scholarly journals A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4485
Author(s):  
Veronika R. Karpina ◽  
Svitlana S. Kovalenko ◽  
Sergiy M. Kovalenko ◽  
Oleksandr G. Drushlyak ◽  
Natalya D. Bunyatyan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Virtual Library ◽  
Antimalarial Agents ◽  
Starting Point ◽  
In Silico Studies

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 μM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

scholarly journals Optimization of Xanthones for Antimalarial Activity: the 3,6-Bis-ω-Diethylaminoalkoxyxanthone Series

2002 ◽  
Vol 46 (1) ◽  
pp. 144-150 ◽  
Author(s):  
Jane Xu Kelly ◽  
Rolf Winter ◽  
David H. Peyton ◽  
David J. Hinrichs ◽  
Michael Riscoe
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Multidrug Resistant ◽  
Food Vacuole ◽  
Ionic Interactions ◽  
Side Chains ◽  
Antimalarial Agents ◽  
Unique Manner

ABSTRACT Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-ω-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R 2 = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC50) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 × 105 and 9.02 × 105 M−1, respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.

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 Anti-tick effect and cholinesterase inhibition caused by Prosopis juliflora alkaloids: in vitro and in silico studies

2020 ◽  
Vol 29 (2) ◽  
Author(s):  
Hélimar Gonçalves de Lima ◽  
Francianne Oliveira Santos ◽  
Acidália Carine Vieira Santos ◽  
Gisele Dias da Silva ◽  
Rafaela Jesus dos Santos ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Inhibitory Concentration ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Prosopis Juliflora ◽  
Cholinesterase Inhibition ◽  
In Silico Studies ◽  
Pi Interactions

Abstract We investigated the in vitro acaricide activity of the methanolic extract (ME) and alkaloid-rich fraction (AF) of Prosopis juliflora on Rhipicephalus microplus and correlated this effect with acetylcholinesterase (AChE) inhibition. The acaricide activity was evaluated using adult and larval immersion tests. Also, we studied the possible interaction mechanism of the major alkaloids present in this fraction via molecular docking at the active site of R. microplus AChE1 (RmAChE1). Higher reproductive inhibitory activity of the AF was recorded, with effective concentration (EC50) four times lower than that of the ME (31.6 versus 121 mg/mL). The AF caused mortality of tick larvae, with lethal concentration 50% (LC50) of 13.8 mg/mL. Both ME and AF were seen to have anticholinesterase activity on AChE of R. microplus larvae, while AF was more active with half-maximal inhibitory concentration (IC50) of 0.041 mg/mL. The LC-MS/MS analyses on the AF led to identification of three alkaloids: prosopine (1), juliprosinine (2) and juliprosopine (3). The molecular docking studies revealed that these alkaloids had interactions at the active site of the RmAChE1, mainly relating to hydrogen bonds and cation-pi interactions. We concluded that the alkaloids of P. juliflora showed acaricide activity on R. microplus and acted through an anticholinesterase mechanism.

scholarly journals Aktivitas Antimalaria Daun Erythrina variegata

2018 ◽  
Vol 10 (1) ◽  
pp. 36
Author(s):  
Tati Herlina ◽  
Unang Supratman ◽  
Anas Subarnas ◽  
Supriyatna Sutardjo ◽  
Noor Rain Abdullah
Keyword(s):  
Plasmodium Falciparum ◽  
Lactate Dehydrogenase ◽  
Column Chromatography ◽  
Active Compound ◽  
Resistant Strain ◽  
Methanol Extract ◽  
Antimalarial Activity ◽  
Antimalarial Agents ◽  
Erythrina Variegata

