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 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.

Antiplasmodial Bis-Indole Alkaloids from the Bark of Flindersia pimenteliana

Planta Medica ◽  
2019 ◽  
Vol 86 (01) ◽  
pp. 19-25 ◽  
Author(s):  
Luke P. Robertson ◽  
Leonardo Lucantoni ◽  
Vicky M. Avery ◽  
Anthony R. Carroll
Keyword(s):  
Plasmodium Falciparum ◽  
Spectroscopic Data ◽  
Indole Alkaloids ◽  
2D Nmr ◽  
Antiplasmodial Activity ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Ic50 Values ◽  
Significant Attention

AbstractThree new (1–3) and 2 known (4–5) bis-indole alkaloids were identified from the bark of Flindersia pimenteliana (Rutaceae). The structures of 1–3 were elucidated on the basis of their (+)-HRESESIMS and 2D NMR spectroscopic data. Antiplasmodial activity for 1–3 against chloroquine sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum is also reported, with IC50 values ranging from 0.96 to 2.41 µg/mL. These results expand our knowledge of the structure-activity relationships of potently antiplasmodial isoborreverine-type alkaloids, the bioactivity of which have recently attracted significant attention in the literature.

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.

Structure─activity relationships in semi-synthetic penicillins

1971 ◽  
Vol 179 (1057) ◽  
pp. 357-367 ◽  
Keyword(s):  
Antibacterial Activity ◽  
Chemical Nature ◽  
Side Chain ◽  
Structural Variations ◽  
Present Survey ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Large Numbers ◽  
The Relationship

Investigation of the relationship between the antibacterial activity of penicillins and the chemical nature of the side chain began in earnest in 1957, when the isolation of 6-aminopenicillanic acid (6-APA) made possible the preparation of large numbers of N -substituted derivatives. Since that time some 1800 different penicillins have been prepared and studied in Beecham Research Laboratories, and the number examined throughout the world must amount to several thousands. The purpose of the present survey is to try to summarize the general patterns of structure-activity relationships which have emerged from these studies. 6-APA itself has only a low order of antibacterial activity, and the same applies to derivatives in which the amino group at position 6 is substituted by radicals other than acyl groups (figure 1). Hence it soon became clear that no advantage was to be gained from such considerable structural variations, and efforts were concentrated on preparing true penicillins containing acyl side-chains. Virtually all of these show considerable activity in vitro against at least some bacteria, but the spectrum of activity varies widely.

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

Sign in / Sign up

Export Citation Format

Share Document