scholarly journals New Acyl Derivatives of 3-Aminofurazanes and Their Antiplasmodial Activities

2021 ◽  
Vol 14 (5) ◽  
pp. 412
Author(s):  
Theresa Hermann ◽  
Patrick Hochegger ◽  
Johanna Dolensky ◽  
Werner Seebacher ◽  
Robert Saf ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antiplasmodial Activity ◽  
Log P ◽  
Substitution Pattern ◽  
Structure Activity ◽  
Different Strains ◽  
Derivatives Of ◽  
Acyl Derivatives ◽  
Multiresistant Strain

An N-acylated furazan-3-amine of a Medicines for Malaria Venture (MMV) project has shown activity against different strains of Plasmodium falciparum. Seventeen new derivatives were prepared and tested in vitro for their activities against blood stages of two strains of Plasmodium falciparum. Several structure–activity relationships were revealed. The activity strongly depended on the nature of the acyl moiety. Only benzamides showed promising activity. The substitution pattern of their phenyl ring affected the activity and the cytotoxicity of compounds. In addition, physicochemical parameters were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability) via a PAMPA. The N-(4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl)-3-(trifluoromethyl)benzamide possessed good physicochemical properties and showed high antiplasmodial activity against a chloroquine-sensitive strain (IC50(NF54) = 0.019 µM) and even higher antiplasmodial activity against a multiresistant strain (IC50(K1) = 0.007 µM). Compared to the MMV compound, the permeability and the activity against the multiresistant strain were improved.

scholarly journals Synthesis and Structure-Activity Relationships of New 2-Phenoxybenzamides with Antiplasmodial Activity

2021 ◽  
Vol 14 (11) ◽  
pp. 1109
Author(s):  
Theresa Hermann ◽  
Patrick Hochegger ◽  
Johanna Dolensky ◽  
Werner Seebacher ◽  
Eva-Maria Pferschy-Wenzig ◽  
...  
Keyword(s):  
Antiplasmodial Activity ◽  
Pharmacokinetic Parameters ◽  
Log P ◽  
Partial Structure ◽  
Substitution Pattern ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Multi Stage ◽  
Different Strains

The 2-phenoxybenzamide 1 from the Medicines for Malaria Venture Malaria Box Project has shown promising multi-stage activity against different strains of P. falciparum. It was successfully synthesized via a retrosynthetic approach. Subsequently, twenty-one new derivatives were prepared and tested for their in vitro activity against blood stages of the NF54 strain of P. falciparum. Several insights into structure-activity relationships were revealed. The antiplasmodial activity and cytotoxicity of compounds strongly depended on the substitution pattern of the anilino partial structure as well as on the size of substituents. The diaryl ether partial structure had further impacts on the activity. Additionally, several physicochemical and pharmacokinetic parameters were calculated (log P, log D7.4 and ligand efficiency) or determined experimentally (passive permeability and CYP3A4 inhibition). The tert-butyl-4-{4-[2-(4-fluorophenoxy)-3-(trifluoromethyl)benzamido]phenyl}piperazine-1-carboxylate possesses high antiplasmodial activity against P. falciparum NF54 (PfNF54 IC50 = 0.2690 µM) and very low cytotoxicity (L-6 cells IC50 = 124.0 µM) resulting in an excellent selectivity index of 460. Compared to the lead structure 1 the antiplasmodial activity was improved as well as the physicochemical and some pharmacokinetic parameters.

Synthesis, in Vitro Anti-Human Immunodeficiency Virus Structure—Activity Relationships and Biological Stability of 5′-O-Myristoyl Analogue Derivatives of 3′-Azido-2′,3′-Dideoxythymidine (AZT) as Potential Prodrugs

1998 ◽  
Vol 9 (4) ◽  
pp. 28-40 ◽  
Author(s):  
K Parang ◽  
LI Wiebe ◽  
EE Knaus
Keyword(s):  
Human Immunodeficiency Virus ◽  
Brain Homogenate ◽  
Rat Plasma ◽  
Log P ◽  
Porcine Liver ◽  
Liver Esterase ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Derivatives Of

5′- O-Myristoyl analogue derivatives of 3′-azido-2′,3′-dideoxythymidine (AZT), designed as potential double-barrelled prodrugs to AZT and the myristic acid analogues, were synthesized. Their ability to protect CEM cells against human immunodeficiency virus (HIV)-induced cytopathogenicity was determined and structure–activity paradigms were developed. 3′-Azido-2′,3′-dideoxy-5′- O-(4-oxate-tradecanoyl)thymidine (EC50=1.4 nM) and 3′-azido-2′,3′-deoxy-5′- O-(12-bromododecanoyl)thymidine (EC50=3.2 nM) were the most effective anti-HIV-1 agents, relative to AZT (EC50=10 nM). These myristoyl analogue derivatives were more lipophilic (calculated log P=4.5–8.1 range) than the parent compound AZT (log P=0.06), and a linear correlation between their log P and HPLC log retention timeswas observed. The ester cleavage half-lives ( t1/2) for esters upon in vitro incubation with porcine liver esterase, rat plasma or rat brain homogenate was dependent on the steric bulk, and electronegative inductive effect of the α-substituent (H, Br, F), of the 5′- O-myristoyl analogue moiety. 3′-Azido-2′,3′-dideoxy-5′- O-(11-(4-iodophenoxy) undecanoyl)-thymidine exhibited t1/2 values of 80.4, 3.7 and 150.0 min upon incubation with porcine liver esterase, rat plasma and rat brain homogenate, respectively.

