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Fulltext Phlebotomine sand flies (Diptera: Psychodidae) and sand fly-borne pathogens in the Greater Mekong Subregion: a systematic review

Hustedt J, Prasetyo DB, Fiorenzano JM, von Fricken ME, Hertz JC

Parasit Vectors, 2022 Oct 05;15(1):355.
PMID: 36199150 DOI: 10.1186/s13071-022-05464-8

Phlebotomine sand flies are proven or suspected vectors of several pathogens of importance, including leishmaniasis, bartonellosis and sand fly fevers. Although sand flies have a worldwide distribution, there has been limited research published on sand flies and sand fly-borne pathogens throughout the Greater Mekong Sub-region (GMS). This review followed the PRISMA guidelines to determine the biodiversity and presence of phlebotomine sand flies and their associated pathogens in the GMS, specifically Cambodia, Thailand, the Lao People's Democratic Republic (Laos), Malaysia and Vietnam. A total of 1472 records were identified by searching electronic databases, scanning reference lists of articles and consulting experts in the field. After screening of title and abstracts, 178 records remained and were further screened for original data (n = 34), not having regional data (n = 14), duplication of data (n = 4), records not available (n = 4) and no language translation available (n = 2). A total of 120 studies were then included for full review, with 41 studies on sand fly-related disease in humans, 33 studies on sand fly-related disease in animals and 54 entomological studies focused on sand flies (5 papers contained data on > 1 category), with a majority of the overall data from Thailand. There were relatively few studies on each country, with the exception of Thailand, and the studies applied different methods to investigate sand flies and sand fly-borne diseases, impacting the ability to conduct meaningful meta-analysis. The findings suggest that leishmaniasis in humans and the presence of sand fly vectors have been reported across several GMS countries over the past 100 years, with local transmission in humans confirmed in Thailand and Vietnam. Additionally, local Mundinia species are likely transmitted by biting midges. Findings from this study provide a framework for future investigations to determine the geographic distribution and risk profiles of leishmaniasis and other associated sand fly-borne disease throughout the GMS. It is recommended that researchers expand surveillance efforts across the GMS, with an emphasis placed on entomological surveys, syndromic and asymptomatic monitoring in both humans and animals and molecular characterization of sand flies and sand fly-borne pathogens, particularly in the understudied countries of Cambodia, Vietnam and Laos.

Matched MeSH terms: Leishmania*
Antileishmanial effects, cellular mechanisms, and cytotoxicity of Elettaria cardamomum essential oil against Leishmania major infection

Majeed QA, Alshammari A, Alanazi AD

Trop Biomed, 2023 Jun 01;40(2):259-265.
PMID: 37650415 DOI: 10.47665/tb.40.2.019

Leishmaniasis is an infectious disease with various clinical manifestations. We studied the therapeutic effects of Elettaria cardamomum essential oil (ECEO) against Leishmania major infection. In vitro effects of ECEO against L. major were examined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and macrophage assays. Nitric oxide (NO) production, infection inhibition in macrophages, and the apoptotic activity of ECEO in treated parasites were also measured. By calculating the 50% cytotoxic concentrations (CC50), we studied the cytotoxicity effects of ECEO on human macrophage cells (THP-1). The efficacy of ECEO for improving cutaneous leishmaniasis (CL) lesions in mice (BALB/c) was determined by evaluating the size of lesions and the number of amastigotes before and after four weeks of treatment. The effects of ECEO on liver and kidney function in the tested mice were also evaluated. ECEO dose-dependently (p<0.001) inhibited the viability and the mean number of promastigotes and amastigote forms of L. tropica. Four weeks of treatment with ECEO at the doses of 2.5 and 5 mg/kg/ day significantly (p<0.001) improved the CL lesions and reduced the number of parasites in the infected mice. ECEO significantly increased NO production, apoptosis induction, and infection rate in parasites. The CC50 value for ECEO and MA was 303.4 µg/mL and 835.2 µg/mL, respectively. In the mice receiving ECEO at the doses of 2.5 and 5 mg/kg/day for 28 days, no significant change was reported between the serum level of liver enzymes and kidney factors when compared with the control group. ECEO displayed promising efficacy in parasite reduction in vitro and in the animal model. ECEO can thus be used as an alternative medicine to treat CL.

