scholarly journals Identification of Suitable Agents against Adenine Phosphoribosyl Transferase for the Management of Leishmaniasis: Synthesis, Characterization and Computational Studies

2021 ◽  
Vol 12 (6) ◽  
pp. 7503-7522
Keyword(s):  
Leishmania Donovani ◽  
Antileishmanial Activity ◽  
Standard Drug ◽  
Docking Analysis ◽  
Equivalent Number ◽  
In Silico Admet ◽  
Drug Score ◽  
Diphenyl Tetrazolium Bromide ◽  
Genus Leishmania

A leishmaniasis is a group of diseases attributable to protozoan parasites of the genus Leishmania. It is a potential disease mostly occurring in developing nations. Various quinoline substituted derivatives (11a-f, 12a-f, and 13a-f) were synthesized by refluxing amino quinolines with an equivalent number of different alkylaminoethyl chlorides and evaluated for their in vitro antileishmanial activity against promastigotes forms of Leishmania donovani by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] reduction assay. Compounds 11f (IC50 = 13.61μg/mL), 12f (IC50 = 11.92 μg/mL) and 13f (IC50 =10.41 μg/mL) have shown significant antileishmanial activity when compared with standard sitamaquine (IC50= 10.09 μg/mL). Furthermore, the molecular docking analysis targeting adenine phosphoribosyltransferase of Leishmania donovani exhibits significant binding interactions. In silico, ADMET predictions revealed that these compounds, i.e., 11f, 12f, and 13f, demonstrated good absorption as well as solubility characteristics with good drug-likeness and drug score values compared to the standard drug.

scholarly journals Cynaroside inhibits Leishmania donovani UDP-galactopyranose mutase and induces reactive oxygen species to exert antileishmanial response

2020 ◽  
Author(s):  
Shams Tabrez ◽  
Fazlur Rahman ◽  
Rahat Ali ◽  
Abdulaziz S Alouffi ◽  
Sajjadul Kadir Akand ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Leishmania Donovani ◽  
Reactive Oxygen ◽  
Antileishmanial Activity ◽  
Dynamics Simulation ◽  
In Vitro Assays ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Standard Drug

Cynaroside, a flavonoid, has been shown to have antibacterial, antifungal and anticancer activities. Here, we evaluated its antileishmanial properties and its mechanism of action through different in silico and in vitro assays. Cynaroside exhibited antileishmanial activity in time and dose-dependent manner with IC50 value of 49.49 ± 3.515 µM in vitro. It inhibited the growth of parasite significantly at only 20 µM concentration when used in combination with miltefosine, a standard drug which have very high toxicity. It also inhibited the intra-macrophagic parasite significantly at low doses when used in combination with miltefosine. It showed less toxicity than the existing antileishmanial drug, miltefosine at similar doses. Propidium iodide staining showed that cynaroside inhibited the parasites in G0/G1 phase of cell cycle. H2DCFDA staining showed cynaroside induced antileishmanial activity through reactive oxygen species (ROS) generation in parasites. Molecular-docking studies with key drug-targets of Leishmania donovani showed significant inhibition. Out of these targets, cynaroside showed strongest affinity with UDP-galactopyranose mutase with -10.4 Kcal/mol which was further validated by molecular dynamics simulation. The bioactivity, ADMET properties, OECD chemical classification and toxicity risk prediction showed cynaroside as an enzyme inhibitor having sufficient solubility and non-toxic properties. In conclusion, cynaroside may be used alone or in combination with existing drug, miltefosine to control leishmaniasis with less cytotoxicity.

scholarly journals EVALUATION AND COMPARISON OF CYTOTOXIC EFFECT OF VILAZODONE HYDROCHLORIDE WITH 5-FLUOROURACIL IN HT-29 BOWEL CANCER CELL LINE

2019 ◽  
pp. 124-127
Author(s):  
LATHA PRIYA A ◽  
ANUSHA D ◽  
DARLING CHELLATHAI K ◽  
HEMALATHA A ◽  
JEGAN MOHAN Y
Keyword(s):  
Cell Line ◽  
Cytotoxic Effect ◽  
Depressive Disorders ◽  
Cancer Cell Line ◽  
Test Sample ◽  
Standard Drug ◽  
Drug Sample ◽  
Diphenyl Tetrazolium Bromide ◽  
Ht 29