The leaves of Erythrina variegata (Leguminosae) used tradisional plant of an antimalarial. In the course of our continuing search for novel an antimalarial compound from Erythrina plants, the methanol extract of the leaves ofE. variegata showed significant antimalarial activity in vitro toward Plasmodium falciparum in vitro using the lactate dehydrogenase (LDH) method. The methanol extract of the leaves of E. variegata showed against bothstrains of parasite with IC50of 6.8 ?g/ml against K1 and > 60 ?g/ml against 3D7, respectively. The methanol extract of the leaves of E. variegata was separated by using bioassay-guide fractionation. The n-buthanol fraction yieldedthe most activity, exhibiting equipotency against both strains of parasite with IC50of 5.1 ?g/ml against K1 and 13.5 ?g/ml against 3D7, respectively. Furthermore, by using the antimalarial activity to follow separation, the n-buthanol fraction was separated by combination of column chromatography to yield an active compound. The active compound showed antimalarial activity against both strains of parasite used with IC50 of 4.3 ?g/ml against K1 and 23.5 ?g/ml against 3D7, respectively. Its inhibition of the resistant strain (K1) was also much better compared to its inhibition of the sensitive strain (3D7), indicated that the leaves of E. variegata to be potential as antimalarial agents, but its lower potency compared to artemisinin and chloroquin.

scholarly journals Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes

2007 ◽  
Vol 51 (4) ◽  
pp. 1463-1472 ◽  
Author(s):  
Françoise Benoit-Vical ◽  
Joël Lelièvre ◽  
Antoine Berry ◽  
Caroline Deymier ◽  
Odile Dechy-Cabaret ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Mice Model ◽  
Additional Advantage ◽  
Antimalarial Agents ◽  
Hybrid Molecules ◽  
Resistant Strains ◽  
Antimalarial Chemotherapy

ABSTRACT Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.

scholarly journals Inhibition of Plasmodium falciparum Growth In Vitro and Adhesion to Chondroitin-4-Sulfate by the Heparan Sulfate Mimetic PI-88 and Other Sulfated Oligosaccharides

2006 ◽  
Vol 50 (8) ◽  
pp. 2850-2852 ◽  
Author(s):  
Yvonne Adams ◽  
Craig Freeman ◽  
Reinhard Schwartz-Albiez ◽  
Vito Ferro ◽  
Christopher R. Parish ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Surface ◽  
Heparan Sulfate ◽  
Phase Ii ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Placental Malaria ◽  
Sulfated Oligosaccharides ◽  
Adhesion Inhibition

ABSTRACT A panel of sulfated oligosaccharides was tested for antimalarial activity and inhibition of adhesion to the placental malaria receptor chondroitin-4-sulfate (CSA). The heparan sulfate mimetic PI-88, currently undergoing phase II anticancer trials, displayed the greatest in vitro antimalarial activity against Plasmodium falciparum (50% inhibitory concentration of 7.4 μM) and demonstrated modest adhesion inhibition to cell surface CSA.

scholarly journals In Vitro Activity of Lumefantrine (Benflumetol) against Clinical Isolates of Plasmodium falciparum in Yaoundé, Cameroon

1998 ◽  
Vol 42 (9) ◽  
pp. 2347-2351 ◽  
Author(s):  
Leonardo K. Basco ◽  
Jean Bickii ◽  
Pascal Ringwald
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Geometric Mean ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
In Vitro Activity ◽  
Antimalarial Agents ◽  
Fluorene Derivative

ABSTRACT The in vitro antimalarial activity of the new Chinese synthetic drug, lumefantrine, also known as benflumetol (a fluorene derivative belonging to the aminoalcohol class), was determined by an isotopic microtest against 61 fresh clinical isolates of Plasmodium falciparum and compared with that of other established antimalarial agents. The geometric mean 50% inhibitory concentration of lumefantrine was 11.9 nmol/liter (95% confidence intervals, 10.4 to 13.6 nmol/liter; range, 3.3 to 25.6 nmol/liter). The in vitro activities of lumefantrine against the chloroquine-sensitive and the chloroquine-resistant isolates did not differ (P > 0.05). There was a significant positive correlation of responses between lumefantrine and two other aminoalcohols studied, mefloquine (r = 0.688) and halofantrine (r = 0.677), and between lumefantrine and artesunate (r = 0.420), suggesting a potential for in vitro cross-resistance. Our data suggest high in vitro activity of lumefantrine, comparable to that of mefloquine, and are in agreement with the promising results of preliminary clinical trials.

scholarly journals Differential in vitro activities of ionophore compounds against Plasmodium falciparum and mammalian cells.