Matched MeSH terms: Leishmania major*
Identification and characterization of Leishmania amastigote and axenic form antigens

Abdelhaleem AA, Elamin EM, Bakheit SM, Mukhtar MM

Trop Biomed, 2019 Dec 01;36(4):866-873.
PMID: 33597459

This study was aimed to identify and characterize Leishmania amastigote, and axenic form antigens. Two in vitro techniques were used to change leishmania parasite isolates from promastigote form to amastigotes and amastigote like (axenic) forms. The main strategy relied upon in vitro infection of murine macrophages cell line J774 with leishmania promastigote, at 37°C with 5% CO2, while the second technique relied upon the culture of promastigote at 37°C with low pH (5.5), and 5-10% CO2. Proteins were extracted and fractionated utilizing 12% Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS PAGE). Antigens were recognized using both immune dot blot and western blot procedures. PCR was performed for recognition of leishmania parasites in infected J774 macrophages. L. major was quicker in infectivity of macrophages cell line than L. donovani. Shared proteins ranging from 26-116 kDa were identified by SDS PAGE in all stages. Immune Dot-blot method showed positive outcomes, while western blot identified an exceptional antigen band of 16 kDa in amastigote, this unique band could be of value in diagnosis and vaccination of leishmaniasis. PCR results confirmed presence of both isolates demonstrating that coinfection is conceivable, and no indications of hereditary recombination at kinetoplast DNA (kDNA) were identified in macrophages simultaneously infected by L. major and L. donovani.

Matched MeSH terms: Leishmania/immunology; Leishmania/isolation & purification*; Leishmania donovani; Leishmania major
Comparison of several lizard Leishmania species and strains in terms of kinetoplast minicircle and maxicircle DNA sequences, nuclear chromosomes, and membrane lipids

Gomez-Eichelmann MC, Holz G, Beach D, Simpson AM, Simpson L

Mol Biochem Parasitol, 1988 Jan 15;27(2-3):143-58.
PMID: 3344003

Eight strains of a lizard Leishmania species, L. tarentolae, were compared with four other saurian species [L. hoogstrali, L. adleri, L. agamae and Leishmania sp. LizS], with L. major from man and with Trypanosoma platydactyli, a putative lizard trypanosome, in terms of kinetoplast DNA minicircle and maxicircle sequences and in terms of nuclear chromosome patterns on orthogonal gel electrophoresis. The L. tarentolae strains fell into two major groups, one (group A) consisting of the L. tarentolae strains, UC, Krassner and Trager, derived from an Algerian gecko isolate and the other (group B) consisting of five L. tarentolae LEM strains isolated from geckos in southern France. T. platydactyli TPCL2, which was postulated by Wallbanks et al. to represent the lizard form of a French L. tarentolae strain, was closely related to the UC strain and not to the LEM strains, in all respects analyzed. Leishmania sp. LizS from a Mongolian gecko and L. hoogstrali from a Sudanese gecko showed some sequence similarities to the L. tarentolae strains, but the leishmanias said to be L. adleri from a Kenyan lacertid and L. agamae from an Israeli agamid showed no minicircle sequence similarities with lizard Leishmania and in fact were probably the same species. The maxicircle divergent region was larger in the group B strains than in the group A strains, but there were sequences in common with both groups, and not with L. hoogstrali and L. major. Four strains of L. tarentolae, the four other supposed saurian Leishmania species, three mammalian leishmanias, T. platydactyli and four other trypanosomes, T. cyclops (Malaysian macaque), T. conorrhini (Hawaiian reduviid bug), T. cruzi (man) and T. lewisi (feral rat) were analyzed for their contents of sterols and phosphoglyceride fatty acyl groups. T. platydactyli TPCL2 contained a sterol (5-dehydroepisterol), a phosphatidylcholine fatty acyl group (alpha-linolenic acid) and a phosphatidylethanolamine fatty acyl group (dihydrosterculic acid) characteristic of members of the genus Leishmania and not the genus Trypanosoma. The proportions of those lipids in the free sterol and phosphoglyceride fractions of T. platydactyli TPCL2 most closely resembled those seen in the Leishmania strains from Algerian, French, Mongolian and Sudanese geckos.

