scholarly journals Discovery of 5-Chlorobenzimidazole-based as Promising Inhibitors of Chloroquine-Resistant Plasmodium Strains: Synthesis, Biological Evaluation, Molecular Docking and Computational Studies

2021 ◽  
pp. 136-147
Author(s):  
Jean Paul N’Guessan ◽  
Songuigama Coulibaly ◽  
Abdulrahim A. Alzain ◽  
Drissa Sissouma ◽  
William Yavo ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimalarial Activity ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Antiplasmodial Activity ◽  
Sensitivity Threshold ◽  
Drug Candidates ◽  
Pharmacokinetic Properties ◽  
Experimental Findings

Background: To overcome drug resistance to current antimalarial drugs, we propose the synthesis and in vitro evaluation of the antiplasmodial activity of a series of 5-chlorobenzimidazolyl-chalcones against chloroquino sensitive (CQ-S) and chloroquino resistant (CQ-R) strains of P. falciparum. Objective: This study aimed to establish through structure-activity relationship studies and docking, the structural elements essential for antiplasmodial activities. Methods: The antiplasmodial activity of these benzimidazolylchalcones was carried out according to the Rieckmann microtest technique, followed by the determination of the concentrations inhibiting 50% of the production of parasitic HRP2 antigens (IC50) by ELISA. Chloroquine was used as a reference molecule with a sensitivity threshold set at 100 µM. Molecular docking was performed using sensitive (PDB ID: 1J3I) and resistant (PDB ID: 4DP3) dihydrofolate reductase-thymidylate synthase proteins (PfDHFR-TS). Results: All benzimidazolylchalcones tested expressed antiplasmodial activities especially against chloroquine resistant isolates (IC50 = 0.32-44.38 µM). The best profile against both isolates was the methoxylated derivative (3e) with an IC50 ranging from 0.32 to 1.96 µM. This compound had the best antimalarial activity against CQ-S isolates. On CQ-R isolates, the unsubstituted 5-chlorobenzimidazole derivative (3b) had exalted activity (IC50 = 0.78 µM).  We selected a weakly active non-chlorinated derivative 3a and chlorinated derivatives 3b, 3d, 3e and 3f) with IC50< 3µM against the chloroquine-resistant strain to perform docking studies. These revealed that the pyrrolic nitrogen of benzimidazole and the ketone of propenone are the main chemical entities involved in the interaction at the receptor. Moreover, ADMET studies showed favorable pharmacokinetic properties. Conclusion: Molecular docking studies confirmed the experimental findings and revealed the possible interactions pattern. Derivatives 3b and 3e, which showed promising binding affinities against PfDHFR-TS, can be proposed as lead compounds for the development of antimalarial drug candidates.

scholarly journals Synthesis and Biological Evaluation of Alanine Derived Bioactive p-Toluenesulphonamide Analogs

2020 ◽  
Vol 11 (4) ◽  
pp. 6449-6458
Author(s):  
Melford C Egbujor ◽  
Uchechukwu C Okoro ◽  
Samuel A Egu ◽  
Pius I Egwuatu ◽  
Florence U Eze ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimalarial Activity ◽  
Biological Activities ◽  
Analytical Data ◽  
Antioxidant Properties ◽  
Antimicrobial Properties ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Agar Dilution

Sulphonamides and carboxamides have great pharmacological importance. The purpose of the study was to synthesize alanine-derived bioactive sulphonamides bearing carboxamides and evaluate their biological activities. The reaction of p-toluenesulphonyl chloride with L-alanine afforded compound 1, which was acetylated to obtain compound 2. The chlorination and ammonolysis of compound 2 gave the carboxamide backbone (3) which was coupled with aryl/heteroaryl halides to afford the hybrid compounds 4, 5 and 6. Structures were confirmed by FTIR, 1H-NMR, 13C-NMR spectra and elemental analytical data. The in vitro antimicrobial properties were determined by agar dilution, and the antioxidant properties were also investigated. Molecular docking interactions of the analogues were determined using PyRx. Compounds 4, 5 and 6 exhibited excellent in vitro antimicrobial properties in the range of 0.5-1.0mg/ml while compounds 1and 2 had half-maximal inhibitory concentration (IC50) of 1.11±0.15µg/ml and 1.12±0.13µg/ml respectively. For the molecular docking studies, compounds 5 and 6 displayed the best antitrypanosomal activity with binding affinities of -13.95 and -13.51kcal/mol respectively while compound 4 showed the highest in silico antimalarial activity having binding affinity of -11.95kcal/mol. All the alanine derived sulphonamides were observed to be potential antimicrobial, antioxidant, antitrypanosomal and antimalarial agents following the biological activities studies.

scholarly journals Synthesis, antimalarial activity evaluation and molecular docking studies of some novel dispiro-1,2,4,5-tetraoxanes

