Synthesis, in vitro and in silico antimalarial activity of 7-chloroquinoline and 4H-chromene conjugates

Background: Malaria is caused by different species of Plasmodium; among which P. falciparum is the most severe. Coptis teeta is an ethnomedicinal plant of enormous importance for tribes of north east India. Objective: In this study, the anti malarial activity of the methanol extracts of Coptis teeta was evaluated in vitro and lead identification via in silico study. Method: On the basis of the in vitro results, in silico analysis by application of different modules of Discovery Studio 2018 was performed on multiple targets of P. falciparum taking into consideration some of the compounds reported from C. teeta. Results: The IC50 of the methanol extract of Coptis teeta 0.08 µg/ml in 3D7 strain and 0.7 µg/ml in Dd2 strain of P. falciparum. From the docking study, noroxyhydrastatine was observed to have better binding affinity in comparison to chloroquine. The binding of noroxyhydrastinine with dihydroorotate dehydrogenase was further validated by molecular dynamics simulation and was observed to be significantly stable in comparison to the co-crystal inhibitor. During simulations it was observed that noroxyhydrastinine retained the interactions, giving strong indications of its effectiveness against the P. falciparum proteins and stability in the binding pocket. From the Density-functional theory analysis, the band gap energy of noroxyhydrastinine was found to be 0.186 Ha indicating a favourable interaction. Conclusion: The in silico analysis as an addition to the in vitro results provide strong evidence of noroxyhydrastinine as an anti malarial agent.

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Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02041-19 ◽

2020 ◽

Vol 64 (9) ◽

Author(s):

Letícia Tiburcio Ferreira ◽

Juliana Rodrigues ◽

Gustavo Capatti Cassiano ◽

Tatyana Almeida Tavella ◽

Kaira Cristina Peralis Tomaz ◽

...

Keyword(s):

Plasmodium Falciparum ◽

In Silico ◽

Antimalarial Activity ◽

Drug Repositioning ◽

Dna Gyrase ◽

Plasmodium Yoelii ◽

Computer Assisted ◽

Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

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In vitro and in silico antimalarial activity of 2-(2-hydrazinyl)thiazole derivatives

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2013.11.001 ◽

2014 ◽

Vol 52 ◽

pp. 138-145 ◽

Cited By ~ 31

Author(s):

Parameshwar Makam ◽

Prasoon Kumar Thakur ◽

Tharanikkarasu Kannan

Keyword(s):

In Silico ◽

Antimalarial Activity ◽

Thiazole Derivatives

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Docking Studies of Structurally Diverse Antimalarial Drugs Targeting PfATP6: No Correlation between in silico Binding Affinity and in vitro Antimalarial Activity.

ChemMedChem ◽

10.1002/cmdc.200900200 ◽

2009 ◽

Vol 4 (9) ◽

pp. 1469-1479 ◽

Cited By ~ 26

Author(s):

Fatima Bousejra-El Garah ◽

Jean-Luc Stigliani ◽

Frédéric Coslédan ◽

Bernard Meunier ◽

Anne Robert

Keyword(s):

Binding Affinity ◽

In Silico ◽

Antimalarial Activity ◽

Docking Studies ◽

Antimalarial Drugs

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In silico analysis, synthesis and biological evaluation of DHFR inhibitors

Folia Medica ◽

10.3897/folmed.63.e56786 ◽

2021 ◽

Vol 63 (5) ◽

pp. 745-759

Author(s):

Chaitali Lad ◽

Ishan Panchal ◽

Ashish Patel ◽

Afzal Nagani ◽

Vruti Parikh ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Antimalarial Activity ◽

In Silico Analysis ◽

Protozoan Parasite ◽

Biological Evaluation ◽

Piperazine Derivatives ◽

Dhfr Inhibitors ◽

Silico Analysis

Introduction: Malaria is one of the varieties of fatal diseases caused by a protozoan parasite that is now considered to be the greatest global health challenge. A parasite of Plasmodium species triggers it transmitting the disease to humans by the bites of female Anopheles mosquitoes. Aim: To screen out designed molecules by molecular docking analysis and assess their pharmacokinetic properties using SwissADME. To synthesize the designed compounds. To characterize the synthesized compounds by TLC, melting point, IR spectroscopy, mass spectrometry, 1H NMR, and 13C NMR. To evaluate the synthesized compounds for antimalarial activity. Materials and methods: In silico analysis was performed with SWISSADME, and molecular docking was performed by AutoDock Vina version 4.2. In vitro antimalarial activity study was performed. Results: In-vitro studies of synthesized molecules showed that compounds C2 (IC50 1.23), C6 (IC50 0.48), C10 (IC50 0.79), and C14 (IC50 0.19) possess good antimalarial activity. Conclusions: 7-chloroquinoline-piperazine derivatives exhibited potential antimalarial compounds for pf-DHFR inhibitors.

