scholarly journals Identification of Chalcone Derivatives as Inhibitors of Leishmania infantum Arginase and Promising Antileishmanial Agents

2021 ◽  
Vol 8 ◽  
Author(s):  
Andreza R. Garcia ◽  
Danielle M. P. Oliveira ◽  
Jessica B. Jesus ◽  
Alessandra M. T. Souza ◽  
Ana Carolina R. Sodero ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Hydrophobic Interactions ◽  
Docking Studies ◽  
Host Cells ◽  
Polyamine Biosynthesis ◽  
Reference Drug ◽  
Growth And Survival ◽  
Chalcone Derivatives ◽  
Antileishmanial Drug

Arginase catalyzes the hydrolysis of l-arginine into l-ornithine and urea, acting as a key enzyme in the biosynthesis of polyamines. Leishmania growth and survival is dependent on polyamine biosynthesis; therefore, inhibition of Leishmania arginase may be a promising therapeutic strategy. Here, we evaluated a series of thirty-six chalcone derivatives as potential inhibitors of Leishmania infantum arginase (LiARG). In addition, the activity of selected inhibitors against L. infantum parasites was assessed in vitro. Seven compounds exhibited LiARG inhibition above 50% at 100 μM. Among them, compounds LC41, LC39, and LC32 displayed the greatest inhibition values (72.3 ± 0.3%, 71.9 ± 11.6%, and 69.5 ± 7.9%, respectively). Molecular docking studies predicted hydrogen bonds and hydrophobic interactions between the most active chalcones (LC32, LC39, and LC41) and specific residues from LiARG's active site, such as His140, Asn153, His155, and Ala193. Compound LC32 showed the highest activity against L. infantum promastigotes (IC50 of 74.1 ± 10.0 μM), whereas compounds LC39 and LC41 displayed the best results against intracellular amastigotes (IC50 of 55.2 ± 3.8 and 70.4 ± 9.6 μM, respectively). Moreover, compound LC39 showed more selectivity against parasites than host cells (macrophages), with a selectivity index (SI) of 107.1, even greater than that of the reference drug Fungizone®. Computational pharmacokinetic and toxicological evaluations showed high oral bioavailability and low toxicity for the most active compounds. The results presented here support the use of substituted chalcone skeletons as promising LiARG inhibitors and antileishmanial drug candidates.

scholarly journals Towards chemical validation of Leishmania infantum ribose 5-phosphate isomerase as a drug target

2021 ◽  
Author(s):  
Emily A. Dickie ◽  
Céline Ronin ◽  
Mónica Sá ◽  
Fabrice Ciesielski ◽  
Nathalie Trouche ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Leishmania Infantum ◽  
Neglected Tropical Diseases ◽  
Docking Studies ◽  
Pentose Phosphate ◽  
Biochemical Processes ◽  
Shift Analysis ◽  
Fragment Library ◽  
Current Therapies

Neglected tropical diseases caused by kinetoplastid parasites (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) place a significant health and economic burden on developing nations worldwide. Current therapies are largely out-dated, inadequate and facing mounting drug resistance from the causative parasites. Thus, there is an urgent need for drug discovery and development. Target-led drug discovery approaches have focused on the identification of parasite enzymes catalysing essential biochemical processes, which significantly differ from equivalent proteins found in humans, thereby providing potentially exploitable therapeutic windows. One such target is ribose 5-phosphate isomerase B (RpiB), an enzyme involved in the non-oxidative branch of the pentose phosphate pathway, which catalyses the inter-conversion of D-ribose 5-phosphate and D-ribulose 5-phosphate. Although protozoan RpiB has been the focus of numerous targeted studies, compounds capable of selectively inhibiting this parasite enzyme have not been identified. Here, we present the results of a fragment library screening against Leishmania infantum RpiB, performed using thermal shift analysis. Hit fragments were shown to be effective inhibitors of LiRpiB in activity assays, and several were capable of selectively inhibiting parasite growth in vitro. These results support the identification of LiRpiB as a validated therapeutic target. The X-ray crystal structure of apo LiRpiB was also solved, permitting docking studies to assess how hit fragments might interact with LiRpiB to inhibit its activity. Overall, this work will guide structure-based development of LiRpiB inhibitors as anti-leishmanial agents.

scholarly journals Hybridization of Curcumin Analogues with Cinnamic Acid Derivatives as Multi-Target Agents Against Alzheimer’s Disease Targets

