scholarly journals Spirofused tetrahydroisoquinoline-oxindole hybrids as a novel class of fast acting antimalarial agents with multiple modes of action

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Noella M. Efange ◽  
Maloba M. M. Lobe ◽  
Rodrigue Keumoe ◽  
Lawrence Ayong ◽  
Simon M. N. Efange
Keyword(s):  
Multidrug Resistant ◽  
Antiplasmodial Activity ◽  
Multiple Modes ◽  
Antimalarial Agents ◽  
Modes Of Action ◽  
Lipid Dynamics ◽  
Current Series ◽  
Hemoglobin Degradation ◽  
Fast Acting

Abstract Molecular hybridization of privileged scaffolds may generate novel antiplasmodial chemotypes that display superior biological activity and delay drug resistance. In the present study, we describe the in vitro activities and mode of action of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones, a novel class of spirofused tetrahydroisoquinoline–oxindole hybrids, as novel antimalarial agents. Whole cell phenotypic screening of these compounds identified (14b), subsequently named (±)-moxiquindole, as the most potent compound in the current series with equipotent antiplasmodial activity against both chloroquine sensitive and multidrug resistant parasite strains with good selectivity. The compound was active against all asexual stages of the parasite including inhibition of merozoite egress. Additionally, (±)-moxiquindole exhibited significant inhibitory effects on hemoglobin degradation, and disrupted vacuolar lipid dynamics. Taken together, our data confirm the antiplasmodial activity of (±)-moxiquindole, and identify 3′4′-dihydro-2′H-spiro[indoline-3,1′-isoquinolin]-2-ones as a novel class of antimalarial agents with multiple modes of action.

scholarly journals Boromycin has Rapid-Onset Antibiotic Activity Against Asexual and Sexual Blood Stages of Plasmodium falciparum

2022 ◽  
Vol 11 ◽  
Author(s):  
Laís Pessanha de Carvalho ◽  
Sara Groeger-Otero ◽  
Andrea Kreidenweiss ◽  
Peter G. Kremsner ◽  
Benjamin Mordmüller ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Knowlesi ◽  
Rapid Onset ◽  
Multidrug Resistant ◽  
Antiplasmodial Activity ◽  
Onset Of Action ◽  
Streptomyces Antibioticus ◽  
Life Cycle Stages ◽  
Almost All

Boromycin is a boron-containing macrolide antibiotic produced by Streptomyces antibioticus with potent activity against certain viruses, Gram-positive bacteria and protozoan parasites. Most antimalarial antibiotics affect plasmodial organelles of prokaryotic origin and have a relatively slow onset of action. They are used for malaria prophylaxis and for the treatment of malaria when combined to a fast-acting drug. Despite the success of artemisinin combination therapies, the current gold standard treatment, new alternatives are constantly needed due to the ability of malaria parasites to become resistant to almost all drugs that are in heavy clinical use. In vitro antiplasmodial activity screens of tetracyclines (omadacycline, sarecycline, methacycline, demeclocycline, lymecycline, meclocycline), macrolides (oleandomycin, boromycin, josamycin, troleandomycin), and control drugs (chloroquine, clindamycin, doxycycline, minocycline, eravacycline) revealed boromycin as highly potent against Plasmodium falciparum and the zoonotic Plasmodium knowlesi. In contrast to tetracyclines, boromycin rapidly killed asexual stages of both Plasmodium species already at low concentrations (~ 1 nM) including multidrug resistant P. falciparum strains (Dd2, K1, 7G8). In addition, boromycin was active against P. falciparum stage V gametocytes at a low nanomolar range (IC50: 8.5 ± 3.6 nM). Assessment of the mode of action excluded the apicoplast as the main target. Although there was an ionophoric activity on potassium channels, the effect was too low to explain the drug´s antiplasmodial activity. Boromycin is a promising antimalarial candidate with activity against multiple life cycle stages of the parasite.

scholarly journals In vitro evaluation of verapamil and other modulating agents in Brazilian chloroquine-resistant Plasmodium falciparum isolates

2003 ◽  
Vol 36 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Carla M.S. Menezes ◽  
Karin Kirchgatter ◽  
Sílvia M. Di Santi ◽  
Carine Savalli ◽  
Fabíola G. Monteiro ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antipsychotic Drug ◽  
Antimalarial Drug ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Antiplasmodial Activity ◽  
Experimental Conditions ◽  
In Vitro Evaluation ◽  
Cardiovascular Therapy