2015 ◽  
Vol 10 (4) ◽  
pp. 917 ◽  
Author(s):  
Mukesh Kumar Kumawat ◽  
Dipak Chetia
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Resistant Strain ◽  
Antimalarial Activity ◽  
Binding Pocket ◽  
Docking Studies ◽  
Spectroscopic Techniques ◽  
Molecular Docking Studies ◽  
Activity Screening

<p class="Abstract">Seven novel dispiro-1,2,4,5-tetraoxane derivatives were synthesized and characterized by a number of analytical and spectroscopic techniques. The molecules were subsequently screened for in vitro antimalarial activity against chloroquine resistant strain of <em>Plasmodium falciparum</em> (RKL-9). At antimalarial activity screening, two compounds, namely 5d (MIC = 15.6 µg/mL or 64.5 µM) and 5f (MIC = 15.6 µg/mL or 54.6 µM) were found to be about 1.5 times more potent against chloroquine resistant strain-RKL-9 compared to chloroquine (MIC = 25.0 µg/mL or 78.3 µM). Molecular docking studies of potent ligands were also performed in cysteine protease binding pocket residues of falcipain-2 as a target protein.</p><p> </p>

scholarly journals Synthesis, Antimalarial Activity, and Docking Studies of Monocarbonyl Analogues of Curcumin

2018 ◽  
Vol 29 (2) ◽  
pp. 92-96
Author(s):  
Amina S. Yusuf ◽  
Ibrahim Sada ◽  
Yusuf Hassan ◽  
Temitope O. Olomola ◽  
Christiana M. Adeyemi ◽  
...  
Keyword(s):  
Biological Activity ◽  
Molecular Docking ◽  
Antimalarial Activity ◽  
Docking Studies ◽  
Aryl Ring ◽  
Molecular Docking Studies ◽  
Plasmodium Parasite

Abstract The synthesis of five monocarbonyl analogues of curcumin is described. In vitro anti-malarial assay of the compounds was carried out and the effect of the substituents on the aryl ring has been described. The results show that all the five compounds exhibited some reasonable activity against the chloroquine-resistant plasmodium parasite. Molecular docking studies further confirmed the observed biological activity of the compounds.

scholarly journals Rhodanine-3-Acetamide Derivatives as Aldose and Aldehyde Reductase Inhibitors to Treat Diabetic Complications; Synthesis, Biological Evaluation and Molecular Docking Studies

2020 ◽  
Author(s):  
Mohsinul Mulk Bacha ◽  
Humaira Nadeem ◽  
Shafiq Ur Rehman ◽  
Sadia Sarwar ◽  
Aqeel Imran ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Molecular Docking ◽  
Aldose Reductase ◽  
Diabetic Complications ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Aldehyde Reductase ◽  
Standard Drug ◽  
Molecular Docking Studies

Abstract In diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is considered to be important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a-g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a-g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2.

scholarly journals PREDICTION OF ANTI-ALZHEIMER’S ACTIVITY OF FLAVONOIDS TARGETING CD33 THROUGH IN-SILICO APPROACH

2021 ◽  
pp. 64-66
Author(s):  
AKILA S. ◽  
MALAR VIZHI S. ◽  
VIJAYALAKSHMI P. ◽  
CLARA MARY A. ◽  
RAJALAKSHMI M.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Social Care ◽  
Docking Studies ◽  
Brain Disorder ◽  
Drug Candidates ◽  
Health And Social Care ◽  
Pharmacokinetic Properties ◽  
Care Systems

Objective: Alzheimer's disease (AD) is a progressive, fatal brain disorder that would be putting a growing strain on health and social care systems. Present anti-AD agents are limited in their application due to their adverse effects, toxicity, and limited targets in AD pathology. As a result, it is important to develop an AD-fighting compound. Some flavonoids (such as kaempferol, myricetin, quercetin, and syringetin) have been shown to be effective in the treatment of Alzheimer's disease. Methods: We chose 284 flavonoids from the NPACT database for molecular docking studies in order to examine their binding interactions with the Alzheimer target protein CD33. Results: These compounds exhibited significant docking interactions with a variety of targets implicated in the pathogenesis of AD. We chose the top three compounds (Rutin, Morin, and,4,4'-Trihydroxydihydrochalcone) based on the scoring parameter. Conclusion: These compounds exhibited favorable pharmacokinetic properties, indicating that they could be attractive drug candidates for the treatment of Alzheimer's disease.

