scholarly journals 2-Phenoxy-3-trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

2021 ◽  
Vol 14 (8) ◽  
pp. 724
Author(s):  
Dyhia Amrane ◽  
Christophe-Sébastien Arnold ◽  
Sébastien Hutter ◽  
Julen Sanz-Serrano ◽  
Miguel Collia ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Biological Evaluation ◽  
Ccl3 Group ◽  
New Perspective ◽  
Sar Study ◽  
New Compounds ◽  
Opening Up ◽  
Activity Cliffs ◽  
Quinoxaline Ring

The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents a drug response by targeting the apicoplast and a quick-killing mechanism acting on another target site.

scholarly journals Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3929
Author(s):  
Dyhia Amrane ◽  
Armand Gellis ◽  
Sébastien Hutter ◽  
Marion Prieri ◽  
Pierre Verhaeghe ◽  
...  
Keyword(s):  
Cell Line ◽  
Hepg2 Cell ◽  
Alkoxy Group ◽  
Hepg2 Cell Line ◽  
Ccl3 Group ◽  
Falciparum Strain ◽  
Structure Activity ◽  
Trichloromethyl Group ◽  
Sar Study

From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

scholarly journals Design, Synthesis and Biological Evaluation of Novel 4-Substituted Coumarin Derivatives as Antitumor Agents

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2281 ◽  
Author(s):  
Ran An ◽  
Zhuang Hou ◽  
Jian-Teng Li ◽  
Hao-Nan Yu ◽  
Yan-Hua Mou ◽  
...  
Keyword(s):  
Antitumor Agents ◽  
Cancer Cell Line ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Hypoxic Conditions ◽  
Ca Ix ◽  
Ic50 Value ◽  
Almost All ◽  
New Compounds

Herein, fifteen new compounds containing coumarin, 1,2,3-triazole and benzoyl- substituted arylamine moieties were designed, synthesized and tested in vitro for their anticancer activity. The results showed that all tested compounds had moderate antiproliferative activity against MDA-MB-231, a human breast cancer cell line, under both normoxic and hypoxic conditions. Furthermore, the 4-substituted coumarin linked with benzoyl 3,4-dimethoxyaniline through 1,2,3-triazole (compound 5e) displayed the most prominent antiproliferative activities with an IC50 value of 0.03 μM, about 5000 times stronger than 4-hydroxycoumarin (IC50 > 100 μM) and 20 times stronger than doxorubicin (IC50 = 0.60 μM). Meanwhile, almost all compounds revealed general enhancement of proliferation-inhibiting activity under hypoxia, contrasted with normoxia. A docking analysis showed that compound 5e had potential to inhibit carbonic anhydrase IX (CA IX).

Synthesis and biological evaluation of S-simplexides and other analogues of simplexide

2019 ◽  
Vol 91 (7) ◽  
pp. 1257-1276
Author(s):  
Amélie Roux ◽  
Stefania Loffredo ◽  
Anne Lise Ferrara ◽  
Paul V. Murphy
Keyword(s):  
Natural Killer T Cells ◽  
Conformational Flexibility ◽  
Biological Evaluation ◽  
Immune Homeostasis ◽  
New Compounds ◽  
Stereoselective Syntheses ◽  
Synthesis And Biological Evaluation ◽  
Killer T Cells ◽  
Active Natural

Abstract Simplexides are natural glycolipids isolated from the marine sponge Plakortis simplex, and contain alkyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside. Simplexides can release of cytokines (IL-6) and chemokines (CXCL-8) from human monocytes and cause the expansion of natural killer T-cells (iNKTs) in vitro, with iNKTs contributing to the sustenance of immune homeostasis. Herein, the stereoselective syntheses of S-glycosidic analogues, i.e. S-simplexides, are described. The routes included Lewis acid promoted anomerisation of glycosyl thiols and thioglycolipids, as well as anomeric S-alkylation. Synthesis of O-glycosidic analogues are included. Heptadecanyl O- and S-glycosides as well as the 17-tritriacontyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside, a component of the natural simplexide isolate, all induced IL-6 and CXCL-8 production at both 10 and 30 μg/mL concentrations from PBMCs whereas the two S-simplexides were inactive. It is speculated that the lack of activity for the S-disaccharide analogue could be due to inhibition of cellular α-glucosidase, preventing degradation of the simplex disaccharide to a simpler galactopyranoside, whereas lack of activity for the S-galactolipid analogue could be due to increased conformational flexibility of S-glycosides. On the other hand, simpler unbranched O- and S-glycolipid analogues were active. Natural simplexide, and a synthetic simplexide, the 18-pentatriacontanyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside, were more potent than the new compounds tested.

