Search

Leishmaniasis being one of the six major tropical diseases that affects nearly 0.7-1.3 million people annually, has so far limited and high toxic therapeutic options. Herein, we report the synthesis, in silico, and in vitro evaluations of novel coumarin-incorporated isatin hydrazones (Spf-1 - Spf-10) as highly potent and safe antileishmanial agents. Molecular docking was initially carried out to decipher the binding confirmation of lead molecules towards the active cavity of the target protein (Leishmanolysin gp63) of Leishmania tropica. Among all the docked compounds, only Spf-6, Spf-8, and Spf-10 showed high binding affinities due to a pattern of strong conventional hydrogen bonds and hydrophobic π-interactions. The molecular dynamics simulations showed the stable pattern of such bonding and structure-based confirmation with a time scale of 50 ns towards the top compound (Spf-10) and protein. These analyses affirmed the high stability of the system. Three out of ten compounds evaluated for their antileishmanial activity against Leishmania tropica promastigotes and amastigotes were found to be active at micromolar concentrations (IC 50 range 0.1-4.13 μmol/L), and most importantly, they were also found to be highly biocompatible when screened for their toxicity in human erythrocytes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Leishmaniasis is a clinical manifestation caused by the parasites of the genus Leishmania. Plants are reservoirs of bioactive compounds, which are known to be chemically balanced, effective and least injurious as compared with synthetic medicines. The current resistance and the toxic effects of the available drugs have brought the trend to assess the antileishmanial effect of various plant extracts and their purified compound/s, which are summarized in this review. Moreover, it also highlights various traditional remedies used by local healers against leishmaniasis. A systematic cross-sectional study for antileishmanial activity of natural products was carried out using multiple literature databases. The records retrieved since 2000 till year 2016 were analysed and summarized in the form of comprehensive tables and graphs. Natural products are potential source of new and selective agents that can significantly contribute to primary healthcare and probably are promising substitutes of chemicals for the treatment of protozoan diseases like leishmaniasis. Where the researchers prefer to use alcoholic solvents for the extraction of antileishmanial agents from plants, most of the studies are limited to in vitro conditions majorly on using promastigote forms of Leishmania. Thus, there is a need to carry out such activities in vivo and in host macrophages. Further, there is a need of mechanistic studies that can help taking few of the promising pure compounds to clinical level. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The aim the present study was to investigate the impact of novel pentavalent organobismuth and organoantimony complexes on membrane integrity and their interaction with DNA, activity against Sb(III)‐sensitive and ‐resistant Leishmania strains and toxicity in mammalian peritoneal macrophages. Ph3M(L)2 type complexes were synthesized, where M = Sb(V) or Bi(V) and L = deprotonated 3‐(dimethylamino)benzoic acid or 2‐acetylbenzoic acid. Both organobismuth(V) and organoantimony(V) complexes exhibited efficacy at micromolar concentrations against Leishmania amazonensis and L. infantum but only the later ones demonstrated biocompatibility. Ph3Sb(L1)2 and Ph3Bi(L1)2 demonstrated distinct susceptibility profiles compared to inorganic Sb(III)‐resistant strains of MRPA‐overexpressing L. amazonensis and AQP1‐mutated L. guyanensis. These complexes were able to permeate the cell membrane and interact with the Leishmania DNA, suggesting that this effect may contribute to the parasite growth inhibition via apoptosis. Taken altogether, our data substantiate the notion of a distinct mechanism of uptake pathway and action in Leishmania for these organometallic complexes, distinguishing them from the conventional inorganic antimonial drugs. [ABSTRACT FROM AUTHOR]

Aim: To investigate the photodynamic therapeutic potential of ferromagnetic iron oxide nanorods (FIONs), using Trigonella foenum-graecum as a reducing agent, against Leishmania tropica. Materials & methods: FIONs were characterized using ultraviolet visible spectroscopy, x-ray diffraction and scanning electron microscopy. Results: FIONs showed excellent activity against L. tropica promastigotes and amastigotes (IC50 0.036 ± 0.003 and 0.072 ± 0.001 μg/ml, respectively) upon 15 min pre-incubation light-emitting diode light (84 lm/W) exposure, resulting in reactive oxygen species generation and induction of cell death via apoptosis. FIONs were found to be highly biocompatible with human erythrocytes (LD50 779 ± 21 μg/ml) and significantly selective (selectivity index >1000) against murine peritoneal macrophages (CC50 102.7 ± 2.9 μg/ml). Conclusion: Due to their noteworthy in vitro antileishmanial properties, FIONs should be further investigated in an in vivo model of the disease. [ABSTRACT FROM AUTHOR]