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Antimalarial Activity of Curcuma Caesia Against 3D7 and K1 Strains of Plasmodium Falciparum

10.21203/rs.3.rs-32452/v1 ◽

2020 ◽

Author(s):

Monika Chaturvedi ◽

Reena Rani ◽

Dushyant Sharma ◽

Jaya Parkash Yadav

Keyword(s):

Plasmodium Falciparum ◽

Ethyl Acetate ◽

In Silico ◽

Antimalarial Activity ◽

Antimalarial Drugs ◽

Mechanism Study ◽

Effective Development ◽

Ethyl Acetate Extracts

Abstract Background: Malaria is a severe and sometimes mortal tropical disease that spreads through parasites. The purpose of the study was to evaluate in vitro and in-silicoantiplasmodial potential of Curcuma caesia extracts against Plasmodium falciparum.Methods: Lack of a vaccine and the widespread resistance to antimalarial drugs have resulted in emphasis on novel antimalarial drugs development. Ethyl acetate and methanol extracts of Curcuma caesia were prepared and analysed for their antiplasmodial activity against Chloroquine sensitive (3D7) and resistant (K1) strains of P. falciparumusingfluorescence-based SYBR Green assay. The cytotoxicity tests were carried out using the verocell lines by MTT assay.The phosphoethanolamine methyltransferase enzyme ((PfPMT) essential for growth of Plasmodium falciparum was used as protein target for in-silicostudy.Result: Curcuma caesia ethyl acetate extracts showedpotentantiplasmodial activitywith IC50 values of 3.37 µg/ml and 1.53 µg/ml against 3D7 and K1 strain respectively.Docking results show that β-selinenol an oxygenized sesquiterpene had the free binding energy of -6.76 Kcal/mol.Conclusion: Sesquiterpene present in the Curcuma caesia extract was responsible for antimalarial potential analyzed by molecular modeling. The present findings, however preliminary in nature. Further studies are required to proven the antimalarial efficacy C. caesia by isolating the active compounds and in vivo mechanism study that may contribute to more effective development of antimalarial drugs in the future.

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Synthesis, Docking, in silico ADMET and Pharmacological Evaluation of Some N-acetyl Pyrazole and Quinoline Conjugates

Letters in Drug Design & Discovery ◽

10.2174/1570180817666200228123347 ◽

2020 ◽

Vol 17 (8) ◽

pp. 1015-1026

Author(s):

Nargisbano Ayyub Peerzade ◽

Shravan Yegu Jadhav ◽

Raghunath Bhikaji Bhosale ◽

Amol Anantrao Kulkarni ◽

Bhushan Dnyandeo Varpe

Keyword(s):

Antioxidant Activity ◽

Ascorbic Acid ◽

In Silico ◽

Amylase Activity ◽

Antimalarial Activity ◽

In Silico Admet ◽

Anti Oxidant ◽

Anti Inflammatory ◽

Almost All

Background: Pyrazolines are reported having anti-inflammatory, anti-oxidant and antidiabetic activities in the literature. Drugs like celecoxib, antipyrine, etc. are structurally similar to the designed compounds. Objectives: To synthesize and characterize N-acetyl pyrazole and quinoline conjugates and test them for Anti-inflammatory, Antioxidant, Antibacterial, Antiamylase and Antimalarial activities. Methods: A series of methoxy substituted quinoline based pyrazoline derivatives (2a-2j) were synthesized in good to excellent yield from corresponding quinoline chalcones (1a-1j). The synthesized compounds were characterized and screened for their in vitro anti-inflammatory, antioxidant, antiamylase, antibacterial and antimalarial activities. Docking and in silico ADMET studies were performed with PDB: 3LN1. Results: Compounds 2b, 2i and 2j showed significant anti-inflammatory activity as compared to standard sodium diclofenac. All compounds (2a-2j) showed excellent antioxidant activity for DPPH even more than standard ascorbic acid. Compounds 2e, 2f, 2h and 2i showed excellent antioxidant activity for NO. as compared to standard ascorbic acid. Compound 2f showed significant antioxidant activity for SOR. Almost all the compounds showed significant antibacterial as well as anti-amylase activity with few exceptions, whereas compounds 2f, 2h and 2j showed potent antimalarial activity. Conclusion: Compounds have shown good anti-inflammatory activities as compared with diclofenac. All the synthesized pyrazoline derivatives showed excellent anti-amylase activity as compared to standard acarbose. Also, compounds have shown good antioxidant antibacterial and antimalarial activities.