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4958 ◽  
Author(s):  
Eirini Chainoglou ◽  
Argyris Siskos ◽  
Eleni Pontiki ◽  
Dimitra Hadjipavlou-Litina
Keyword(s):  
Cinnamic Acid ◽  
Hydrophobic Interactions ◽  
Docking Studies ◽  
The Novel ◽  
Chromatography Method ◽  
Cinnamic Acid Derivatives ◽  
Curcumin Analogues ◽  
Antioxidant Agents ◽  
Good Oral Bioavailability

The synthesis of the new hybrids followed a hybridization with the aid of hydroxy-benzotriazole (HOBT) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI.HCL) in dry DMF or thionyl chloride between curcumin analogues and cinnamic acid derivatives. IR, 1H-NMR, 13C-NMR, LC/MS ESI+, and elemental analysis were used for the confirmation of the structures of the novel hybrids. The lipophilicity values of compounds were calculated theoretically and experimentally via the reversed chromatography method as RM values. The novel derivatives were studied through in vitro experiments for their activity as antioxidant agents and as inhibitors of lipoxygenase, cyclooxygenase-2, and acetyl-cholinesterase. All the compounds showed satisfying anti-lipid peroxidation activity of linoleic acid induced by 2,2′-azobis(2-amidinopropane) hydrochloride (AAPH). Hybrid 3e was the most significant pleiotropic derivative, followed by 3a. According to the predicted results, all hybrids could be easily transported, diffused, and absorbed through the blood–brain barrier (BBB). They presented good oral bioavailability and very high absorption with the exception of 3h. No inhibition for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was noticed. According to the Ames test, all the hybrids induced mutagenicity with the exception of 3d. Efforts were conducted a) to correlate the in vitro results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Docking studies were performed on soybean lipoxygenase (LOX) and showed hydrophobic interactions with amino acids. Docking studies on acetylcholinesterase (AChE) exhibited: (a) hydrophobic interactions with TRP281, LEU282, TYR332, PHE333, and TYR336 and (b) π-stacking interactions with TYR336.

scholarly journals In silico and antithrombotic studies of 1,3,4-oxadiazoles derived from benzimidazole

2015 ◽  
Vol 11 (1) ◽  
pp. 67 ◽  
Author(s):  
B. Vishwanathan ◽  
B. M. Gurupadayya ◽  
K. Venkata Sairam
Keyword(s):  
In Silico ◽  
Factor Xa ◽  
Docking Studies ◽  
Negative Control ◽  
Clot Lysis ◽  
Drug Candidate ◽  
Thrombolytic Activity ◽  
Reference Drug ◽  
Oxadiazole Derivatives

<p class="Abstract">In the present study, a series of 1,3,4-oxadiazole derivatives (4a-4k) derived from benzimidazole were docked onto factor Xa (PDB: 1NFY) protein using SYBYLX 2.1. and also evaluated for <em>in vitro</em> clot lysis for thrombolytic activity. The synthesized molecules were also screened for in silico ADME studies. The molecular docking studies highlighted that the molecules showed high affinity towards 1NFY with higher docking score and the <em>in silico</em> ADME results were promising and indicated that the molecules holds great potential as a drug candidate. The thrombolytic evaluation was performed for decrease in solid clot weight by the clot lysis study at a concentration of 6.25, 12.5 and 25 µM strengths, respectively. The results of in vitro clot lysis for thrombolytic evaluation revealed that the tested compounds 4a-4k exhibited significant clot lysis with respect to negative control phosphate buffered saline and in comparison to the reference drug streptokinase (30,000 IU). Among all the tested compounds, compound 4j, 4d and 4g exhibited potent thrombolytic activity with EC<sub>50</sub> value of 16.2, 18.1 and 23.7 µM, respectively. The thrombolytic efficacy investigation highlights that the synthesized compound 4j could be considered for further clinical studies to ascertain its possible hit as thrombolytic agents.</p><p> </p>

Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines

2020 ◽  
Vol 20 (9) ◽  
pp. 788-800 ◽  
Author(s):  
Sobhi M. Gomha ◽  
Zeinab A. Muhammad ◽  
Elham Ezz El-Arab ◽  
Amira M. Elmetwally ◽  
Abdelaziz A. El-Sayed ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Docking ◽  
Docking Study ◽  
Docking Studies ◽  
Binding Modes ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Reference Drug ◽  
Ic50 Value

