Synthesis and Activity of Some Antimalarial Bisquinolinemethanols

1997 ◽  
Vol 50 (11) ◽  
pp. 1091 ◽  
Author(s):  
Alan F. Cowman, ◽  
Leslie W. Deady, ◽  
Eric Deharo, ◽  
José Desneves ◽  
Leann Tilley
Keyword(s):  
Plasmodium Falciparum ◽  
Resistant Strain ◽  
Cinchona Alkaloids ◽  
Cross Resistance ◽  
Side Chain ◽  
Highly Active ◽  
New Type ◽  
Resistant Strains ◽  
Further Development

A new type of bisquinoline antimalarial, containing the basic side chain of the cinchona alkaloids, has been evaluated. Five bis ethers, from 10,11-dihydrocupreine linked through the 6′-hydroxy group by -(CH2)2n- bridges (n = 2-5) (series A), and six bis amides, from 8′-amino-10,11-dihydrocinchonidine linked by -CO(CH2)2nCO- bridges (n = 1-6) (series B), were synthesized and screened against chloroquine-sensitive and -resistant strains and a mefloquine-resistant strain of Plasmodium falciparum in vitro. Two analogues of series B (n= 4; 5), with a 2-(dibutylamino)-1-hydroxyethyl side chain (series C), were also included. Compounds within series A were generally least active. Among the rest were compounds as active as mefloquine, with diminished cross-resistance to the mefloquine-resistant strain. The most potent (series B, n = 4) was highly active against chloroquine-sensitive, chloroquine-resistant and mefloquine-resistant parasites. Invivo testing, however, showed the compound to be too toxic for further development

In Vitro Activities of StrychnosAlkaloids and Extracts against Plasmodium falciparum

1999 ◽  
Vol 43 (9) ◽  
pp. 2328-2331 ◽  
Author(s):  
Michel Frederich ◽  
Marie-Pierre Hayette ◽  
Monique Tits ◽  
Patrick De Mol ◽  
Luc Angenot
Keyword(s):  
Plasmodium Falciparum ◽  
Resistant Strain ◽  
Inhibitory Concentration ◽  
Sensitive Strain ◽  
Resistant Strains

ABSTRACT The in vitro antimalarial activities of 46 alkaloids and extracts from Strychnos species were evaluated. Two types of quasidimeric alkaloids exhibit high and selective activities againstPlasmodium. Strychnopentamine and isostrychnopentamine were active against chloroquine-sensitive and -resistant strains (50% inhibitory concentration [IC50] ≈ 0.15 μM), while dihydrousambarensine exhibited a 30-fold higher activity against the chloroquine-resistant strain (IC50 = 0.03 μM) than it did against the chloroquine-sensitive strain.

scholarly journals 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum.

1996 ◽  
Vol 40 (8) ◽  
pp. 1846-1854 ◽  
Author(s):  
R G Ridley ◽  
W Hofheinz ◽  
H Matile ◽  
C Jaquet ◽  
A Dorn ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Falciparum Malaria ◽  
Cross Resistance ◽  
In Vivo Model ◽  
Pharmacokinetic Analysis ◽  
European Patent ◽  
Side Chains ◽  
Resistant Strains

We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

scholarly journals In Vitro Activities of Piperaquine and Other 4-Aminoquinolines against Clinical Isolates of Plasmodium falciparum in Cameroon

2003 ◽  
Vol 47 (4) ◽  
pp. 1391-1394 ◽  
Author(s):  
Leonardo K. Basco ◽  
Pascal Ringwald
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Geometric Mean ◽  
Central Africa ◽  
New Drugs ◽  
Clinical Isolates ◽  
Highly Active ◽  
Synthetic Drug ◽  
Further Development