Matched MeSH terms: Leishmania/classification; Leishmania/isolation & purification*
Fulltext First Molecular Characterization of Leishmania Species Causing Visceral Leishmaniasis among Children in Yemen

Mahdy MA, Al-Mekhlafi AM, Abdul-Ghani R, Saif-Ali R, Al-Mekhlafi HM, Al-Eryani SM, et al.

PLoS One, 2016;11(3):e0151265.
PMID: 26966902 DOI: 10.1371/journal.pone.0151265

Visceral leishmaniasis (VL) is a debilitating, often fatal disease caused by Leishmania donovani complex; however, it is a neglected tropical disease. L. donovani complex comprises two closely related species, L. donovani that is mostly anthroponotic and L. infantum that is zoonotic. Differentiation between these two species is critical due to the differences in their epidemiology and pathology. However, they cannot be differentiated morphologically, and their speciation using isoenzyme-based methods poses a difficult task and may be unreliable. Molecular characterization is now the most reliable method to differentiate between them and to determine their phylogenetic relationships. The present study aims to characterize Leishmania species isolated from bone marrows of Yemeni pediatric patients using sequence analysis of the ribosomal internal transcribed spacer-1 (ITS1) gene. Out of 41 isolates from Giemsa-stained bone marrow smears, 25 isolates were successfully amplified by nested polymerase chain reaction and sequenced in both directions. Phylogenetic analysis using neighbor joining method placed all study isolates in one cluster with L. donovani complex (99% bootstrap). The analysis of ITS1 for microsatellite repeat numbers identified L. infantum in 11 isolates and L. donovani in 14 isolates. These data suggest the possibility of both anthroponotic and zoonotic transmission of VL-causing Leishmania species in Yemen. Exploring the possible animal reservoir hosts is therefore needed for effective control to be achieved.

Matched MeSH terms: Leishmania donovani/classification; Leishmania donovani/genetics*; Leishmania donovani/isolation & purification; Leishmania infantum/classification; Leishmania infantum/genetics*; Leishmania infantum/isolation & purification
Recombinant C-Reactive Protein: A Potential Candidate for the Treatment of Cutaneous Leishmaniasis of BALB/c Mice Caused by Leishmania major

Zahedi SN, Hejazi SH, Boshtam M, Amini F, Fazeli H, Sarmadi M, et al.

Acta Parasitol, 2021 Mar;66(1):53-59.
PMID: 32676917 DOI: 10.1007/s11686-020-00251-w

PURPOSE: Leishmaniasis, a widespread parasitic disease, is a public health concern that is endemic in more than 90 countries. Owing to the drug resistance and also undesirable complications, designing new therapeutic methods are essential. C-reactive protein (CRP) is an acute phase protein of plasma with several immune modulatory functions. This study aimed to evaluate the effect of human recombinant CRP (hrCRP) on treating cutaneous leishmaniasis in mice models.
METHODS: hrCRP was expressed in E. coli Rosetta-gami and extracted from the SDS-PAGE gel. Male BALB/c mice were inoculated subcutaneously at the base of their tails by 1 × 105 stationary-phase of Leishmania major promastigotes (MHRO/IR/75/ER) suspended in sterile phosphate buffered saline (PBS). Nodules and subsequently, ulcers developed 14 days post-injection. 1.5 µg of the purified protein was administered on lesions of pre-infected mice by Leishmania major in the intervention group for five consecutive days.
RESULTS: The mean area of the lesions was decreased by about seven folds in the intervention group as compared to the control group after two weeks of the treatment (p = 0.024). The results were verified by the real-time polymerase chain reaction so that the parasite burden was determined 27 times in the control group as compared to the intervention group (p = 0.02). Two weeks after treatment, the conversion of the lesions to scars in the intervention group was observed.
CONCLUSION: The results indicate a potential therapeutic role for hrCRP in improving cutaneous leishmaniasis due to Leishmania major in mice models. The healing was in a stage-dependent manner.