1996 ◽  
Vol 40 (3) ◽  
pp. 602-608 ◽  
Author(s):  
C Gumila ◽  
M L Ancelin ◽  
G Jeminet ◽  
A M Delort ◽  
G Miquel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Monovalent Cations ◽  
Macrophage Cell ◽  
Mammalian Cell Lines ◽  
Gramicidin D

Twenty-two ionophore compounds were screened for their antimalarial activities. They consisted of true ionophores (mobile carriers) and channel-forming quasi-ionophores with different ionic specificities. Eleven of the compounds were found to be extremely efficient inhibitors of Plasmodium falciparum growth in vitro, with 50% inhibitory concentrations of less than 10 ng/ml. Gramicidin D was the most active compound tested, with 50% inhibitory concentration of 0.035 ng/ml. Compounds with identical ionic specificities generally had similar levels of antimalarial activity, and ionophores specific to monovalent cations were the most active. Compounds were further tested to determine their in vitro toxicities against mammalian lymphoblast and macrophage cell lines. Nine of the 22 compounds, i.e., alborixin, lonomycin, nigericin, narasin, monensin and its methylated derivative, lasalocid and its bromo derivative, and gramicidin D, most specific to monovalent cations, were at least 35-fold more active in vitro against P. falciparum than against the two other mammalian cell lines. The enhanced ability to penetrate the erythrocyte membrane after infection could be a factor that determines ionophore selectivity for infected erythrocytes.

scholarly journals Phytochemical, Biological and Computational Investigations of Erythrina fusca Lour. to Assess Antimalarial Property against Plasmodium falciparum

2020 ◽  
Author(s):  
Saiful Arefeen Sazed ◽  
Ohedul Islam ◽  
Sarah L. Bliese ◽  
Muhammad Riadul Haque Hossainey ◽  
Mahfuza Afroz Soma ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Docking ◽  
Antimalarial Drug ◽  
Antimalarial Activity ◽  
Drug Candidate ◽  
Separation And Purification ◽  
Membrane Stabilization ◽  
Phytochemical Investigation ◽  
Biological Tests

For centuries medicinal plants have been traditionally used for prophylaxis and ailment of diseases. Nowadays it&rsquo;s easy to isolate, purify, and characterize bioactive compounds with high efficacy. To investigate the medicinal especially antimalarial property of traditionally used plants, a number of Erythrina spp have been reviewed systematically where Erythrina fusca has been selected for further analysis. Phytochemical investigation included chromatographic separation and purification of compounds followed by characterization using NMR. In-vitro antimalarial drug sensitivity ELISA was carried out against chloroquine (CQ) sensitive 3D7 and resistant Dd2 strains. Additional biological tests such as central and peripheral analgesic, antioxidant, anti-diarrheal, hypoglycemic, thrombolytic, and membrane stabilization activities were also investigated. Molecular docking was performed using the isolated compounds against clinically important 14 Plasmodium falciparum proteins. For the first time, Phaseolin, Phytol, &beta;-amyrin, Lupeol, and Stigmasterol are reported here and extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94-22 &micro;g/mL). Potent central analgesic, antioxidant and anti-diarrheal activities (p&amp;lt;0.05) and mild thrombolytic and membrane stabilization properties were also observed. Molecular docking of Phaseolin bolsters its potential as a new antimalarial drug candidate. This study projects significant medicinal values and necessitates further investigations to reveal its potential as a novel source of therapeutics.

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