Expanding the scope of prenylated 1,2,3-triazoles as new antiparasitic drug candidates

We have previously shown that prenyl and aliphatic triazoles are interesting motifs to prepare new chemical entities for antiparasitic and antituberculosis drug development. In this opportunity a new series of prenyl-1,2,3-triazoles were prepared from isoprenyl azides and different alkynes looking for new antimalarial drug candidates. The compounds were prepared by copper(I) catalyzed dipolar cycloaddition of the isoprenyl azide equilibrium mixture providing exclusively 1,4-disubstituted 1,2,3-triazols in a regiospecific fashion. The complete collection of 64 compounds was tested on chloroquine -sensitive, Sierra Leone (D6), and the chloroquine-resistant, Indochina (W2), strains of Plasmodium falciparum and those compounds which were not previously reported were also tested against Leishmania donovani , the causative agent for visceral leishmaniasis. Thirteen analogs displayed antimalarial activity with IC50 below 10 uM, while the antileishmanial activity was less potent than the previously reported analogs. The cytotoxicity assay against Vero cells revealed that none of the compounds was cytotoxic up to concentrations of 4.75 ug/mL. Compounds 1o and 1r were identified as the most promising antimalarial drug leads with IC50 below 3.0 uM for both CQ-sensitive and resistant P. falciparum strains. Finally, a chemoinformatic in silico analysis was performed to evaluate physicochemical parameters, cytotoxicity risk and drug score. The validation of a bifunctional farnesyl/geranylgeranyl diphosphate synthase PfFPPS/GGPPS as the potential target of the antimalarial activity of selected analogs should be further investigated.

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Synthesis, characterization and biological activity of organometallic derivatives of the antimalarial drug mefloquine as new antischistosomal drug candidates

MedChemComm ◽

10.1039/c8md00396c ◽

2018 ◽

Vol 9 (11) ◽

pp. 1905-1909 ◽

Cited By ~ 7

Author(s):

Faustine d'Orchymont ◽

Jeannine Hess ◽

Gordana Panic ◽

Marta Jakubaszek ◽

Lea Gemperle ◽

...

Keyword(s):

Biological Activity ◽

Antimalarial Drug ◽

Biological Evaluation ◽

Design Synthesis ◽

Drug Candidates ◽

Derivatives Of

The design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the antimalarial mefloquine is described.

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New acetylphenol-based acyl thioureas broaden the scope of drug candidates for urease inhibition: synthesis, in vitro screening and in silico analysis

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2021.12.064 ◽

2021 ◽

Author(s):

Urage Zahra ◽

Sumera Zaib ◽

Aamer Saeed ◽

Mujeeb ur Rehman ◽

Ghulam Shabir ◽

...

Keyword(s):

In Silico ◽

In Silico Analysis ◽

In Vitro Screening ◽

Urease Inhibition ◽

Drug Candidates ◽

Silico Analysis

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Exploratory Analysis into the in vitro and in silico Activity of E. fusca Lour. (Fabaceae) Elucidates Substantial Antiplasmodial Activity of the Plant

10.20944/preprints202010.0576.v2 ◽

2021 ◽

Author(s):

Saiful Arefeen Sazed ◽

Ohedul Islam ◽

Sarah L. Bliese ◽

Muhammad Riadul Haque Hossainey ◽

Jakaria Shawon ◽

...

Keyword(s):