Objective: The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives. Methods: The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method. Results: Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9μM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 μM). Conclusion: Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.

scholarly journals Leishmanicidal Activity of Nine Novel Flavonoids fromDelphinium staphisagria

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Inmaculada Ramírez-Macías ◽  
Clotilde Marín ◽  
Jesús G. Díaz ◽  
María José Rosales ◽  
Ramón Gutiérrez-Sánchez ◽  
...  
Keyword(s):  
Leishmania Infantum ◽  
Mammalian Cells ◽  
Mechanisms Of Action ◽  
Reference Drug ◽  
Ultrastructural Alteration ◽  
Leishmanicidal Activity ◽  
Design And Methods ◽  
Electronic Microscope ◽  
Intracellular Amastigote

Objectives. To evaluate thein vitroleishmanicidal activity of nine flavonoid derivatives fromDelphinium staphisagriaagainstL. infantumandL. braziliensis.Design and Methods. Thein vitroactivity of compounds1–9was assayed on extracellular promastigote and axenic amastigote forms and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were carried on J774.2 macrophage cells using Glucantime as the reference drug. The mechanisms of action were analysed performing metabolite excretion and transmission electronic microscope ultrastructural alteration studies.Results. Nine flavonoids showed leishmanicidal activity against promastigote as well as amastigote forms ofLeishmania infantumandL. braziliensis. These compounds were nontoxic to mammalian cells and were effective at similar concentrations up to or lower than that of the reference drug (Glucantime). The results showed that2″-acetylpetiolaroside (compound8) was clearly the most active.Conclusion. This study has demonstrated that flavonoid derivatives are active againstL. infantumandL. braziliensis.

scholarly journals Carbonic Anhydrase Is Essential for Streptococcus pneumoniae Growth in Environmental Ambient Air

2010 ◽  
Vol 192 (15) ◽  
pp. 4054-4062 ◽  
Author(s):  
Peter Burghout ◽  
Lorelei E. Cron ◽  
Henrik Gradstedt ◽  
Beatriz Quintero ◽  
Elles Simonetti ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Carbonic Anhydrase ◽  
Unsaturated Fatty Acids ◽  
De Novo ◽  
Ambient Air ◽  
Host Cells ◽  
Ambient Conditions ◽  
Growth And Survival ◽  
Cellular Processes

ABSTRACT The respiratory tract pathogen Streptococcus pneumoniae needs to adapt to the different levels of carbon dioxide (CO2) it encounters during transmission, colonization, and infection. Since CO2 is important for various cellular processes, factors that allow optimal CO2 sequestering are likely to be important for pneumococcal growth and survival. In this study, we showed that the putative pneumococcal carbonic anhydrase (PCA) is essential for in vitro growth of S. pneumoniae under the CO2-poor conditions found in environmental ambient air. Enzymatic analysis showed that PCA catalyzes the reversible hydration of CO2 to bicarbonate (HCO3 −), an essential step to prevent the cellular release of CO2. The addition of unsaturated fatty acids (UFAs) reversed the CO2-dependent in vitro growth inhibition of S. pneumoniae strains lacking the pca gene (Δpca), indicating that PCA-mediated CO2 fixation is at least associated with HCO3 −-dependent de novo biosynthesis of UFAs. Besides being necessary for growth in environmental ambient conditions, PCA-mediated CO2 fixation pathways appear to be required for intracellular survival in host cells. This effect was especially pronounced during invasion of human brain microvascular endothelial cells (HBMEC) and uptake by murine J774 macrophage cells but not during interaction of S. pneumoniae with Detroit 562 pharyngeal epithelial cells. Finally, the highly conserved pca gene was found to be invariably present in both CO2-independent and naturally circulating CO2-dependent strains, suggesting a conserved essential role for PCA and PCA-mediated CO2 fixation pathways for pneumococcal growth and survival.

scholarly journals The N-Terminal Carbamate is Key to High Cellular and Antiviral Potency for Boceprevir-Based SARS-CoV-2 Main Protease Inhibitors

2021 ◽  
Author(s):  
Yugendar R. Alugubelli ◽  
Zhi Zachary Geng ◽  
Kai Yang ◽  
Namir Shaabani ◽  
Kaustav Khatua ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Hydrophobic Interactions ◽  
Complex Structure ◽  
Host Cells ◽  
Side Chain ◽  
Active Site Cysteine ◽  
Main Protease ◽  
Control Compound ◽  
Inhibition Potency