Verapamil, was assayed to record its modulating effect upon Brazilian Plasmodium falciparum isolates resistant to chloroquine. Other cardiovascular drugs known to be modulating agents in resistant malaria and/or multidrug-resistant neoplasias, including nifedipine, nitrendipine, diltiazem and propranolol, were also evaluated. Concentrations similar to those for cardiovascular therapy were used in the in vitro microtechnique for antimalarial drug susceptibility. Intrinsic antiplasmodial activity was observed from the lowest concentrations without a significant modulating action. Other reported modulating agents, such as the antipsychotic drug trifluoperazine and the antidepressants desipramine and imipramine, demonstrated similar responses under the same experimental conditions. Results suggest a much higher susceptibility of Brazilian strains, as well as an indifferent behaviour in relation to modulating agents.

scholarly journals Cytotoxic and Antimalarial Alkaloids from the Twigs of Dasymaschalon obtusipetalum

2015 ◽  
Vol 10 (7) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Atchara Jaidee ◽  
Thanika Promchai ◽  
Kongkiat Trisuwan ◽  
Surat Laphookhieo ◽  
Roonglawan Rattanajak ◽  
...  
Keyword(s):  
Resistant Strain ◽  
Multidrug Resistant ◽  
Acetone Extract ◽  
Antiplasmodial Activity ◽  
Spectroscopic Methods ◽  
Aporphine Alkaloid ◽  
Multidrug Resistant Strain

One new p-quinonoid aporphine alkaloid, obtusipetadione (1), and eleven known compounds (2–12) were isolated from the acetone extract of the twigs of Dasymaschalon obtusipetalum. Their structures were elucidated by spectroscopic methods. The cytotoxic and antimalarial activities of the isolated compounds were evaluated. Compound 1 showed significant in vitro antiplasmodial activity against the P. falciparum strains TM4 and K1 (multidrug resistant strain) with IC50 values of 2.46±0.12 and 1.38±0.99 μg/mL, respectively with no cytotoxicity. Compound 9 had more modest antiplasmodial activity, but significant cytotoxicity.

scholarly journals Crude Ethanolic Stem Bark Extract of Zanthoxylum zanthoxyloides and Its Fractions: In-Vitro and In-Vivo Antiplasmodial Activity

2021 ◽  
pp. 4153-4163
Author(s):  
Sulaiman S. Rukayyah ◽  
Jigam, Audu Ali ◽  
Abubakar Abdulkadir ◽  
Salau, Rasaq Bolakale
Keyword(s):  
Crude Extract ◽  
Stem Bark ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Antiplasmodial Activity ◽  
Bark Extract ◽  
Zanthoxylum Zanthoxyloides ◽  
Stem Bark Extract

Malaria is a global problem, as treatment failure has hampered the efficacy of most anti-malarial medications. The goal of this study was to see if stem bark extract from Zanthoxylum zanthoxyloides had antiplasmodial properties that could be used to treat both susceptible and resistant parasites. The stem bark of Z. zanthoxyloides (500g) was crushed and extracted with ethanol. The extract was tested for antiplasmodial activity in vitro against the chloroquine-sensitive (CQS) strain NF54 and chloroquine-resistant strains (CQR) K1 of P. falciparum, as well as in vivo against the CQS(NK65) strain of P. berghei at 100, 200, and 400 mg/kg bw. Bioassay-guided fractionation of the extract was performed. The crude extract had an in vitro activity of 1076.4 56.4 and 1315.1 121.6 ng/ml against chloroquine sensitive and resistant parasites, respectively while standard drugs (chloroquine and artesunate) were 10.94 nM (3478.92 ng/ml) and 9.24 nM (3215.52ng/ml) for CQS and 310.68 nM (98796 ng/ml) and 10.94 nM (3650.52 ng/ml) for CQR respectively. At Day 7, mice treated with 100, 200, and 400 mg/kg bw crude extract had parasite densities of 1159, 928, and 869 parasites/ µl, respectively (compared to positive control that had 123 parasites /µl). In vitro antiplasmodial activity was best in the K2, K4, and K6 fractions (IC50 were 6670, 6890, and 6480 ng/ml), but in vivo antiplasmodial activity was best in the K4 fraction (1183 parasites/ µl).The stem bark extract of Z. zanthoxyloides have remarkable antiplasmodial activity against both chloroquine sensitive and drug resistant P. falciparum supporting it ethnomedicinal use in malaria treatment.The extract of Z. zanthoxyloides has promising antiplasmodial activity and could be used to generate therapeutic leads against the multidrug-resistant K1 strain of P. falciparum, in addition to providing an alternative allopathic antiplasmodial medication.

scholarly journals Antiplasmodial activity of Anthocleista djalonensis leaves extracts against clinical isolates of Plasmodium falciparum and multidrug resistant K1 strains

2020 ◽  
Vol 8 (3) ◽  
pp. 130-138
Author(s):  
Brice Kouakou Bla ◽  
Oléfongo Dagnogo ◽  
Rolland Gueyraud Kipré ◽  
Opportune Gogo Ballé ◽  
Jonhson David Trébissou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistant ◽  
Traditional Healers ◽  
Antiplasmodial Activity ◽  
Clinical Isolates ◽  
Aqueous Extracts ◽  
Phytochemical Screening ◽  
Primary Health ◽  
Ethanolic Extracts