scholarly journals Synthesis, biological evaluation and molecular docking studies of new 2-ethoxy-4-{[3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonate derivatives on human aldose reductase enzyme

2021 ◽  
Author(s):  
Gül Özdemir ◽  
Namık Kılınç ◽  
Sevda Manap ◽  
Murat Beytur ◽  
Muzaffer Alkan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antibacterial Activities ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Binding Energies ◽  
Diffusion Method ◽  
Alkyl Aryl ◽  
Molecular Docking Studies ◽  
New Compounds

A series of 2-ethoxy-4-{[3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonates (3) were synthesized from the reactions of 3-alkyl(aryl)-4-amino-4,5-dihydro-1H-1,2,4-triazol-5-ones (1) with 2-ethoxy-4-formyl-phenyl benzenesulfonate (2). N-acetyl derivatives (4) of compounds 3 were also obtained. Then, the compounds 3 have been treated with morpholine and 2,6-dimethylmorpholine in the presence of formaldehyde to synthesize 2-ethoxy-4-{[1-(morpholine-4-yl-methyl)-3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonates (5) and 2-ethoxy-4-{[1-(2,6-dimethylmorpholine-4-yl-methyl)-3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl]-azomethine}-phenyl benzenesulfonates (6), respectively. The structures of twenty-six new compounds were identified by using elemental analysis, IR, 1H NMR, 13C NMR, and MS spectral data. In addition, in vitro antibacterial activities of the new compounds were evaluated against six bacteria such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Bacillus cereus and Klepsiella pneumonia according to agar well diffusion method. Furthermore, in order to determine the possible antidiabetic properties of the synthesized 1,2,4-triazole derivatives, inhibition effects on the AR enzyme were investigated and molecular docking studies were carried out to determine the receptor-ligand interactions of these compounds. IC50 values of triazole-derived compounds (6a, 6b, 6d-g) against AR enzyme were determined as 0.95 µM, 0.75 µM, 1.83 µM, 0.62 µM, 1.05 µM, 1.06 µM, respectively. Considering the docking scores and binding energies obtained docking studies, it has been shown that molecules fit very well to the active site of the AR enzyme.

scholarly journals Structure Activity Relationship of N-Substituted Phenyldihydropyrazolones Against Trypanosoma cruzi Amastigotes

2021 ◽  
Vol 9 ◽  
Author(s):  
Maarten Sijm ◽  
Louis Maes ◽  
Iwan J. P. de Esch ◽  
Guy Caljon ◽  
Geert Jan Sterk ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Drug Effects ◽  
Treatment Compliance ◽  
Treatment Regimens ◽  
Poor Treatment ◽  
Sar Study ◽  
New Compounds ◽  
Relationship Of ◽  
Selection Of

Current drugs for Chagas disease have long treatment regimens with occurrence of adverse drug effects leading to poor treatment compliance. Novel and efficacious medications are therefore highly needed. We previously reported on the discovery of NPD-0227 (2-isopropyl-5-(4-methoxy-3-(pyridin-3-yl)phenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one) as a potent in vitro inhibitor of Trypanosoma cruzi (pIC50 = 6.4) with 100-fold selectivity over human MRC-5 cells. The present work describes a SAR study on the exploration of substituents on the phenylpyrazolone nitrogen. Modifications were either done directly onto this pyrazolone nitrogen or alternatively by introducing a piperidine linker. Attention was pointed toward the selection of substituents with a cLogP preferably below NPD-0227s cLogP of 3.5. Generally the more apolar compounds showed better activities then molecules with cLogPs <2.0. Several new compounds were identified with potencies that are in the same range as NPD-0227 (pIC50 = 6.4) and promising selectivities. While the potency could not be improved, valuable SAR was obtained. Furthermore the introduction of a piperidine linker offers new opportunities for derivatization as valuable novel starting points for future T. cruzi drug discovery.