Matched MeSH terms: Leishmania major*
Efficacy of pentamidine-loaded chitosan nanoparticles as a novel drug delivery system for Leishmania tropica

Khan RU, Khan M, Sohail A, Ullah R, Iqbal A, Ahmad B, et al.

Trop Biomed, 2022 Dec 01;39(4):511-517.
PMID: 36602209 DOI: 10.47665/tb.39.4.003

The present study compares the in vitro effects of nanoparticles loaded pentamidine drug and conventional pentamidine on Leishmania tropica. Herein, pentamidine-loaded chitosan nanoparticles (PTN-CNPs) have been synthesized through an ionic gelation method with sodium tripolyphosphate (TPP). Next, the physical characteristics of PTN-CNPs were determined through the surface texture, zeta potential, in vitro drug release, drug loading content (DLC), and encapsulation efficacy (EE) and compared its efficacy with free pentamidine (PTN) drug against promastigotes and axenic amastigotes forms of L. tropica in vitro. The PTN-CNPs displayed a spherical shape having a size of 88 nm, an almost negative surface charge (-3.09 mV), EE for PTN entrapment of 86%, and in vitro drug release of 92% after 36 h. In vitro antileishmanial activity of PTN-CNPs and free PTN was performed against Leishmania tropica KWH23 promastigote and axenic amastigote using 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyletetrazolium bromide (MTT) assay. It was observed that the effect of PTN-CNPs and free PTN on both forms of the parasite was dose and time dependent. Free PTN presented low efficacy even at higher dose (40 µg/ml) with 25.6 ± 1.3 and 26.5 ±1.4 mean viability rate of the promastigotes and axenic amastigotes, respectively after 72 hrs incubation. While PTN-CNPs showed strong antileishmanial effects on both forms of parasite with 16 ± 0.4 and 19 ± 0.7 mean viability rate at the same higher concentration (40 µg/ml) after 72 hrs incubation. Half maximal inhibitory concentration (IC50) values of PTN-CNPs toward promastigotes and amastigotes were obtained as 0.1375 µg/ml and 0.1910 µg/ml, respectively. In conclusion, PTN-CNPs effectively inhibited both forms of the L. tropica; however, its effect was more salient on promastigotes. This data indicates that the PTN-CNPs act as a target drug delivery system. However, further research is needed to support its efficacy in animal and human CL.

Matched MeSH terms: Leishmania tropica*
A case report of an uncommon presentation of cutaneous leishmaniasis: A nose lesion

Alamin AA, Gebreyesus MW, Mohamed I

Trop Biomed, 2023 Jun 01;40(2):250-252.
PMID: 37650413 DOI: 10.47665/tb.40.2.017

Leishmaniasis is a widely spread zoonotic disease caused by the bite of infected sandflies, particularly in developing countries. Cutaneous leishmaniasis can have a diverse range of presentations, ranging from minor skin nodules to significant mucosal damage. However, nose involvement is infrequent. Our report highlights a 15-year-old female patient with a persistent skin lesion on her nose for three months, which is a rare manifestation of cutaneous leishmaniasis. The lesion started as a raised spot with a brownish-red color and a crust but eventually developed into an ulcer that spread over the entire lobe of the nose and even moved toward the eye. Microscopic examination revealed the presence of Leishmania amastigotes, and a biopsy confirmed a diagnosis of cutaneous leishmaniasis. The patient received daily intravenous sodium stibogluconate doses of 9 mg/kg for 20 days, and three weeks later, there was a significant clinical improvement, with the ulcer beginning to heal and no more amastigotes visible on microscopic examination. It is crucial to keep cutaneous leishmaniasis in mind as a possible diagnosis for patients with skin lesions, even in regions where the condition is not prevalent.

