scholarly journals Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives

2021 ◽  
Vol 14 (11) ◽  
pp. 1174
Author(s):  
Mohd Asyraf Shamsuddin ◽  
Amatul Hamizah Ali ◽  
Nur Hanis Zakaria ◽  
Mohd Fazli Mohammat ◽  
Ahmad Sazali Hamzah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Lactate Dehydrogenase ◽  
Mammalian Cells ◽  
Antimalarial Activity ◽  
Resistance Index ◽  
Selective Inhibition ◽  
Docking Analysis ◽  
Hybrid Molecules ◽  
Index Value

Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Haicheng Liu ◽  
Yushi Futamura ◽  
Honghai Wu ◽  
Aki Ishiyama ◽  
Taotao Zhang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimalarial Activity ◽  
In Vitro Assays ◽  
Compound Library ◽  
Antimalarial Agents ◽  
Phenotypic Screen ◽  
Ic50 Values ◽  
Substituted Benzamides

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3-cinnamamido-N-substituted benzamides. Method: In this study, a screening of our compound library was carried out against the multidrug-sensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, phenotypic screen of our compound library resulted in the first report of 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

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 Synthetic spirocyclic endoperoxides: new antimalarial scaffolds

MedChemComm ◽  
2015 ◽  
Vol 6 (2) ◽  
pp. 357-362 ◽  
Author(s):  
Margherita Brindisi ◽  
Sandra Gemma ◽  
Sanil Kunjir ◽  
Luisa Di Cerbo ◽  
Simone Brogi ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimalarial Activity ◽  
Design Synthesis ◽  
Docking Calculation

Design, synthesis and molecular docking calculation studies led to the identification of novel spirocyclic peroxides with in vitro and in vivo antimalarial activity.

scholarly journals Rationale design and synthesis of some novel imidazole linked thiazolidinone hybrid molecules as DNA minor groove binders

2020 ◽  
Vol 11 (2) ◽  
pp. 120-132
Author(s):  
Javeed Ahmad War ◽  
Santosh Kumar Srivastava
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Specific Binding ◽  
Minor Groove ◽  
Stable Complex ◽  
Binding Studies ◽  
In Vitro Susceptibility ◽  
Reference Drug ◽  
Hybrid Molecules

A new series of imidazole linked thiazolidinone hybrid molecules was designed and subsequently synthesized through a feasible, three step reaction protocol. The structures of these molecules were established using FT-IR, 1H NMR, 13C NMR and HRMS techniques. In vitro susceptibility tests against some Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa) exhibited broad spectrum potency of the molecules. The most potent molecule (S2A7) amongst the screened molecules, showed minimum inhibitory concentration (MIC) value not less than 2.0 µg/mL which was at par with the reference drug Streptomycin. Structure activity relationships revealed nitro and chloro groups being crucial for bioactivity when present at meta position of arylidene ring in 3-(3-(imidazol-1-yl)propyl)-5-(benzylidene)-2-(phenylimino)thiazolidin-4-one. Deoxyribonucleic acid (DNA)and bovine serum albumin (BSA) binding studies for S2A7 under simulated physiological pH were probed using UV-Visible, fluorescence quenching, gel electrophoresis and molecular docking techniques. These studies established that S2A7 has strong binding affinity towards DNA and binds at the minor groove of DNA with binding constant (Kb) of 0.1287×102 L/mol. Molecular docking simulations of S2A7 with DNA and BSA predicted binding affinity of -9.2 and -7.2 kcal/mol, respectively. Van der Waals forces and hydrogen bonding interactions were predicted as the main forces of interaction. With DNA, S2A7 exhibited specific binding affinity towards adenine-thiamine base pairs. The compound S2A7 forms a stable complex with BSA by binding at subdomain IIIA implying high bio-distribution of the compound.

scholarly journals In vitro and molecular docking analysis of chalconeimine derivatives with α-glucosidase

2020 ◽  
Vol 16 (11) ◽  
pp. 949-957
Author(s):  
R Asaithambi ◽  
Keyword(s):  
Antioxidant Activity ◽  
Molecular Docking ◽  
Docking Analysis ◽  
Molecular Docking Analysis

It is known that α-glucosidase is linked with the antioxidant activity. Therefore, it is of interest to document the in- vitro and molecular docking analysis of chalconeimine derivatives with α-glucosidase (PDB ID: 2ZEO) for further consideration.

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