cell death. [Display omitted] • Two new isomeric cobalt(II) complexes, containing coumarin groups are described. • X-ray diffraction studies were performed for complex (2). • Complex (1) exhibited in vitro anti-Leishmania activity (promastigote form). • TEM shows mitochondria impairment and apoptosis-like cell death of the parasite. [ABSTRACT FROM AUTHOR]

• Biotransformation of 2-phenylquinoline by microorganisms was used as a strategy to obtain quinolinic derivatives as anti-leishmania agents. • 5,6-dihydro-5,6-dihydroxy-2-phenylquinoline and 4'-hydroxy-2-phenylquinoline were produced, respectively, by Aspergillus fumigatus and A. flavus , and spectroscopically characterized. • 5,6-dihydro-5,6-dihydroxy-2-phenylquinoline is a new diol for the first time reported. • Both substances hit promastigote forms of three Leishmanias spp. in assays for leishmanicidal activity. • In assays for biological properties within an inflammatory context present in leishmaniasis, both presented significant unreported anti-inflammatory properties. Quinolines are heterocyclic molecules with a wide range of pharmacological purposes. The quinolinic system has been used for the synthesis of derivatives, producing molecules with significant improvement of the original activities. In this work, the alkaloid 2-phenylquinoline, the main substance of the Bolivian tree Galipea longiflora , traditionally employed for treating leishmaniasis, served as a substrate for biotransformation to obtain compounds for leishmaniasis applications. Using Aspergillus fumigatus , the novel and for the first-time reported 5,6-dihydro-5,6-dihydroxy-2-phenylquinoline diol was produced. Its biotransformation by A. flavus resulted in 4′‑hydroxy-2-phenylquinoline. When tested against Leishmania amazonensis, L. infantum , and L. braziliensis promastigotes, both showed time-related leishmanicidal effects significantly higher than those observed for the parental molecule. Transmission electron microscopy revealed that the derivatives affected several cellular structures including the nucleus. When assayed for biological properties within an inflammatory context usually present in leishmaniasis, they were neither toxic for macrophages and fibroblasts nor affected the behavior of immune cells or the expression levels of some adhesion integrins, but significantly altered the chemotaxis of neutrophils, suggesting additional properties in enhancing some important steps necessary for the defense and healing processes that develop just after the sand fly-infected saliva injection that triggers the infection. Our results indicate that monitored biotransformation of 2-phenylquinoline by Aspergillus genera can be a viable route to obtain highly active leishmanicidal substances with additional anti-inflammatory properties not reported before, as particularly observed for the new diol, which may be efficient in controlling leishmaniasis and its parasite burden. [Display omitted] [ABSTRACT FROM AUTHOR]

Leishmaniasis is a group of neglected vector-borne tropical diseases caused by protozoan parasites of the genus Leishmania that multiply within phagocytic cells and have a wide range of clinical manifestations. Cutaneous leishmaniasis (CL) is a serious public health that affects more than 98 countries, putting 350 million people at risk. There are no vaccines that have been proven to prevent CL, and the treatment relies on drugs that often have severe side effects, justifying the search for new antileishmanial treatments. In the present investigation, it is demonstrated that 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1 H -1,2,3-triazole (7k) presents significant antileishmanial activity (IC 50 of 7.4 μmol L−1 and 1.6 μmol L−1 for promastigote and amastigote forms, respectively), low cytotoxicity against macrophage cells (IC 50 of 211.9 μmol L−1), and a selective index of 132.5. Under similar conditions, compound 7k outperformed glucantime and pentamidine, two commonly used drugs in clinics. In vivo assays on CL-infected female BALB/c mice demonstrated that compound 7k had activity similar to intralesional glucantime when administered orally, with decreased lesion and parasitic load, and a low systemic toxic effect. Given the importance of understanding the relationship between compound structure and biological activity in the research and development of new drugs, the development of a quantitative structure-activity relationship (QSAR) model for the leishmanicidal activity presented by the eugenol derivatives with 1,2,3-triazole functionalities is also described herein. This study demonstrates the therapeutic potential of orally active eugenol derivatives against CL and provides useful insights into the relationship between the chemical structures of triazolic eugenol derivatives and their biological profile. [Display omitted] • Leishmanicide activity of eugenol derivatives is presented. • The most active derivative 7k displays important effects on cutaneous leishmaniasis. • Derivative 7k is more effective than glucantime and pentamidine. • Infected BALB/c mice were orally treated with 7k leading to decrease lesion and parasitic loading. • a QSAR model regarding leishmanicide activity of eugenol derivatives is presented. [ABSTRACT FROM AUTHOR]

Eight gallic acid alkyl esters (1−8) were synthesized via Fischer esterification and evaluated for their trypanocidal and leishmanicidal activity using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. The general cytotoxicity of the esters was evaluated with human HL-60 cells. The compounds displayed moderate to good trypanocidal but zero to low leishmanicidal activity. Gallic acid esters with alkyl chains of three or four carbon atoms in linear arrangement (propyl (4), butyl (5), and isopentyl (6)) were found to be the most trypanocidal compounds with 50% growth inhibition values of ~3 μM. On the other hand, HL-60 cells were less susceptible to the compounds, thus, resulting in moderate selectivity indices (ratio of cytotoxic to trypanocidal activity) of >20 for the esters 4−6. Modeling studies combining molecular docking and molecular dynamics simulations suggest that the trypanocidal mechanism of action of gallic acid alkyl esters could be related to the inhibition of the T. brucei alternative oxidase. This suggestion is supported by the observation that trypanosomes became immobile within minutes when incubated with the esters in the presence of glycerol as the sole substrate. These results indicate that gallic acid alkyl esters are interesting compounds to be considered for further antitrypanosomal drug development.