Matched MeSH terms: Leishmania*
Fulltext Molecular characterization of Leishmania species isolated from cutaneous leishmaniasis in Yemen

Mahdy MA, Al-Mekhlafi HM, Al-Mekhlafi AM, Lim YA, Bin Shuaib NO, Azazy AA, et al.

PLoS One, 2010 Sep 20;5(9).
PMID: 20862227 DOI: 10.1371/journal.pone.0012879

BACKGROUND: Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in the tropics and subtropics with a global yearly incidence of 1.5 million. Although CL is the most common form of leishmaniasis, which is responsible for 60% of DALYs lost due to tropical-cluster diseases prevalent in Yemen, available information is very limited.
METHODOLOGY/PRINCIPAL FINDINGS: This study was conducted to determine the molecular characterization of Leishmania species isolated from human cutaneous lesions in Yemen. Dermal scrapes were collected and examined for Leishmania amastigotes using the Giemsa staining technique. Amplification of the ribosomal internal transcribed spacer 1(ITS-1) gene was carried out using nested PCR and subsequent sequencing. The sequences from Leishmania isolates were subjected to phylogenetic analysis using the neighbor-joining and maximum parsimony methods. The trees identified Leishmania tropica from 16 isolates which were represented by two sequence types.
CONCLUSIONS/SIGNIFICANCE: The predominance of the anthroponotic species (i.e. L. tropica) indicates the probability of anthroponotic transmission of cutaneous leishmaniasis in Yemen. These findings will help public health authorities to build an effective control strategy taking into consideration person-to-person transmission as the main dynamic of transmission of CL.

Matched MeSH terms: Leishmania/classification; Leishmania/genetics*; Leishmania/isolation & purification*; Leishmaniasis, Cutaneous/epidemiology; Leishmaniasis, Cutaneous/parasitology*
Fulltext Integration of proteomics and metabolomics to elucidate metabolic adaptation in Leishmania

Akpunarlieva S, Weidt S, Lamasudin D, Naula C, Henderson D, Barrett M, et al.

J Proteomics, 2017 02 23;155:85-98.
PMID: 28040509 DOI: 10.1016/j.jprot.2016.12.009

Leishmania parasites multiply and develop in the gut of a sand fly vector in order to be transmitted to a vertebrate host. During this process they encounter and exploit various nutrients, including sugars, and amino and fatty acids. We have previously generated a mutant Leishmania line that is deficient in glucose transport and which displays some biologically important phenotypic changes such as reduced growth in axenic culture, reduced biosynthesis of hexose-containing virulence factors, increased sensitivity to oxidative stress, and dramatically reduced parasite burden in both insect vector and macrophage host cells. Here we report the generation and integration of proteomic and metabolomic approaches to identify molecular changes that may explain these phenotypes. Our data suggest changes in pathways of glycoconjugate production and redox homeostasis, which likely represent adaptations to the loss of sugar uptake capacity and explain the reduced virulence of this mutant in sand flies and mammals. Our data contribute to understanding the mechanisms of metabolic adaptation in Leishmania and illustrate the power of integrated proteomic and metabolomic approaches to relate biochemistry to phenotype.
BIOLOGICAL SIGNIFICANCE: This paper reports the application of comparative proteomic and metabolomic approaches to reveal the molecular basis for important phenotypic changes Leishmania parasites that are deficient in glucose uptake. Leishmania cause a very significant disease burden across the world and there are few effective drugs available for control. This work shows that proteomics and metabolomics can produce complementary data that advance understanding of parasite metabolism and highlight potential new targets for chemotherapy.

Matched MeSH terms: Leishmania mexicana/metabolism*
Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishmanial potential and molecular docking studies

Almandil NB, Taha M, Rahim F, Wadood A, Imran S, Alqahtani MA, et al.