ABSTRACT The spread of chloroquine-resistant Plasmodium falciparum calls for a constant search for new drugs. The in vitro activity of piperaquine, a new Chinese synthetic drug belonging to the bisquinolines, was evaluated in 103 fresh clinical isolates of P. falciparum in Cameroon, Central Africa, and compared with that of other 4-aminoquinoline and Mannich base derivatives and dihydroartemisinin. Piperaquine was highly active (geometric mean 50% inhibitory concentration, 38.9 nmol/liter; range, 7.76 to 78.3 nmol/liter) and equally active (P > 0.05) against the chloroquine-sensitive and the chloroquine-resistant isolates. There was a significant but low correlation of response between chloroquine and piperaquine (r = 0.257, P < 0.05). These results suggest that further development of piperaquine, in combination with dihydroartemisinin, holds promise for use in chloroquine-resistant regions of endemicity.

scholarly journals Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum

2004 ◽  
Vol 48 (11) ◽  
pp. 4097-4102 ◽  
Author(s):  
Quinton L. Fivelman ◽  
Ipemida S. Adagu ◽  
David C. Warhurst
Keyword(s):  
Plasmodium Falciparum ◽  
Treatment Failure ◽  
Resistant Strain ◽  
Fixed Ratio ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
In Vitro Interactions

ABSTRACT A modified fixed-ratio isobologram method for studying the in vitro interactions between antiplasmodial drugs is described. This method was used to examine the interactions between atovaquone, proguanil, and dihydroartemisinin. The interaction between atovaquone and proguanil was synergistic against atovaquone-sensitive strains K1 and T996; however, there was a loss of synergy against atovaquone-resistant strain NGATV01 isolated after Malarone (the combination of atovaquone and proguanil) treatment failure. While the interaction between atovaquone and dihydroartemisinin was indifferent against isolate NGATV01, the interaction displayed indifference tending toward antagonism against the atovaquone-sensitive strains tested. The relevance of in vitro interactions to in vivo treatment is discussed.

scholarly journals Metallocene Antimalarials: The Continuing Quest

2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Margaret A. L. Blackie ◽  
Kelly Chibale
Keyword(s):  
Plasmodium Falciparum ◽  
Antiplasmodial Activity ◽  
Side Chain ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Resistant Strains ◽  
Antimalarial Compounds

Over the last decade, a significant body of research has been developed around the inclusion of a metallocene moiety into known antimalarial compounds. Ferroquine is the most successful of these compounds. Herein, we describe our contribution to metallocene antimalarials. Our approach has sought to introduce diversity sites in the side chain of ferroquine in order to develop a series of ferroquine derivatives. The replacement of the ferrocenyl moiety with ruthenocene has given rise to ruthenoquine and a modest series of analogues. The reaction of ferroquine and selected analogues with Au(PPh3)NO3, Au(C6F5)(tht), and [Rh(COD)Cl2] has resulted in a series of heterobimetallic derivatives. In all cases, compounds have been evaluated for in vitro antiplasmodial activity in both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Preliminary structure-activity relationships have been delineated.

scholarly journals In Vitro Activity of Ferroquine Is Independent of Polymorphisms in Transport Protein Genes Implicated in Quinoline Resistance in Plasmodium falciparum

2008 ◽  
Vol 52 (8) ◽  
pp. 2755-2759 ◽  
Author(s):  
Maud Henry ◽  
Sébastien Briolant ◽  
Albin Fontaine ◽  
Joel Mosnier ◽  
Eric Baret ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Transport Proteins ◽  
Vitro Activity ◽  
Cross Resistance ◽  
In Vitro Activity ◽  
Highly Active ◽  
In Vitro Response

ABSTRACT The in vitro activity of ferroquine (FQ) (SR97193), a 4-aminoquinoline antimalarial compound that contains a ferrocenic nucleus, against 15 Plasmodium falciparum strains was assessed and compared with those of chloroquine (CQ), quinine (QN), monodesethylamodiaquine (MDAQ), and mefloquine (MQ). These 15 strains were genotyped for polymorphisms in quinoline resistance-associated genes such as Pfcrt, Pfmdr1, Pfmrp, and Pfnhe-1. FQ was highly active against CQ-resistant parasites or in parasites with reduced susceptibility to QN, MDAQ, or MQ. Encouragingly, we did not find a correlation between responses to FQ and those to other quinoline drugs. These results suggest that no cross-resistance exits between FQ and CQ or quinoline antimalarial drugs. Mutations in codons 74, 75, 76, 220, 271, 326, 356, and 371 of the Pfcrt gene; codons 86, 184, 1034, 1042, and 1246 of the Pfmdr1 gene; and codons 191 and 437 of the Pfmrp gene were not significantly associated with P. falciparum susceptibility to FQ. Neither the number of ms4760 DNNND or DDNHNDNHNN repeats in Pfnhe-1 nor the profile of ms4760 was significantly associated with the FQ in vitro response. These data suggest the FQ may not interact with transport proteins in quinoline-resistant parasites. The present results justify further clinical trials of FQ in multidrug resistance areas.