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Pass and Swiss ADME collaborated in silico docking approach to the synthesis of certain pyrazoline spacer compounds for dihydrofolate reductase inhibition and antimalarial activity

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v13i1.33625 ◽

2018 ◽

Vol 13 (1) ◽

pp. 23 ◽

Cited By ~ 6

Author(s):

Krishnakumar Lohidakshan ◽

Manju Rajan ◽

Andhale Ganesh ◽

Mathew Paul ◽

Jithu Jerin

Keyword(s):

In Silico ◽

Antimalarial Activity ◽

Video Clip ◽

Acid Hydrazide ◽

Building Blocks ◽

Docking Study ◽

Discovery Studio ◽

In Silico Docking ◽

Docking Approach

New series of pyrazoline spacer compounds were prepared by the reaction between benzimidazole chalcones and (2-methyl-5-nitro-imidazole-1-yl)-acetic acid hydrazide by the sensible use of Michael addition. The building blocks used for the synthesis of pyrazoline derivatives were opted by using virtual screening by molinspiration search engine. The hypothetically resulted pyrazoline spacer compounds from this list are checked for their reliability on other in silico drug designing online web services like PASS online bioactivity, Swiss ADME predictor. The docking study on final four pyrazoline compounds was carried out using Accelrys Discovery Studio 3.5. These synthesized compounds were, later, characterized with the help of UV, IR, mass and 1H NMR techniques. These compounds were further screened for their in vitro antimalarial effect. The PASS, Swiss ADME assisted docking approach and the use of combo heterocyclic ring with pyrazoline scaffold were found to be beneficial to derive and synthesize effective antimalarial agents in the present study.Video Clip of Methodology:6 min 20 sec: <a href="https://www.youtube.com/v/RWwaZuG1j9E">Full Screen</a> <a href="https://www.youtube.com/watch?v=RWwaZuG1j9E">Alternate</a>

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Antimalarial activity of Curcuma caesia against 3D7 and K1 strains of Plasmodium falciparum

10.21203/rs.3.rs-32452/v2 ◽

2020 ◽

Author(s):

Monika Chaturvedi ◽

Reena Rani ◽

Dushyant Sharma ◽

Jaya Parkash Yadav

Keyword(s):

Plasmodium Falciparum ◽

Ethyl Acetate ◽

Vero Cell ◽

Cell Lines ◽

In Silico ◽

Antimalarial Activity ◽

Antimalarial Drugs ◽

Antiplasmodial Activity ◽

Vero Cell Lines

Abstract Background: Malaria is one of the severe tropical disease and majority of deaths occurred due to Plasmodium falciparum. Lack of a vaccine and the widespread resistance to antimalarial drugs have resulted in emphasis on novel antimalarial drugs development. The purpose of the study was to evaluate in vitro and in-silico antiplasmodial potential of Curcuma caesia extracts against P. falciparum.Methods: Ethyl acetate and methanol extracts of C. caesia were prepared and analysed for their antiplasmodial activity against Chloroquine sensitive (3D7) and resistant (K1) strains of P. falciparum using fluorescence-based SYBR Green assay. The cytotoxicity tests were carried out using the vero cell lines by MTT assay. The phosphoethanolamine methyltransferase enzyme ((PfPMT) essential for growth of P. falciparum was used as protein target for in-silico study. Result: C. caesia ethyl acetate extracts showed the potent antiplasmodial activity with IC50 values of 3.37 µg/ml and 1.53 µg/ml against 3D7 and K1 strain respectively. The IC50 values of methanol extract were reported, 8.57 µg/ml against 3D7 and 18.29 µg/ml against K1 strains The cytotoxicity assay revealed that the extracts were not toxic against vero cell lines as the CC50 values were less than IC50. Docking results show that β-selinenol an oxygenized sesquiterpene present in C. caesia had the free binding energy of -6.76 Kcal/mol.Conclusion: The compounds β-selinenol, α-eudesmol, α –acorenol, boldione and xanthinin present in the C. caesia extract possess antimalarial potential being inhibitor of PfPMT. The present findings, however preliminary in nature. Further studies are needed to identify the active compounds and in vivo mechanism to prove the antimalarial efficacy of C. caesia in the development of antimalarial drugs.

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