Objectives: Vilazodone hydrochloride is a novel selective serotonin reuptake inhibitor (SSRI) used to treat major depressive disorders. There are only sparse data available to know about the SSRI’s and its association with colon cancer. This study aims to evaluate and compare the in vitro cytotoxic effect of vilazodone with 5-fluorouracil (5-FU) in HT-29 cell line. Methods: Cell viability was tested by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay (Mosmann, 1983). Test sample and standard drug in variable concentrations were added to the HT-29 cell lines for incubation over 24 h under ideal conditions. After washing the test and standard drug sample from the well with saline, MTT was added and incubated for 4 h. Dimethyl sulfoxide of 1 ml was added in all wells after incubation with MTT. The absorbance at 570 nm was measured with an ultraviolet - spectrophotometer. Results: The values were tabulated, and the graph was plotted to find the IC-50 value (inhibitory concentration at 50%) which was struck at 28.5 μg/ml and12. 8 μg/ml for vilazodone hydrochloride and 5-FU, respectively. Conclusion: The results show that vilazodone hydrochloride has good anticancer property comparable with 5-FU, which would probably play a role as a cytotoxic agent in tumor cells. The proposed mechanism of action could be by activation of caspase-3 enzyme, thereby increasing apoptosis and indicates its use in coexisting depression and colon carcinoma. Other mechanism includes suppression of oncogene p53, which can be confirmed by future studies.

scholarly journals Antileishmanial Activities of Several Classes of Aromatic Dications

2002 ◽  
Vol 46 (3) ◽  
pp. 797-807 ◽  
Author(s):  
James J. Brendle ◽  
Abram Outlaw ◽  
Arvind Kumar ◽  
David W. Boykin ◽  
Donald A. Patrick ◽  
...  
Keyword(s):  
Cell Line ◽  
Leishmania Donovani ◽  
Pneumocystis Carinii ◽  
Antileishmanial Activity ◽  
Microbial Pathogens ◽  
Mouse Macrophage ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Mouse Macrophage Cell Line

ABSTRACT Aromatic dicationic molecules possess impressive activity against a broad spectrum of microbial pathogens, including Pneumocystis carinii, Cryptosporidium parvum, and Candida albicans. In this work, 58 aromatic cations were examined for inhibitory activity against axenic amastigote-like Leishmania donovani parasites. In general, the most potent of the compounds were substituted diphenyl furan and thiophene dications. 2,5-Bis-(4-amidinophenyl)thiophene was the most active compound. This agent displayed a 50% inhibitory concentration (IC50) of 0.42 ± 0.08 μM against L. donovani and an in vitro antileishmanial potency 6.2-fold greater than that of the clinical antileishmanial dication pentamidine and was 155-fold more toxic to the parasites than to a mouse macrophage cell line. 2,4-Bis-(4-amidinopheny)furan was twice as active as pentamidine (IC50, 1.30 ± 0.21 μM), while 2,5-bis-(4-amidinopheny)furan and pentamidine were essentially equipotent in our in vitro antileishmanial assay. Carbazoles, dibenzofurans, dibenzothiophenes, and benzimidazoles containing amidine or substituted amidine groups were generally less active than the diphenyl furans and thiophenes. In all cases, aromatic dications possessing strong antileishmanial activity were severalfold more toxic to the parasites than to a cultured mouse macrophage cell line. These structure-activity relationships demonstrate the potent antileishmanial activity of several aromatic dications and provide valuable information for the future design and synthesis of more potent antiparasitic agents.

scholarly journals Recombinant human granulocyte/macrophage colony-stimulating factor activates intracellular killing of Leishmania donovani by human monocyte-derived macrophages.

1987 ◽  
Vol 166 (5) ◽  
pp. 1436-1446 ◽  
Author(s):  
W Y Weiser ◽  
A Van Niel ◽  
S C Clark ◽  
J R David ◽  
H G Remold
Keyword(s):  
Leishmania Donovani ◽  
Human Monocyte ◽  
Peripheral Blood Monocyte ◽  
Antileishmanial Activity ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF) obtained from cloned complementary Mo cell DNA and expressed in COS-1 cells activates cultured peripheral blood monocyte-derived macrophages in vitro to become cytotoxic for intracellular L. donovani. The antileishmanial effect of rGM-CSF, which can be completely neutralized by anti-rGM-CSF antiserum, is maximal after 36 h preincubation with the cultured macrophages, compared with that of rIFN-gamma, which reaches its maximum at 72 h of preincubation. The antileishmanial effect of GM-CSF as well as IFN-gamma is independent of detectable amounts of LPS and is not augmented by the addition of 10 or 50 ng/ml of LPS. Simultaneous administration of suboptimal doses of rGM-CSF and rIFN-gamma to monocyte-derived macrophages results in greater antileishmanial activity by these cells than administration of either lymphokine alone, although no enhancement of antileishmanial activity is observed when optimal doses of these two lymphokines are applied together.