Bioorg Chem, 2019 04;85:109-116.
PMID: 30605884 DOI: 10.1016/j.bioorg.2018.12.025

New series of quinoline-based thiadiazole analogs (1-20) were synthesized, characterized by EI-MS, 1H NMR and 13C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1-10, 12, 13, 16, 17, 18 and 19 with IC50 values in the range of 0.04 ± 0.01 to 5.60 ± 0.21 µM showed tremendously potent inhibition as compared to the standard pentamidine with IC50 value 7.02 ± 0.09 µM. Analogs 11, 14, 15 and 20 with IC50 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and 9.60 ± 0.40 µM respectively showed good inhibition when compared with the standard. Structure-activity relationships have been also established for all compounds. Molecular docking studies were performed to determine the binding interaction of the compounds with the active site target.

Matched MeSH terms: Leishmania donovani/chemistry; Leishmania major/drug effects
Inhibitors of leishmania mexicana phosphoglycerate mutase identified by virtual screening and verified by inhibition studies

Fazia Adyani Ahmad Fuad, Houston Douglas R, Michels Paul AM, Fothergill-gilmore Linda A, Walkinshaw Malcolm D

Sains Malaysiana, 2016;45:1113-1120.

Cofactor-independent phosphoglycerate mutase has been proposed as a therapeutic target for the treatment of
trypanosomatid diseases. In this paper, we report the identification of compounds that could potentially be developed as
selective inhibitors of cofactor-independent phosphoglycerate mutase from Leishmania mexicana (LmiPGAM). Virtual
screening was used in this search, as well as compounds identified by high-throughput screening. A ligand-based virtual
screen programme, ultra fast shape recognition with atom types (UFSRAT), was used to screen for compounds resembling
the substrate/product, before a structure-based approach was applied using AutoDock 4 and AutoDock Vina in a consensus
docking scheme. In this way eight selected compounds were identified. In addition, three compounds from the Library of
Pharmacologically Active Compounds (LOPAC) were selected from the published results of high-throughput screening of
this library. The inhibitory effects of these compounds were tested at a fixed concentration of 1 mM. The results showed
that seven compounds inhibited LmiPGAM activity and of these, two compounds (one each from high-throughput and
virtual screening) showed substantial inhibition (i.e. 14% and 49% remaining activity, respectively). Taken together, the
findings from this study indicate that these compounds have potential as novel inhibitors that specifically target LmiPGAM.

Matched MeSH terms: Leishmania mexicana
Fulltext The antiacetylcholinesterase and antileishmanial activities of Canarium patentinervium Miq

Mogana R, Adhikari A, Debnath S, Hazra S, Hazra B, Teng-Jin K, et al.

Biomed Res Int, 2014;2014:903529.
PMID: 24949478 DOI: 10.1155/2014/903529

In continuation of our natural and medicinal research programme on tropical rainforest plants, a bioassay guided fractionation of ethanolic extract of leaves of Canarium patentinervium Miq. (Burseraceae Kunth.) led to the isolation of scopoletin (1), scoparone (2), (+)-catechin (3), vomifoliol (4), lioxin (5), and syringic acid (6). All the compounds exhibited antiacetylcholinesterase activity with syringic acid, a phenolic acid exhibiting good AChE inhibition (IC50 29.53 ± 0.19 μ g/mL). All compounds displayed moderate antileishmanial activity with scopoletin having the highest antileishmanial activity (IC50 163.30 ± 0.32 μ g/mL). Given the aforementioned evidence, it is tempting to speculate that Canarium patentinervium Miq. represents an exciting scaffold from which to develop leads for treatment of neurodegenerative and parasitic diseases.