Information collected from nine (09) traditional healers in the Moronou village in the Department of Toumodi revealed that Anthocleista djanlonensis is regularly used by the population for primary health care in the processing of malaria. Evaluation of the In vitro antiplasmodial activity showed that the aqueous extracts inhibit growth of clinical isolates and chloroquinoresistant strains (K1) with IC50 of 8.29 µg/mL and 10.23 µg/mL while the ethanolic extracts had IC50 of 37.65 µg/mL and 46.07 µg/mL on the same strains respectively. Results of the In vitro antimalarial bioassay showed that aqueous extracts have promising antiplasmodial effects on clinical isolates and on Plasmodium falciparum multidrug resistant K1 strain (3 µg/mL <IC50 <15 µg/mL). Phytochemical screening revealed that the extracts contain mainly alkaloids, polyphenols, polyterpenes and flavonoids

scholarly journals The pfmdr1 Gene Is Associated with a Multidrug-Resistant Phenotype in Plasmodium falciparumfrom the Western Border of Thailand

1999 ◽  
Vol 43 (12) ◽  
pp. 2943-2949 ◽  
Author(s):  
R. N. Price ◽  
C. Cassar ◽  
A. Brockman ◽  
M. Duraisingh ◽  
M. van Vugt ◽  
...  
Keyword(s):  
Copy Number ◽  
Multidrug Resistant ◽  
Antimalarial Agents ◽  
Resistant Phenotype ◽  
Western Border ◽  
Almost All ◽  
Parasite Populations ◽  
Relationship Of ◽  
The Relationship

ABSTRACT On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship ofpfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC50) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increasedpfmdr1 copy number was associated with higher IC50s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.

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 Assessment of Azithromycin in Combination with Other Antimalarial Drugs against Plasmodium falciparum In Vitro

2002 ◽  
Vol 46 (8) ◽  
pp. 2518-2524 ◽  
Author(s):  
Colin Ohrt ◽  
George D. Willingmyre ◽  
Patricia Lee ◽  
Charles Knirsch ◽  
Wilbur Milhous
Keyword(s):  
Plasmodium Falciparum ◽  
Single Agent ◽  
In Vitro Study ◽  
Field Trials ◽  
Multidrug Resistant ◽  
Malaria Treatment ◽  
Malaria Prophylaxis ◽  
Initial Field ◽  
Antimalarial Agents

ABSTRACT Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC50s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC50s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

scholarly journals SYNTHESIS AND ANTIPLASMODIAL ACTIVITY TESTING OF (1)-N-ALKYL- AND (1)-N-BENZYL-6-NITRO-1,10-PHENANTHROLINIUM SALTS AS NEW POTENTIAL ANTIMALARIAL AGENTS

2012 ◽  
Vol 12 (2) ◽  
pp. 152-162 ◽  
Author(s):  
Ruslin Hadanu ◽  
Sabirin Mastjeh ◽  
Jumina Jumina ◽  
Mustofa Mustofa ◽  
Eti Nurwening Sholikhah ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Benzyl Chloride ◽  
Dimethyl Sulphate ◽  
Starting Material ◽  
Antiplasmodial Activity ◽  
Antimalarial Agents ◽  
Inhibition Concentration ◽  
Phenanthroline Monohydrate

The synthesis of 5-nitro-1,10-phenanthroline hydrate 2 derivatives from 1,10-phenanthroline monohydrate as starting material has been carried out. The 5-nitro-1,10-phenanthroline hydrate 2 was obtained through nitration reaction using H2SO4 and HNO3 as catalyst and reagent, respectively. Synthesis of (1)-N-alkyl-6-nitro- and (1)-N-benzyl-6-nitro-1,10-phenanthrolinium have been prepared using dimethyl sulphate (DMS), diethyl sulphate (DES), benzyl chloride, benzyl bromine, and benzyl iodide. The reagents of benzyl bromine, and benzyl iodide were synthesized from benzyl chloride using NaBr in ethanol absolute and NaI in acetone, respectively. The five compounds of 5-nitro-1,10-phenanthroline hydrate 2 derivatives were conducted to evaluate the in vitro antiplasmodial activity. The in vitro antiplasmodial was evaluated on strains of Plasmodium falciparum FCR-3 resistant chloroquine and D10 sensitive chloroquine. The 50% inhibition concentration (IC50) of the five compounds ranged from 2.41±1.41 to 0.07±0.01 μM. The results showed that the (1)-N-benzyl-6-nitro-1,10-phenanthrolinium iodide had highest antiplasmodial activity.

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