Antileishmanial activities of leaf latex and compound isolated from Aloe ghibensis Sebsebe & Friis

2020 ◽  
Vol 35 (1) ◽  
pp. 51-58
Author(s):  
Tamirat Tekassa ◽  
Yitagesu Tewabe ◽  
Daniel Bisrat ◽  
Asrat Hailu ◽  
Kaleab Asres
Keyword(s):  
Leishmania Donovani ◽  
Leishmania Species ◽  
2D Nmr ◽  
Antileishmanial Activity ◽  
Spectroscopic Techniques ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Phytochemical Constituents ◽  
Antileishmanial Activities

Aloe ghibensis Sebsebe & Friis is traditionally used in Ethiopia for the treatment of various ailments including skin problem, wounds and malaria. Phytochemical constituents and antileshimanial properties of the leaf latex of A. ghibensis have not been reported. The objective of this study was, therefore, to determine the phytochemical constituents and in vitro antileishmanial activities of the leaf latex of A. ghibensis and its major compounds against two Leishmania species. Preparative TLC was used to isolate compounds from the leaf latex of A. ghibensis and spectroscopic techniques including 1D- and 2D-NMR as well as ESI-MS were employed to elucidate structures of the isolated compounds. In vitro antileishmanial activity was performed against promastigotes and axenically cultured amastigotes of Leishmania aethiopica and Leishmania donovani clinical isolates using Alamar Blue assay. Phytochemical investigation led to the isolation of two major anthrones, identified as aloin A/B and 7-hydroxyaloin A/B. Both the leaf latex of A. ghibensis and isolated compounds showed antileishmanial activity with IC50 values ranging from 1.6 ± 0.43 to 3.64 ± 0.09 µg/ml and 1.87 ± 0.21 to 3.72 ± 0.12 against promastigotes and axenically cultured amastigotes of L. aethopica and L. donovani, respectively. Moreover, the test substances were found to be less toxic (LC50 = 145 ± 0.72 to 156 ± 0.08 µg/ml) than amphotericin B (LC50 = 12.11 ± 0.51 µg/ml) towards human monocytic cell line (THP-1). The present study revealed that the latex and pure compounds possess genuine antileishmanial activity with high selectivity indices (SIs). Therefore, the isolated compounds can be used as a scaffold for the development of effective drugs for leishmaniasis.  

scholarly journals Novel Arsenic Nanoparticles Are More Effective and Less Toxic than As (III) to Inhibit Extracellular and Intracellular Proliferation ofLeishmania donovani

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Sudipta Chakraborty ◽  
Kaushik Bhar ◽  
Sandip Saha ◽  
Rajarshi Chakrabarti ◽  
Anjali Pal ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Protozoan Parasite ◽  
Antileishmanial Activity ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Vector Borne ◽  
First Time ◽  
Intracellular Proliferation ◽  
Mouse Macrophage Cell Line

Visceral leishmaniasis, a vector-borne tropical disease that is threatening about 350 million people worldwide, is caused by the protozoan parasiteLeishmania donovani. Metalloids like arsenic and antimony have been used to treat diseases like leishmaniasis caused by the kinetoplastid parasites. Arsenic (III) at a relatively higher concentration (30 μg/mL) has been shown to have antileishmanial activity, but this concentration is reported to be toxic in several experimental mammalian systems. Nanosized metal (0) particles have been shown to be more effective than their higher oxidation state forms. There is no information so far regarding arsenic nanoparticles (As-NPs) as an antileishmanial agent. We have tested the antileishmanial properties of the As-NPs, developed for the first time in our laboratory. As-NPs inhibited thein vitrogrowth, oxygen consumption, infectivity, and intramacrophage proliferation ofL. donovaniparasites at a concentration which is about several fold lower than that of As (III). Moreover, this antileishmanial activity has comparatively less cytotoxic effect on the mouse macrophage cell line. It is evident from our findings that As-NPs have more potential than As (III) to be used as an antileishmanial agent.

scholarly journals Novel Arylimidamides for Treatment of Visceral Leishmaniasis

2010 ◽  
Vol 54 (6) ◽  
pp. 2507-2516 ◽  
Author(s):  
Michael Zhuo Wang ◽  
Xiaohua Zhu ◽  
Anuradha Srivastava ◽  
Qiang Liu ◽  
J. Mark Sweat ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Oral Treatment ◽  
Antileishmanial Activity ◽  
Repeat Dose ◽  
Lead Discovery ◽  
Preclinical Development