Matched MeSH terms: Leishmania/drug effects*; Leishmania/enzymology; Leishmaniasis/drug therapy; Leishmaniasis/parasitology
Potential application of Leishmania tarentolae as an alternative platform for antibody expression

Lai JY, Klatt S, Lim TS

Crit Rev Biotechnol, 2019 May;39(3):380-394.
PMID: 30720351 DOI: 10.1080/07388551.2019.1566206

Through the discovery of monoclonal antibody (mAb) technology, profound successes in medical treatment against a wide range of diseases have been achieved. This has led antibodies to emerge as a new class of biodrugs. As the "rising star" in the pharmaceutical market, extensive research and development in antibody production has been carried out in various expression systems including bacteria, insects, plants, yeasts, and mammalian cell lines. The major benefit of eukaryotic expression systems is the ability to carry out posttranslational modifications of the antibody. Glycosylation of therapeutic antibodies is one of these important modifications, due to its influence on antibody structure, stability, serum half-life, and complement recruitment. In recent years, the protozoan parasite Leishmania tarentolae has been introduced as a new eukaryotic expression system. L. tarentolae is rich in glycoproteins with oligosaccharide structures that are very similar to humans. Therefore, it is touted as a potential alternative to mammalian expression systems for therapeutic antibody production. Here, we present a comparative review on the features of the L. tarentolae expression system with other expression platforms such as bacteria, insect cells, yeasts, transgenic plants, and mammalian cells with a focus on mAb production.

Matched MeSH terms: Leishmania/genetics*; Leishmania/immunology
Fulltext Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities

Levaique H, Pamlard O, Apel C, Bignon J, Arriola M, Kuhner R, et al.

Molecules, 2021 Mar 11;26(6).
PMID: 33799883 DOI: 10.3390/molecules26061551

Leishmaniasis is a vector-borne disease caused by the protozoan parasite Leishmania found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in Leishmania. In this study, a chemical library of 5000 compounds was screened on both L. infantum (LiGDP-MP) and human (hGDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J (2 and 3) were described for the first time from nature, were then evaluated on both enzymes as well as on L. infantum axenic and intramacrophage amastigotes. From this evaluation, compounds 1 and 3 inhibited both GDP-MPs at the micromolar level, and compound 9 displayed a three-times lower IC50 on LiGDP-MP, at 11 µM, than on hGDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.

Matched MeSH terms: Leishmania/drug effects; Leishmania/pathogenicity; Leishmaniasis/drug therapy*
Molecular hybridization conceded exceptionally potent quinolinyl-oxadiazole hybrids through phenyl linked thiosemicarbazide antileishmanial scaffolds: In silico validation and SAR studies

Taha M, Ismail NH, Ali M, Rashid U, Imran S, Uddin N, et al.

Bioorg Chem, 2017 04;71:192-200.
PMID: 28228228 DOI: 10.1016/j.bioorg.2017.02.005

The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover a novel series of compounds 6-23 based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal potential. The most potent compound (23, IC50=0.10±0.001μM) among the series was found ∼70 times more lethal than the standard drug. The current series 6-23 conceded in the development of fourteen (14) extraordinarily active compounds against leishmaniasis. In silico analysis were also performed to probe the mode of action while all the compounds structure were established by NMR and Mass spectral analysis.

Matched MeSH terms: Leishmania/drug effects*; Leishmania/enzymology; Leishmaniasis/drug therapy
Fulltext Synthesis, anti-leishmanial and molecular docking study of bis-indole derivatives

Taha M, Uddin I, Gollapalli M, Almandil NB, Rahim F, Farooq RK, et al.

BMC Chem, 2019 Dec;13(1):102.
PMID: 31410413 DOI: 10.1186/s13065-019-0617-4

We have synthesized new series of bisindole analogs (1-27), characterized by 1HNMR and HR-EI-MS and evaluated for their anti-leishmanial potential. All compounds showed outstanding inhibitory potential with IC50 values ranging from 0.7 ± 0.01 to 13.30 ± 0.50 µM respectively when compared with standard pentamidine with IC50 value of 7.20 ± 0.20 µM. All analogs showed greater potential than standard except 10, 19 and 23 when compared with standard. Structure activity relationship has been also established for all compounds. Molecular docking studies were carried out to understand the binding interaction of active molecules.