scholarly journals Diversity-oriented synthesis derived indole based spiro and fused small molecules kills artemisinin-resistant Plasmodium falciparum

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Akshaykumar Nayak ◽  
Himani Saxena ◽  
Chandramohan Bathula ◽  
Tarkeshwar Kumar ◽  
Souvik Bhattacharjee ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Small Molecules ◽  
New Drugs ◽  
Developmental Cycle ◽  
Oxygen Species ◽  
Compound Library ◽  
Diversity Oriented Synthesis ◽  
Resistant Strains ◽  
Acid Catalyzed

Abstract Background Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. Methods The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.e., 1-aryltetrahydro/dihydro-β-carbolines and piperidine/pyrrolidine-fused indole derivatives, for their in vitro anti-plasmodial activity. Trifluoroacetic acid catalyzed transformation involving tryptamine and various aldehydes/ketones provided the library. Results Among all the compounds screened, 1-aryltetrahydro-β-carbolines 2 and 3 displayed significant anti-plasmodial activity against both the artemisinin-sensitive and artemisinin-resistant strain of Plasmodium falciparum. It was observed that these compounds inhibited the overall parasite growth in intra-erythrocytic developmental cycle (IDC) via reactive oxygen species-mediated parasitic death and thus could be potential anti-malarial compounds. Conclusion Overall the compounds 2 and 3 identified in this study shows promising anti-plasmodial activity that can kill both artemisinin-sensitive and artemisinin-resistant strains of P. falciparum.

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 1360. Antimicrobial Activity of Cefepime in Combination with VNRX-5133 Against a Global Collection of Enterobacteriaceae Including Resistant Phenotypes

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S416-S417 ◽  
Author(s):  
Meredith Hackel ◽  
Dan Sahm
Keyword(s):  
Vitro Activity ◽  
In Vitro Activity ◽  
First Line ◽  
First Line Therapy ◽  
Carbapenem Resistant ◽  
Line Therapy ◽  
Resistant Strains ◽  
Further Development ◽  
Dose Dependent

Abstract Background VNRX-5133 is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C, and D). In this analysis, we evaluated the activity of cefepime (FEP) in combination with VNRX-5133 and comparators against 1,120 recent Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Methods MICs of FEP with VNRX-5133 fixed at 4 µg/mL (FEP/VNRX-5133) were determined following CLSI M07-A10 guidelines against 1,120 Enterobacteriaceae from community and hospital infections collected globally in 2012–2013. Resistant phenotypes were based on 2017 CLSI breakpoints. As FEP/VNRX-5133 breakpoints have not yet been established, the FEP 2 g q8h susceptible dose-dependent (SDD) breakpoint of ≤8 µg/mL was considered for comparative purposes. Results FEP/VNRX-5133 showed potent in vitro activity against drug-resistant subsets of Enterobacteriaceae, with MIC90 values ranging from 1 µg/mL against ceftazidime-, levofloxacin-, or piperacillin–tazobactam-nonsusceptible isolates, to 8 µg/mL against meropenem-nonsusceptible isolates. FEP/VNRX-5133 inhibited &gt;93% of all resistant subsets at ≤8 µg/mL. Conclusion Cefepime in combination with VNRX-5133 demonstrated potent in vitro activity against Enterobacteriaceae, including cephalosporin-, fluoroquinolone- and carbapenem-resistant (CRE) isolates. Because this drug combination exhibited substantial potential for the treatment of infections caused by isolates often resistant to first-line therapy, further development is warranted. Disclosures M. Hackel, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee. D. Sahm, IHMA, Inc.: Employee, Salary. VenatoRx: Consultant, Consulting fee.

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