ABSTRACT Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC50], <1 μM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC50 ≤ 0.12 μM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.

scholarly journals SEARCH FOR NEW ANTILEISHMANIAL CHEMOTHERAPEUTICS

2018 ◽  
Vol 10 (1) ◽  
pp. 46
Author(s):  
Nabanita Kar ◽  
Santanu Ghosh ◽  
Leena Kumari ◽  
Shreyasi Chakraborty ◽  
Tanmoy Bera
Keyword(s):  
Betulinic Acid ◽  
Leishmania Donovani ◽  
Antileishmanial Activity ◽  
Gas Chromatography Mass Spectrometry ◽  
Drug Resistant ◽  
Wild Type ◽  
Leaf Oil ◽  
Resistant Strains ◽  
Type Strains

Objective: The objective of this work was to screen a number of compounds for their antileishmanial efficacy and cytotoxicity profiling.Methods: Curry leaf oil, cypress oil and spikenard oil were identified by gas chromatography-mass spectrometry (GC/MS) analysis. Betulinic acid, spikenard oil, cypress oil and curry leaf oil were evaluated for their in vitro antileishmanial activity against Leishmania donovani AG83 wild-type, sodium stibogluconate resistant (SSG-resistant), paromomycin (PMM-resistant) and GE1 field type strains on axenic and cellular amastigote model and compared the results with standard drugs used to treat leishmaniasis.Results: Betulinic acid showed strong antileishmanial activity against wild-type (SI= 192.8), SSG-resistant (SI= 19.3) and GE1 strains (SI= 100), whereas cypress oil has produced highest antileishmanial activity against PMM-resistant strains (SI= 15.09) among all the tested drugs. The data obtained also revealed that cypress oil had the maximum CC50 value of 452.9 μl among all standard and tested drugs.Conclusion: All tested drugs had antileishmanial property but among them, betulinic acid possess strong antileishmanial activity in case of both wild-type and drug-resistant leishmaniasis.

Purpureone, an antileishmanial ergochrome from the endophytic fungus Purpureocillium lilacinum

2016 ◽  
Vol 71 (11) ◽  
pp. 1159-1167 ◽  
Author(s):  
Bruno Ndjakou Lenta ◽  
Jules Ngatchou ◽  
Marcel Frese ◽  
Flora Ladoh-Yemeda ◽  
Steve Voundi ◽  
...  
Keyword(s):  
Cell Line ◽  
Leishmania Donovani ◽  
Antileishmanial Activity ◽  
E Coli ◽  
Purpureocillium Lilacinum ◽  
Fusarium Sp ◽  
Aspergillus Sp ◽  
Providencia Stuartii ◽  
The One

AbstractThe ethyl acetate extracts prepared from the mycelia of three endophytic fungi Purpureocillium lilacinum, Aspergillus sp., and Fusarium sp., isolated from the roots of Rauvolfia macrophylla (Apocynaceae) were screened for their antiprotozoal activity in vitro against Plasmodium falciparum (NF54), Leishmania donovani, Trypanosoma brucei rhodesiense, and Trypanosoma cruzi. Amongst these extracts, the one from P. lilacinum showed potent antileishmanial activity against L. donovani (IC50 value of 0.174 μg mL−1) with good selectivity (SI=94.9) toward the L6 cell line, whereas the other extracts were inactive and not selective. The fractionation and purification of the active extract from P. lilacinum by column chromatography over silica gel yielded a new ergochromone derivative (1), together with six known compounds: (22E,24R)-stigmasta-5,7,22-trien-3-β-ol (2), (22E,24R)-stigmasta-4,6,8(14),22-tetraen-3-one (3), emodin (4), chrysophanol (5), aloe-emodin (6), and palmitic acid, whose structures were elucidated spectroscopically. Compound 1 was tested in vitro for its antiparasitic activities against the above listed parasites and for its antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Escherichia coli, Providencia stuartii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The compound displayed potent antileishmanial activity against L. donovani with an IC50 value of 0.63 μg mL−1 (0.87 μm) with good selectivity (SI=49.5) toward the L6 cell line. It also exhibited good antibacterial activity against three of the tested microbial strains B. cereus, E. coli ATCC879, and P. stuartii ATCC29916 with minimum inhibitory concentrations below 62.6 μg mL−1. Compound 1 is thus a promising active compound that could be investigated for antileishmanial and antimicrobial drug development.

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