Boceprevir is an HCV NSP3 inhibitor that has been explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (MPro) and contains an α-ketoamide warhead, a P1 β-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based MPro inhibitors including PF-07321332 and characterized their MPro inhibition potency in test tubes (in vitro) and human host cells (in cellulo). Crystal structures of MPro bound with 10 inhibitors and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a β-(S-2-oxopyrrolidin-3-yl)-alanyl (opal) residue and the war-head with an aldehyde leads to high in vitro potency. The original moieties at P2, P3 and the P4 N-terminal cap positions in boceprevir are better than other tested chemical moieties for high in vitro potency. In crystal structures, all inhibitors form a covalent adduct with the MPro active site cysteine. The P1 opal residue, P2 dime-thylcyclopropylproline and P4 N-terminal tert-butylcarbamide make strong hydrophobic interactions with MPro, explaining high in vitro potency of inhibitors that contain these moieties. A unique observation was made with an inhibitor that contains a P4 N-terminal isovaleramide. In its MPro complex structure, the P4 N-terminal isovaleramide is tucked deep in a small pocket of MPro that originally recognizes a P4 alanine side chain in a substrate. Although all inhibitors show high in vitro potency, they have drastically different in cellulo potency in inhibiting ectopically expressed MPro in human 293T cells. All inhibitors including PF-07321332 with a P4 N-terminal carbamide or amide have low in cellulo potency. This trend is reversed when the P4 N-terminal cap is changed to a carbamate. The installation of a P3 O-tert-butyl-threonine improves in cellulo potency. Three molecules that contain a P4 N-terminal carbamate were advanced to antiviral tests on three SARS-CoV-2 variants. They all have high potency with EC50 values around 1 μM. A control compound with a nitrile warhead and a P4 N-terminal amide has undetectable antiviral potency. Based on all observations, we conclude that a P4 N-terminal carbamate in a boceprevir derivative is key for high antiviral potency against SARS-CoV-2.

scholarly journals In Vitro and Insilico screening platform for the identification of aldose reductase inhibitors for antidiabetic lead compounds from Abutilon indicum (L.)

2020 ◽  
Author(s):  
L Lavanya ◽  
V. Veeraraghavan ◽  
CN Prashantha ◽  
Renuka Srihari
Keyword(s):  
Aldose Reductase ◽  
Developed Countries ◽  
Docking Studies ◽  
Binding Interaction ◽  
Reference Drug ◽  
Rat Lens Aldose Reductase ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Abutilon Indicum

AbstractIntroductionType 2 Diabetes Mellitus (T2DM) is a long-term metabolic disorder that primarily characterized by impaired insulin resistance to become hyperglycemia. People suffering from T2DM have a higher risk of developing various diseases but, on top of that, some diabetic drugs are also suspected of increasing the risk in some cases. Aldose reductase is a key target enzyme to catalyze the reduction of glucose to sorbitol and does not readily diffuse across cell membranes and cause retinopathy and neuropathy. The aldolase reductase inhibitors prevent the conversion of glucose to sorbitol and may have the capacity of preventing and / or treating several diabetic complications. It will be expected to be twofold in the subsequent decade due to intensification in the senile population with the number of people affected, thus adding to the liability on medical providers in poor developed countries using herbal medicine to control the diabetes. In recent investigation, the antidiabetic property of phytochemicals extracted from leafs of Abutilon indicum (L.) is elucidated using animal models.Materials and MethodsIn the current study using aldose reductase enzyme assay inhibitor of Rat lens Aldose reductase were treated with A. indicum methanolic leaf extract at different concentrations (6.25, 12.5, 25, 50, 100, and 200μg/mL). Copper sulphate was used as reference drug and docking studies to predict the screen the best aldose reductase inhibitor.Results and DiscussionThe crude extract exhibited cytotoxicity against rat lens aldose reductase (IC50 = 135.8 μg/L vs ref 13.60 μg/L) using In Vitro. The docking is performed with 11 compounds shows Ertugliflozin, 9H-Cycloisolongifolene, 8-oxo and 7-hydroxy cadalene showed a good binding interaction with aldose reductase.ConclusionWe are concluding that the invitro and in silico analysis helps researchers to utilize these compound for aldose reductase inhibitors and further can be used for clinical applications.

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