Antimalarial Drug ◽

Simulation Analysis ◽

Antimalarial Activity ◽

Dynamics Simulation ◽

Drug Candidate ◽

Phytochemical Investigation ◽

High Degree ◽

Emergence Of Resistance ◽

First Time

The exploration of alternative antimalarial therapeutics is a requisite for the emergence of resistance against Artemisinin. Considering the required cost and time length of classical small molecule drug discovery process, phytochemical screening of traditionally used medicinal plant which are repertoire of active compounds with antimalarial activity has become popular. To investigate the antimalarial property of traditionally used medicinal plants, a number of Erythrina spp have been reviewed systematically where less studied E. fusca has been selected for further analysis. Phytochemical investigation yielded five compounds namely; Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol. In-vitro antimalarial drug sensitivity HRP-II ELISA was carried out against chloroquine (CQ) sensitive 3D7 and CQ-resistant Dd2 strains. Extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94 – 22 µg/mL) and these compounds have been reported here for the first time. Molecular docking analysis showed high binding energy (−9.0 ± 0.32 kcal/mole) indicating high degree of interaction between Phaseolin and 14 clinically important Plasmodium falciparum proteins at the active site. Stable interaction was also observed between ligand and protein from molecular dynamics simulation analysis with high free energy (−75.156 ± 11.459) that substantiates the potential of Phaseolin as an antimalarial drug candidate.

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Caspofungin and LTX-315 inhibit SARS-CoV-2 replication by targeting the nsp12 polymerase

10.21203/rs.3.rs-19872/v1 ◽

2020 ◽

Author(s):

Min Wang ◽

Fei Ye ◽

Jiaqi Su ◽

Jingru Zhao ◽

Bin Yuan ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Vero Cells ◽

Polymerase Activity ◽

Structural Protein ◽

Live Virus ◽

Drug Candidates ◽

Virtual Screen ◽

Virus Assay ◽

Promising Target

Abstract The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously designated as 2019-nCoV) outbreak has caused global concern1. Currently, there are no clinically approved specific drugs or vaccines available for this virus. The viral polymerase is a promising target for developing broad- spectrum antiviral drugs. Here, based on the highly similar structure of SARS- CoV non-structural protein 12 (nsp12) polymerase subunit2, we applied virtual screen for the available compounds, including both the FDA-approved and under- clinic drugs, to identify potential antiviral molecules against SARS-CoV-2. We found two drugs, the clinically approved anti-fungi drug Caspofungin Acetate (Cancidas) and the oncolytic peptide LTX-315, can bind SARS-CoV-2 nsp12 protein to block the polymerase activity in vitro. Further live virus assay revealed that both Caspofungin Acetate and LTX-315 can effectively inhibit SARS-CoV-2 replication in vero cells. These findings present promising drug candidates for treatment of related diseases and would also stimulate the development of pan- coronavirus antiviral agents.Authors Min Wang, Fei Ye, Jiaqi Su, Jingru Zhao, and Bin Yuan contributed equally to this work.

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ADMET Prediction and In silico Analysis of Mangostin Derivatives and Sinensetin on Maltase-Glucoamylase Target for Searching Anti-Diabetes Drug Candidates

Pharmacognosy Journal ◽

10.5530/pj.2021.13.113 ◽

2021 ◽

Vol 13 (4) ◽

pp. 883-889

Author(s):

Intan Kris Prasetyanti ◽

Sukardiman Sukardiman ◽

Suharjono Suharjono

Keyword(s):

In Silico ◽

In Silico Analysis ◽

Drug Candidates ◽

Diabetes Drug ◽

Silico Analysis

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In vitro evaluation and molecular dynamics, DFT guided investigation of antimalarial activity of ethnomedicinally used Coptis teeta Wall

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210118095503 ◽

2021 ◽

Vol 24 ◽

Author(s):

Ashis Kumar Goswami ◽

Hemanta Kumar Sharma ◽

Neelutpal Gogoi ◽

Ankita Kashyap ◽

Bhaskar Jyoti Gogoi

Keyword(s):

Molecular Dynamics ◽

In Silico ◽

Density Functional ◽

Antimalarial Activity ◽

In Silico Analysis ◽

Dynamics Simulation ◽

Discovery Studio ◽

North East ◽

Silico Analysis

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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In Silico Analysis of the Subtype Selective Blockage of KCNA Ion Channels through the µ-Conotoxins PIIIA, SIIIA, and GIIIA

Marine Drugs ◽

10.3390/md17030180 ◽

2019 ◽

Vol 17 (3) ◽

pp. 180 ◽

Cited By ~ 4

Author(s):