From classical antimalarial drugs to new compounds based on the mechanism of action of artemisinin

2001 ◽  
Vol 73 (7) ◽  
pp. 1173-1188 ◽  
Author(s):  
Anne Robert ◽  
Françoise Benoit-Vical ◽  
Odile Dechy-Cabaret ◽  
Bernard Meunier
Keyword(s):  
Mechanism Of Action ◽  
Antimalarial Activity ◽  
Short Review ◽  
Mechanisms Of Action ◽  
Antimalarial Drugs ◽  
Molecular Aspect ◽  
New Compounds

A short review of the antimalarial drugs currently used in human clinics is reported. The molecular aspect of the different possible mechanisms of action of artemisinin is documented, including recent data on heme alkylation. The preparation and the in vitro antimalarial activity of new modular molecules named "trioxaquines" are also presented.

scholarly journals 1,2,3-triazole-dithiocarbamate-naphthalimides: Synthesis, characterization, and biological evaluation

2020 ◽  
pp. 174751982096697
Author(s):  
Qiu Mei Chen ◽  
Zhen Li ◽  
Guang Xun Tian ◽  
Yi Chen ◽  
Xiang Hua Wu
Keyword(s):  
Antimicrobial Agents ◽  
Analytical Techniques ◽  
Antibacterial Activities ◽  
Biological Evaluation ◽  
Antitumor Activities ◽  
X Ray Crystallography ◽  
Mtt Method ◽  
New Compounds ◽  
Clinical Drug

Fifteen novel dithiocarbamate-derived naphthalimides as a type of potential anticancer and antimicrobial agents were synthesized and characterized by spectral and analytical techniques. The structures of 2b, 5a, and 7b were established by X-ray crystallography. Their in vitro antitumor activities were evaluated by the MTT method against MDA-MB-231, HepG-2, PC12, as well as A549. Based on the results of the MTT assay, compound 7c bearing a morpholinyl substituent displayed the highest activity and selectivity toward HepG-2 cancer cells with an IC50 of 10.86 µM. All new compounds were screened for their antimicrobial activity against Candida albicans, Escherichia coli, Bacillus subtilis, and Staphylococcus aureus. The preliminary results showed that compound 7d (an N-methyl piperazine) showed high efficacy against B. subtilis with a minimum inhibitory concentration value of 7.6 µM, which was superior to that of the clinical drug, Cefuroxim. It is found that the anticancer and antibacterial activities of the dithiocarbamate-naphthalimide derivatives were significantly enhanced when bearing a 1,2,3-triazole group.

scholarly journals Synthesis, Molecular Docking Analysis and in Vitro Biological Evaluation of Some New Heterocyclic Scaffolds-Based Indole Moiety as Possible Antimicrobial Agents

2022 ◽  
Vol 8 ◽  
Author(s):  
Entesar A. Hassan ◽  
Ihsan A. Shehadi ◽  
Awatef M. Elmaghraby ◽  
Hadir M. Mostafa ◽  
Salem E. Zayed ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimicrobial Agents ◽  
Antibacterial Activities ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Standard Drug ◽  
Docking Analysis ◽  
Excellent Activity ◽  
New Compounds

In the present study, a general approach for the synthesis of 1-(1H-indol-3-yl)-3,3-dimercaptoprop-2-en-1-one (1) and 5-(1H-indol-3-yl)-3H-1,2-dithiole-3-thione (2) was performed. They are currently used as efficient precursors for the synthesis of some new compounds bearing five- and/or six-membered heterocyclic moieties, e.g., chromenol (3, 4), 3,4-dihydroquinoline (7, 8) and thiopyran (10, 12)-based indole core. In addition, molecular docking studies were achieved, which showed that all the newly synthesized compounds are interacting with the active site region of the target enzymes, the targets UDP-N-acetylmuramatel-alanine ligase (MurC), and human lanosterol14α-demethylase, through hydrogen bonds and pi-stacked interactions. Among these docked ligand molecules, the compound (9) was found to have the minimum binding energy (−11.5 and −8.5 Kcal/mol) as compared to the standard drug ampicillin (−8.0 and −8.1 Kcal/mol) against the target enzymes UDP-N-acetylmuramatel-alanine ligase (MurC), and Human lanosterol14α-demethylase, respectively. Subsequently, all new synthesized analogues were screened for their antibacterial activities against Gram-positive (Bacillus subtilis), and Gram-negative bacteria (Escherichia coli), as well as for antifungal activities against Candida albicans and Aspergillus flavus. The obtained data suggest that the compounds exhibited good to excellent activity against bacterial and fungi strains. The compound (E)-2-(6-(1H-indole-3-carbonyl)-5-thioxotetrahydrothieno [3,2-b]furan-2(3H)-ylidene)-3-(1H-indol-3-yl)-3-oxopropanedithioic acid (9) showed a high binding affinity as well as an excellent biological activity. Therefore, it could serve as the lead for further optimization and to arrive at potential antimicrobial agent.

