scholarly journals Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors

2020 ◽  
Vol 6 (5) ◽  
pp. 1121-1139 ◽  
Author(s):  
Luiza G. Tunes ◽  
Roberta E. Morato ◽  
Adriana Garcia ◽  
Vinicius Schmitz ◽  
Mario Steindel ◽  
...  
Keyword(s):  
Oral Drug ◽  
Trypanothione Reductase ◽  
Gold Complexes ◽  
Drug Candidates ◽  
Reductase Inhibitors

Novel Scaffolds for Leishmania infantum Trypanothione Reductase Inhibitors Derived from Brazilian Natural Products Biodiversity

2021 ◽  
Vol 18 (4) ◽  
pp. 398-418
Author(s):  
Vinícius Guimarães da Paixão ◽  
Samuel Silva da Rocha Pita
Keyword(s):  
Natural Products ◽  
Leishmania Infantum ◽  
In Vitro Assays ◽  
Current Therapy ◽  
Pharmacokinetic Analysis ◽  
Trypanothione Reductase ◽  
Resistant Species ◽  
Reductase Inhibitors ◽  
Thiol Redox

Background: Leishmania infantum causes the most lethal form of Leishmaniasis: Visceral leishmaniasis. Current therapy for this disease is related to the development of drug-resistant species and toxicity. Trypanothione Reductase (LiTR), a validated target for the drug discovery process, is involved with parasites' thiol-redox metabolism. Objective: In this study, through Virtual Screening employing two distinct Natural Products Brazilian databases, we aimed to identify novel inhibitor scaffolds against LiTR. Results: Thus, the “top 10” LiTR-ligand energies have been selected and their interaction profiles into LiTR sites through the AuPosSOM server have been verified. Finally, Pred-hERG, Aggregator Advisor, FAF-DRUGS, pkCSM and DataWarrior were employed and their results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false-positive compounds (PAINS) and their toxicities. Conclusion: Three molecules that overcame the in silico pharmacokinetic analysis and have a good interaction with LiTR, were chosen to use in vitro assays hoping that our computational results reported here would aid the development of new anti-leishmanial compounds.

Metal-Based Compounds as Prospective Antileishmanial Agents: Inhibition of Trypanothione Reductase by Selected Gold Complexes

ChemMedChem ◽  
2013 ◽  
pp. n/a-n/a ◽  
Author(s):  
Gianni Colotti ◽  
Andrea Ilari ◽  
Annarita Fiorillo ◽  
Paola Baiocco ◽  
Maria Agostina Cinellu ◽  
...  
Keyword(s):  
Trypanothione Reductase ◽  
Gold Complexes

Predicting biopharmaceutical performance of oral drug candidates – Extending the volume to dissolve applied dose concept

2016 ◽  
Vol 102 ◽  
pp. 191-201 ◽  
Author(s):  
Uwe Muenster ◽  
Wolfgang Mueck ◽  
Dorina van der Mey ◽  
Karl-Heinz Schlemmer ◽  
Susanne Greschat-Schade ◽  
...  
Keyword(s):  
Oral Drug ◽  
Drug Candidates ◽  
Applied Dose

scholarly journals GoldLeish: gold(I) Complexes as Oral Drug Candidates to Treat Leishmaniasis are Potent Trypanothione Reductase Inhibitors and Exert in vivo Efficacy

2019 ◽  
Author(s):  
Luiza Tunes ◽  
Roberta Morato ◽  
Adriana Garcia ◽  
Joana Chaves ◽  
Tharcilla Aglio ◽  
...  
Keyword(s):  
Treatment Time ◽  
Parasite Burden ◽  
Lesion Size ◽  
Oral Drug ◽  
Cross Resistance ◽  
Trypanothione Reductase ◽  
Ros Production ◽  
New Therapeutic Approaches ◽  
Ic50 Values

The drugs currently used to treat leishmaniasis have limitations concerning cost, efficacy and safety, making urgent the search for new therapeutic approaches. Here we report the antileishmanial activity of 14 gold(I) complexes. We found that the complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 μM. All complexes were potent inhibitors of trypanothione reductase (TR), with IC50 ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced ROS production and decreased mitochondrial respiration after 2 h exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing L. braziliensis or L. amazonensis and treated orally with 12.5 mg/kg/day of AdT Et (3) or AdO Et (4) presented reduced lesion size and parasite burden, as revealed by bioimaging. Combination of (3) and miltefosine allowed for a 50 % reduction in miltefosine treatment time. Complexes (3) and (4) presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites.<br>

scholarly journals In vivo study and thermodynamic investigation of two lanthanum complexes, La(dpp)3 and La(XT), for the treatment of bone resorption disorders

2015 ◽  
Vol 6 (11) ◽  
pp. 6439-6447 ◽  
Author(s):  
J. F. Cawthray ◽  
D. M. Weekes ◽  
O. Sivak ◽  
A. L. Creagh ◽  
F. Ibrahim ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Ex Vivo ◽  
In Vivo Study ◽  
Oral Drug ◽  
Thermodynamic Investigation ◽  
Preventative Measure ◽  
Drug Candidates

Lanthanum could act as a preventative measure against bone resorption disorders; two compounds are thoroughly investigated both in vivo and ex vivo as potential oral drug candidates.

scholarly journals A Simple Decision Tree Suited for Identification of Early Oral Drug Candidates With Likely Pharmacokinetic Nonlinearity by Intestinal CYP3A Saturation

2021 ◽  
Vol 110 (1) ◽  
pp. 510-516
Author(s):  
Atsuko Tomaru ◽  
Kota Toshimoto ◽  
Wooin Lee ◽  
Keiko Ishigame ◽  
Yuichi Sugiyama
Keyword(s):  
Decision Tree ◽  
Oral Drug ◽  
Drug Candidates

scholarly journals Synthesis of Novel Sulfamethaoxazole 4-Thiazolidinone Hybrids and Their Biological Evaluation

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3570 ◽  
Author(s):  
Mashooq A. Bhat ◽  
Mohamed A. Al-Omar ◽  
Ahmed M. Naglah ◽  
Azmat Ali Khan
Keyword(s):  
Antitubercular Activity ◽  
Antimycobacterial Activity ◽  
Biological Evaluation ◽  
Oral Drug ◽  
Drug Candidates ◽  
Cyclocondensation Reaction ◽  
Aryl Aldehyde ◽  
Hct 116 ◽  
Mcf 7

A search for potent antitubercular agents prompted us to design and synthesize sulfamethaoxazole incorporated 4-thiazolidinone hybrids (7a–l) by using a cyclocondensation reaction between 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (4), aryl aldehyde (5a–l), and mercapto acetic acid (6) resulting in good to excellent yields. All the newly synthesized 4-thiazolidinone derivatives were screened for their in vitro antitubercular activity against M. Bovis BCG and M. tuberculosis H37Ra (MTB) strains. The compounds 7d, 7g, 7i, 7k, and 7l revealed promising antimycobacterial activity against M. Bovis and MTB strains with IC90 values in the range of 0.058–0.22 and 0.43–5.31 µg/mL, respectively. The most active compounds were also evaluated for their cytotoxicity against MCF-7, HCT 116, and A549 cell lines and were found to be non-cytotoxic. Moreover, the synthesized compounds were also analyzed for ADME (absorption, distribution, metabolism, and excretion) properties and showed potential as good oral drug candidates.

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