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.

Synthesis of Novel 1,2,3-Triazole Derivatives of Isocoumarins and 3,4-Dihydroisocoumarin with Potential Antiplasmodial Activity In Vitro

2020 ◽  
Vol 16 ◽  
Author(s):  
Lucas da Silva Santos ◽  
Matheus Fillipe Langanke de Carvalho ◽  
Ana Claudia de Souza Pinto ◽  
Amanda Luisa da Fonseca ◽  
Julio César Dias Lopes ◽  
...  
Keyword(s):  
Triazole Ring ◽  
Antiplasmodial Activity ◽  
World Health ◽  
Dipolar Cycloaddition ◽  
Terminal Alkynes ◽  
The World ◽  
Ic50 Values ◽  
Derivatives Of ◽  
Active Substances

Background: Malaria greatly affects the world health, having caused more than 228 million cases only in 2018. The emergence of drug resistance is one of the main problems in its treatment, demonstrating the urge for the development of new antimalarial drugs. Objective: Synthesis and in vitro antiplasmodial evaluation of triazole compounds derived from isocoumarins and a 3,4- dihydroisocoumarin. Method: The compounds were synthesized in 4 to 6-step reactions with the formation of the triazole ring via the Copper(I)-catalyzed 1,3-dipolar cycloaddition between isocoumarin or 3,4-dihydroisocoumarin azides and terminal alkynes. This key reaction provided compounds with an unprecedented connection of isocoumarin or 3,4-dihydroisocoumarin and the 1,2,3-triazole ring. The products were tested for their antiplasmodial activity against a Plasmodium falciparum chloroquine resistant and sensitive strains (W2 and 3D7, respectively). Results: Thirty-one substances were efficiently obtained by the proposed routes with an overall yield of 25-53%. The active substances in the antiplasmodial test displayed IC50 values ranging from 0.68-2.89 μM and 0.85-2.07 μM against W2 and 3D7 strains, respectively.

scholarly journals In vitro Assessment of Antiplasmodial Activity and Acute Oral Toxicity of Dissotis rotundifolia Extracts and Fractions on Plasmodium falciparum Strains

2020 ◽  
pp. 8-19
Author(s):  
Rock Djehoue ◽  
Rafiou Adamou ◽  
Abdou Madjid O. Amoussa ◽  
Adande A. Medjigbodo ◽  
Anatole Laleye ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Acute Toxicity ◽  
Ethanolic Extract ◽  
Antiplasmodial Activity ◽  
Oral Toxicity ◽  
Aqueous Fraction ◽  
Vector Borne Diseases ◽  
Natural Substances ◽  
Study Laboratory

Aim: Dissotis rotundifolia were selected after an ethnopharmacological survey conducted on plants used traditionally for malaria treatment in South Benin, with the aim of discovering new natural active extracts against malaria parasites. Place and Duration of Study: Laboratory of Biochemistry and Bioactive Natural Substances, University of Abomey-Calavi (Benin)/ Laboratory of Infectious Vector Borne Diseases, Regional Institute of Public Health (Benin)/ Laboratoire d’Histologie, de Cytogénétique et d’Embryologie, Faculté des Sciences de la Santé (Benin). The study was conduct from October 2018 to June 2019 in Benin. Methodology: The antiplasmodial activity of the plant extracts was evaluated using the parasite lactate dehydrogenase (pLDH) immunodetection assay. The extract with the best antiplasmodial activity were used on Wistar rats for acute toxicity. Results: Ethanolic extract of Dissotis rotundifolia showed promising activity (Isolate: IC50 = 22.58 ± 1.12 µg/mL; 3D7: IC50 = 6.81 ± 0.85 µg/mL) on Plasmodium falciparum compared to the aqueous extract (Isolate: IC50 > 100 µg/mL; 3D7: IC50> 100 µg/mL). The aqueous fraction of D. rotundifolia exhibit highly potent activity against P. falciparum strain (Isolate: IC50 > 100 µg/mL μg/mL; 3D7: IC50 = 4.05 ± 0.72 μg/mL). Haemolytic effect of actives extracts and fractions is less than 5%. Ethanolic extract of D. rotundifolia revealed no obvious acute toxicity in rat up to the highest dose administered (2000 mg/kg). Conclusion: This study justifies traditional uses of D. rotundifolia against malaria. A bioguided fractionation of these extracts would identify molecules responsible for their antiplasmodial activity. Moreover, these results could lead to the design of improved traditional medicines in the basis of this plant.

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 antiplasmodial activity of Phyllanthus amarus against Plasmodium falciparum and evaluation of its acute toxicity effect in mouse model

2021 ◽  
Vol 11 (1) ◽  
pp. 31
Author(s):  
Yusuf Mohammed ◽  
Karimatu Aliyu ◽  
IdrisNasir Abdullahi ◽  
AminaAbdullahi Umar ◽  
Fatima Bashir ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Acute Toxicity ◽  
Mouse Model ◽  
Antiplasmodial Activity ◽  
Phyllanthus Amarus ◽  
Toxicity Effect
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