Matched MeSH terms: Leishmania
Fulltext A Review of Quercus infectoria (Olivier) Galls as a Resource for Anti-parasitic Agents: In Vitro and In Vivo Studies

Zin NNINM, Rahimi WNAWM, Bakar NA

Malays J Med Sci, 2019 Nov;26(6):19-34.
PMID: 31908584 MyJurnal DOI: 10.21315/mjms2019.26.6.3

Parasitic diseases represent one of the causes for significant global economic, environmental and public health impacts. The efficacy of currently available anti-parasitic drugs has been threatened by the emergence of single drug- or multidrug-resistant parasite populations, vector threats and high cost of drug development. Therefore, the discovery of more potent anti-parasitic drugs coming from medicinal plants such as Quercus infectoria is seen as a major approach to tackle the problem. A systematic review was conducted to assess the efficacy of Q. infectoria in treating parasitic diseases both in vitro and in vivo due to the lack of such reviews on the anti-parasitic activities of this plant. This review consisted of intensive searches from three databases including PubMed, Science Direct and Scopus. Articles were selected throughout the years, limited to English language and fully documented. A total of 454 potential articles were identified, but only four articles were accepted to be evaluated based on inclusion and exclusion criteria. Although there were insufficient pieces of evidence to account for the efficacy of Q. infectoria against the parasites, this plant appears to have anti-leishmanial, anti-blastocystis and anti-amoebic activities. More studies in vitro and in vivo are warranted to further validate the anti-parasitic efficacy of Q. infectoria.

Matched MeSH terms: Leishmania
Synthesis of symmetrical bis-Schiff base-disulfide hybrids as highly effective anti-leishmanial agents

Taha M, Sain AA, Ali M, Anouar EH, Rahim F, Ismail NH, et al.

Bioorg Chem, 2020 06;99:103819.
PMID: 32325334 DOI: 10.1016/j.bioorg.2020.103819

Leishmaniasis has affected a wider part of population around the globe. Most often, the existing regiments to battle against leishmaniasis are inadequate and limited. In our ongoing efforts to develop new leishmanicidal agents, we have synthesized a series of novel and symmetrical bis-Schiff base-disulfide hybrids 1-27. Intermediate disulfide was synthesized from corresponding 2-aminothiol followed by reacting the coupled adduct with various aromatic aldehydes. All these compounds showed outstanding inhibition when compared with standard (Table 1). Out of twenty seven analogues, twenty two analogues i.e. 1-5, 7-13, 17-21, 23-27 analogues showed excellent inhibitory potential with EC50 values ranging from 0.010 ± 0.00 to 0.096 ± 0.01 μM while five compounds i.e. 6, 14-16, and 22 showed good inhibitory potential with EC50 values ranging from 0.10 ± 0.00 to 0.137 ± 0.01 μM when compared with the standard Amphotericin B. Structure-activity relationship has been established while molecular docking studies were performed to pin the binding interaction of active molecules. This study will help to develop new antileishmanial lead compounds.

Matched MeSH terms: Leishmania/drug effects*
Synthesis and antileishmanial activity of fluorinated rhodacyanine analogues: The 'fluorine-walk' analysis

Lasing T, Phumee A, Siriyasatien P, Chitchak K, Vanalabhpatana P, Mak KK, et al.

Bioorg Med Chem, 2020 01 01;28(1):115187.
PMID: 31761725 DOI: 10.1016/j.bmc.2019.115187

In a search for potent antileishmanial drug candidates, eighteen rhodacyanine analogues bearing fluorine or perfluoroalkyl substituents at various positions were synthesized. These compounds were tested for their inhibitory activities against Leishmania martiniquensis and L. orientalis. This 'fluorine-walk' analysis revealed that the introduction of fluorine atom at C-5, 6, 5', or 6' on the benzothiazole units led to significant enhancement of the activity, correlating with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. On the other hand, CF3 and OCF3 groups were found to have detrimental effects, which agreed with the poor aqueous solubility predicted by the in silico ADMET analysis. In addition, some of the analogues including the difluorinated species showed exceptional potency against the promastigote and axenic amastigote stages (IC50 = 40-85 nM), with the activities surpassing both amphotericin B and miltefosine.

Matched MeSH terms: Leishmania/drug effects*

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