Evaluation of Antiplasmodial Potential of C2 and C8 Modified Quinolines: in vitro and in silico Study

2019 ◽  
Vol 15 (7) ◽  
pp. 790-800 ◽  
Author(s):  
Rakesh Kumar ◽  
Ritika Sharma ◽  
Inder Kumar ◽  
Pooja Upadhyay ◽  
Ankit Kumar Dhiman ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Malaria Parasite ◽  
Resistance Index ◽  
Microtiter Plate ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molecular Docking Studies ◽  
Human Red Blood Cells ◽  
Computational Molecular Docking

Background: Malaria remains a common life-threatening infectious disease across the globe due to the development of resistance by Plasmodium parasite against most antimalarial drugs. The situation demands new and effective drug candidates against Plasmodium. Objectives: The objective of this study is to design, synthesize and test novel quinoline based molecules against the malaria parasite. Methods: C2 and C8 modified quinoline analogs obtained via C-H bond functionalization approach were synthesized and evaluated for inhibition of growth of P. falciparum grown in human red blood cells using SYBR Green microtiter plate based screening. Computational molecular docking studies were carried out with top fourteen molecules using Autodoc software. Results: The biological evaluation results revealed good activity of quinoline-8-acrylate 3f (IC50 14.2 µM), and the 2-quinoline-α-hydroxypropionates 4b (IC50 6.5 µM), 4j (IC50 5.5 µM) and 4g (IC50 9.5 µM), against chloroquine sensitive Pf3D7 strain. Top fourteen molecules were screened also against chloroquine resistant Pf INDO strain and the observed resistant indices were found to lie between 1 and 7.58. Computational molecular docking studies indicated a unique mode of binding of these quinolines to Falcipain-2 and heme moiety, indicating these to be the probable targets of their antiplasmodial action. Conclusion: An important finding of our work is the fact that unlike Chloroquine which shows a resistance Index of 15, the resistance indices for the most promising molecules studied by us were about one indicating equal potency against drug sensitive and resistant strains of the malaria parasite.

Design, Synthesis and Biological Evaluation of Anti-tuberculosis Agents based on Bedaquiline Structure

2020 ◽  
Vol 16 (5) ◽  
pp. 703-714
Author(s):  
Chengjun Wu ◽  
Jinghan Luo ◽  
Mengtong Wu ◽  
Fanzhen Meng ◽  
Zhiqiang Cai ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Atp Synthase ◽  
Docking Study ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Mycobacterium Tuberculosis H37rv ◽  
Inhibitory Activities ◽  
Relationship Of

Background: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial ATP synthase. However, studies have found that bedaquiline has serious side effects due to high lipophilicity. Recently, the complete structure of ATP synthase was first reported in the Journal of Science. Objective: The study aimed to design, synthesise and carry out biological evaluation of antituberculosis agents based on the structure of bedaquiline. Methods: The mode of action of bedaquiline and ATP synthase was determined by molecular docking, and a series of low lipophilic bedaquiline derivatives were synthesized. The inhibitory activities of bedaquiline derivatives towards Mycobacterium phlei 1180 and Mycobacterium tuberculosis H37Rv were evaluated in vitro. A docking study was carried out to elucidate the structureactivity relationship of the obtained compounds. The predicted ADMET properties of the synthesized compounds were also analyzed. Results: The compounds 5c3, 6a1, and 6d3 showed good inhibitory activities (MIC=15.62 ug.mL-1). At the same time, the compounds 5c3, 6a1, and 6d3 also showed good drug-like properties through molecular docking and ADMET properties prediction. Conclusion: The results of in vitro anti-tuberculosis activity assays, docking studies and ADMET predictions indicate that the synthesized compounds have potential antifungal activity, with compounds 6a1 being further optimized and developed as lead compounds.

In Vitro Antioxidant, Antimicrobial and Molecular Docking Studies of Fosphenytoin and Regadenoson Impurities

2020 ◽  
Vol 8 (1) ◽  
pp. 63-69
Author(s):  
S. Sathiyanarayanan ◽  
◽  
C.S. Venkatesan ◽  
S. Kabilan ◽  
◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Product ◽  
Active Pharmaceutical Ingredient ◽  
Docking Study ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Gaba A ◽  
Pharmacokinetic Properties ◽  
Approved Drugs

Regadenoson and Fosphenytoin are USFDA approved drugs which is used for coronary vasodilator and convulsive status epileptics respectively. It is quite natural that low levels of reagents or side products are present in the final active pharmaceutical ingredient (API) or drug product as impurities. Such impurities may have unwanted toxicities, including genotoxicity and carcinogenicity. Hence, it is important to study on impurities present in both the drugs. There are 9 impurities were identified from both drugs and studied pharmacokinetic properties using Qikprop module from Schrödinger software. From the 9 compounds of both the drug’s impurities, 5 compounds obey the Lipinski rule of five and the remaining compounds are having 1 to 3 penalties. All the compounds were subjected to molecular docking study with thermo stabilised HUMAN A2A Receptor with adenosine bound protein (PDB ID: 2YDO) for regadenoson impurities and fosphenytoin impurities were docked with Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and flumazenil, conformation A protein (PDB id: 6D6U). All the compounds are showed very good interaction with docked proteins. Further selected compound subjected to in vitro Antibacterial (Gram positive, Gram negative), Antifungal and Antioxidant (DPPH and FRAP) studies.

Sign in / Sign up

Export Citation Format

Share Document