Desirée Kaufmann ◽

Alesia Tietze ◽

Daniel Tietze

Keyword(s):

In Silico Analysis ◽

Binding Mode ◽

Dynamic Simulations ◽

Drug Candidates ◽

Toxin Binding ◽

Subtype Specificity ◽

Pore Blockage ◽

Natural Peptide ◽

Dynamics Simulations ◽

Subtype Selective

Understanding subtype specific ion channel pore blockage by natural peptide-based toxins is crucial for developing such compounds into promising drug candidates. Herein, docking and molecular dynamics simulations were employed in order to understand the dynamics and binding states of the µ-conotoxins, PIIIA, SIIIA, and GIIIA, at the voltage-gated potassium channels of the KV1 family, and they were correlated with their experimental activities recently reported by Leipold et al. Their different activities can only adequately be understood when dynamic information about the toxin-channel systems is available. For all of the channel-bound toxins investigated herein, a certain conformational flexibility was observed during the molecular dynamic simulations, which corresponds to their bioactivity. Our data suggest a similar binding mode of µ-PIIIA at KV1.6 and KV1.1, in which a plethora of hydrogen bonds are formed by the Arg and Lys residues within the α-helical core region of µ-PIIIA, with the central pore residues of the channel. Furthermore, the contribution of the K+ channel’s outer and inner pore loops with respect to the toxin binding. and how the subtype specificity is induced, were proposed.

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Antiplasmodial and Cytotoxic Cytochalasins from an Endophytic Fungus, Nemania sp. UM10M, Isolated from a Diseased Torreya taxifolia Leaf

Molecules ◽

10.3390/molecules24040777 ◽

2019 ◽

Vol 24 (4) ◽

pp. 777 ◽

Cited By ~ 7

Author(s):

Mallika Kumarihamy ◽

Daneel Ferreira ◽

Edward Croom ◽

Rajnish Sahu ◽

Babu Tekwani ◽

...

Keyword(s):

Mouse Model ◽

Solid Tumor ◽

Endophytic Fungus ◽

Antimalarial Activity ◽

Vero Cells ◽

Antiplasmodial Activity ◽

Etoac Extract ◽

Bioassay Guided Fractionation

Bioassay-guided fractionation of an EtOAc extract of the broth of the endophytic fungus Nemania sp. UM10M (Xylariaceae) isolated from a diseased Torreya taxifolia leaf afforded three known cytochalasins, 19,20-epoxycytochalasins C (1) and D (2), and 18-deoxy-19,20-epoxy-cytochalasin C (3). All three compounds showed potent in vitro antiplasmodial activity and phytotoxicity with no cytotoxicity to Vero cells. These compounds exhibited moderate to weak cytotoxicity to some of the cell lines of a panel of solid tumor (SK-MEL, KB, BT-549, and SK-OV-3) and kidney epithelial cells (LLC-PK11). Evaluation of in vivo antimalarial activity of 19,20-epoxycytochalasin C (1) in a mouse model at 100 mg/kg dose showed that this compound had weak suppressive antiplasmodial activity and was toxic to animals.

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Cheminformatics techniques in antimalarial drug discovery and development from natural products 1: basic concepts

Physical Sciences Reviews ◽

10.1515/psr-2018-0130 ◽

2019 ◽

Vol 4 (7) ◽

Author(s):

Samuel Egieyeh ◽

Sarel F. Malan ◽

Alan Christoffels

Keyword(s):

Natural Products ◽

Drug Development ◽

Antimalarial Drug ◽

Drug Discovery And Development ◽

Drug Candidates ◽

Structure Activity ◽

Preclinical And Clinical Studies ◽

Research Cost

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, limited manpower, high research cost coupled with high failure rate during preclinical and clinical studies might militate against the pursuit of this mission. These limitations may be overcome with cheminformatic techniques. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of cheminformatics techniques (including molecular diversity analysis, quantitative-structure activity/property relationships and Machine learning) to natural products with in vitro and in vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

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