scholarly journals Synthesis and Biological Evaluation of Novel Hybrid Molecules Containing Purine, Coumarin and Isoxazoline or Isoxazole Moieties

2017 ◽  
Vol 11 (1) ◽  
pp. 196-211 ◽  
Author(s):  
Michael G. Kallitsakis ◽  
Angelo Carotti ◽  
Marco Catto ◽  
Aikaterini Peperidou ◽  
Dimitra J. Hadjipavlou-Litina ◽  
...  
Keyword(s):  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Catalytic Amount ◽  
Biological Evaluation ◽  
Mao B ◽  
Antioxidant Agents ◽  
Hybrid Molecules ◽  
New Compounds

Introduction: The 1,3-dipolar cycloaddition reactions of nitrile oxides formed in situ (in the presence of NCS and Et3N) from the oximes of (purin-9-yl)acetaldehyde or (coumarinyloxy)acetaldehyde with allyloxycoumarins or 9-allylpurines, respectively resulted in 3,5-disubstituted isoxazolines. The similar reactions of propargyloxycoumarins or 9-propargylpurines led to 3,5-disubstituted isoxazoles by treatment with PIDA and catalytic amount of TFA. Methods: The new compounds were tested in vitro as antioxidant agents and inhibitors of soybean lipoxygenase LO, AChE and MAO-B. Results: The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 4k and 4n presented LO inhibitory activity. Conclusion: Compound 13e presents an antioxidant significant profile combining anti-LO, anti-AChE and anti-MAO-B activities.

scholarly journals Structure–Activity Relationships of the Antimalarial Agent Artemisinin 10. Synthesis and Antimalarial Activity of Enantiomers of rac-5β-Hydroxy-d-Secoartemisinin and Analogs: Implications Regarding the Mechanism of Action

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4163
Author(s):  
Mohamed Jahan ◽  
Francisco Leon ◽  
Frank R. Fronczek ◽  
Khaled M. Elokely ◽  
John Rimoldi ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Antimalarial Activity ◽  
Crystallographic Analysis ◽  
Hydroxyl Group ◽  
Moderate Activity ◽  
Ether Oxygen ◽  
Tricyclic Analog ◽  
Intramolecular Hydrogen ◽  
New Compounds

An efficient synthesis of rac-6-desmethyl-5β–hydroxy-d-secoartemisinin 2, a tricyclic analog of R-(+)-artemisinin 1, was accomplished and the racemate was resolved into the (+)-2b and (−)-2a enantiomers via their Mosher Ester diastereomers. Antimalarial activity resided with only the artemisinin-like enantiomer R-(−)-2a. Several new compounds 9–16, 19a, 19b, 22 and 29 were synthesized from rac-2 but the C-5 secondary hydroxyl group was surprisingly unreactive. For example, the formation of carbamates and Mitsunobu reactions were unsuccessful. In order to assess the unusual reactivity of 2, a single crystal X-ray crystallographic analysis revealed a close intramolecular hydrogen bond from the C-5 alcohol to the oxepane ether oxygen (O-11). All products were tested in vitro against the W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs had moderate activity in comparison to the natural product 1. Iron (II) bromide-promoted rearrangement of 2 gave, in 50% yield, the ring-contracted tetrahydrofuran 22, while the 5-ketone 15 provided a monocyclic methyl ketone 29 (50%). Neither 22 nor 29 possessed in vitro antimalarial activity. These results have implications in regard to the antimalarial mechanism of action of artemisinin.

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