• Euphorbia wallichii carry high antileishmanial potentials. • Euphorbia wallichii kills Leishmania cells via membrane permeability and apoptosis. • Euphorbia wallichii carry low cytotoxicity to human blood erythrocytes. Clinically available synthetic chemotherapeutics to treat the vector-borne protozoan infection, leishmaniasis, are associated with serious complications such as toxicity and emergence of resistance. Natural products from plants consist of interesting biomolecules that may interfere with DNA or membrane integrity of the parasite and can possibly minimise the associated side effects. In the present study, various fractions of Euphorbia wallichii (EW) root extracts including n-hexane (EWNX), ethyl acetate (EWEA), chloroform (EWCH) and aqueous (EWAQ), were evaluated for their antileishmanial potential against Leishmania tropica followed by investigation of the possible mechanism of action via reactive oxygen species (ROS) quantification, membrane permeability (via sytox green dye) and apoptotic assay (via AO/EB method) using fluorescent microscopy. Two of the fractions i.e. EWEA and EWAQ inhibited the growth of promastigotes (IC 50 7.8 and 10.2 μg/mL, respectively) and amastigotes (IC 50 9.9 and 13.3 μg/mL, respectively) forms almost at similar concentrations as found for the standard antileishmanial drugs, tartar emetic (TA) and Glucantime (IC 50 9.4 and 21.5 μg/mL, respectively). Both the active fractions remained non-toxic towards human blood erythrocytes and were able to cause membrane permeability and apoptotic induction (using Triton X-100 as a positive control) leading to death of Leishmania parasites. However, both the fractions could not triger significant and persistent ROS generation, compared to hydrogen peroxide used as a positive control. Antilesihmanial activity of the two active fractions might be attributed to the presence of high quantity of tannins and saponins. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the association of the drug meglumine antimoniate (MA) with β-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release MA and modulate the serum levels of Sb after oral administration in mice. Analysis of the MA/ribose composition by high performance liquid chromatography coupled to mass spectrometry (LCMS-IT-TOF) revealed the presence of mixed meglumine-Sb-ribose and Sb-ribose complexes. Analysis of the MA/maltose composition suggested the formation of MA-maltose association compounds. Circular dichroism characterization of these compositions following dilution in water at 37 °C suggested a partial and slow dissociation of the association compounds. When the MA/ribose composition was administered orally and compared to MA, the serum concentration of Sb was significantly lower after 1 h and greater after 3 h. On the other hand, the MA/maltose composition showed similar serum Sb concentration after 1 h and higher level of Sb after 3 h, when compared to MA. In conclusion, the present study has demonstrated the formation of mixed or association complexes of MA with sugars, such as maltose and ribose, which promoted sustained serum level of Sb after oral administration. [ABSTRACT FROM AUTHOR]

The antileishmanial drugs presently available have stern limitations regarding efficiency, safety and cost that make it crucial to hunt for novel therapeutic approaches from natural products. In current study crude methanolic extracts (CMEs) of four medicinally important plants were evaluated for their phytochemical constituents, antioxidant potentials, cytotoxicity and antileishmanial activities. Digera muricata (L) and Cannabis sativa (Linn) showed highest total phenolic and flavonoid content (273.4 μg GAE/mg DW and 206.8 μg QA/mg DW, respectively), amongst others. Total antioxidant capacity determined in vitro by phosphomolybdenum assay exhibited that Saccharum spontaneum (L) and Mangifera indica (L) were the strongest antioxidants (∼108 and ∼100 μg AAE/g of DW, respectively) plants amongst other tested. The S. spontaneum showed remarkable scavenging activity (EC 50 44.9 μg/mL), while M. indica showed to possess the lowest scavenging activity (EC 50 105.7 μg/mL) on 1,1-diphenyl-2-picrylhydrazyl. S. spontaneum and C. sativa were the least toxic (CC 50, 113.0 and 109.4 μg/mL respectively), while M. indica remained the most toxic (CC 50 42.46 μg/mL). Moreover, the in vitro evaluation of antileishmanial potential of plants CMEs, demonstrated a dose-dependent growth inhibition of L. major promastigotes and axenic amastigotes. M. indica and D. muricate extracts exhibited to possess antileishmanial potential at minute concentrations (IC 50 5.2 and 18.9 μg/mL, respectively) comparable to that of tartar emetic (IC 50 4.7μg/mL) against L. major promastigotes. Each CME was significantly active (p < 0.0001) against L. major axenic amastigotes when compared to Glucantime®. This study encourages the isolation of bioactive compounds from these plants for antileishmanial drug development. [ABSTRACT FROM AUTHOR]

• High levels of IL-4 and cell-free mitochondrial DNA were detected in CL patients infected with L. tropica or L. major. • In both groups of patients, the level of CD4+ T - cells was higher while no significant difference in levels of CD8+ T - cells was observed. • Levels of CF mt-DNA and IL-4 in CL can be used to determine the disease progression. • These biomarkers could help in designing vaccine strategies and immunotherapies. The pathophysiology of Cutaneous Leishmaniasis (CL), an infection caused by Leishmania tropica (L. tropica) and Leishmania major (L. major) is primarily determined by inflammation-mediated immune cells. The immune response mainly depends on cells and molecules related to T-cells that influence susceptibility and disease development. Understanding the immunological mechanisms that cause tissue injury or lesion healing is critical for developing appropriate treatment strategies. In the present study, T-cells profile and cell-free mitochondrial DNA (CF mt-DNA) were investigated in CL patients infected with L. tropica (n = 34) and L. major (n = 2) and compared with non-infected healthy controls (n = 20). There was a significant (p <0.0001) difference between CD4+ T - cells among L. tropica and L. major CL-infected groups as compared to control while no significant difference (p = 0.8597) was found in the percentages of CD8+ T - cells. When L. tropica and L. major CL-infected individuals were compared to controls, the levels of IL-4 and expression of CF mt-DNA were significantly higher (p <0.0001). Higher levels of CF mt-DNA were detected in CL patients, irrespective of the infective Leishmania species. We proposed that the levels of CF mt-DNA and IL-4 in CL-infected individuals can be used to determine the disease progression. A better understanding of these biomarkers and evaluation of the immune responses in CL patients might benefit the development of vaccines and immunotherapies. [ABSTRACT FROM AUTHOR]