Potential antimalarials. II. N4-Substituted 2-Methoxy(and 2-hydroxy)-1,5-naphthyridin-4-amines

1984 ◽  
Vol 37 (12) ◽  
pp. 2469 ◽  
Author(s):  
GB Barlin ◽  
W Tan
Keyword(s):  
Hydrogen Chloride ◽  
Sodium Methoxide ◽  
Antimalarial Activity ◽  
In Vivo Screen ◽  
Plasmodium Vinckei

Several new N4-substituted 2-methoxy(and 2-hydroxy)-1,5-naphthyridin-4-amines have been prepared from ethyl 3-aminopyridine-2-carboxylate. 2,4-Dichloro-1,5-naphthyridine with methanolic sodium methoxide gave 4-chloro-2-methoxy-1,5-naphthyridine but with methanolic hydrogen chloride afforded 4-chloro-1,5-naphthyridin-2-ol. The N4-substituted 1,5-naphthyridin-4-amines showed no significant antimalarial activity compared to chloroquine or primaquine in a preliminary in vivo screen against Plasmodium vinckei vinckei in mice.

Potential Antimalarials. I. 1,8-Naphthyridines

1984 ◽  
Vol 37 (5) ◽  
pp. 1065 ◽  
Author(s):  
G Barlin ◽  
W Tan
Keyword(s):  
Antimalarial Activity ◽  
In Vivo Screen ◽  
Plasmodium Vinckei

A number of 1,8-naphthyridines including 8-aza analogues of chloroquine and amodiaquine, and similar 1,8-naphthyridines with 2- and 7-methyl substituents have been prepared. These compounds showed minimal antimalarial activity in a preliminary in vivo screen against Plasmodium vinckei vinckei.

scholarly journals In vitro and in vivo inhibition of erythrocytic development of malarial parasites by docetaxel.

1996 ◽  
Vol 40 (2) ◽  
pp. 358-361 ◽  
Author(s):  
V Sinou ◽  
P Grellier ◽  
J Schrevel
Keyword(s):  
Antimalarial Activity ◽  
Single Injection ◽  
Short Exposure ◽  
Parasite Development ◽  
Schizont Stage ◽  
Drug Injection ◽  
Sensitive Stage ◽  
Plasmodium Vinckei

The stage-dependent susceptibility of Plasmodium falciparum to a short exposure to docetaxel (Taxotere) was evaluated by subjecting ring-infected, trophozoite-infected, and schizont-infected erythrocytes to a 5-h exposure to various concentrations of the drug. The schizont stage was shown to be the most sensitive stage; an inhibition of more than 60% of parasite development was observed at 10 nM. At this drug concentration, the development of the younger ring and trophozoite forms was unaffected. The in vivo antimalarial activity of docetaxel against the development in blood of old trophozoites of a species that causes malaria in rodents, Plasmodium vinckei petteri, was evaluated in IOPS-OF1 mice. Two tests were performed: the 4-day suppressive test, as described by Peters (W. Peters, p. 145-273, in Chemotherapy, and Drug Resistance in Malaria, vol. 1, 1987), and the effects of a single injection of docetaxel after inoculation of the parasites. A single injection of docetaxel at 40 mg/kg of body weight was sufficient to reduce drastically the level of parasitemia; 90% inhibition of the development of parasites in blood was observed 5 days after drug injection. This program avoided the toxicity observed when mice were treated with four injections of docetaxel. The possibility of using a single bolus of taxoids to treat malaria infections is discussed.

scholarly journals Antimalarial Activity of Simalikalactone E, a New Quassinoid from Quassia amara L. (Simaroubaceae)

2009 ◽  
Vol 53 (10) ◽  
pp. 4393-4398 ◽  
Author(s):  
N. Cachet ◽  
F. Hoakwie ◽  
S. Bertani ◽  
G. Bourdy ◽  
E. Deharo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Selectivity Index ◽  
Strain Sensitivity ◽  
Isolation And Identification ◽  
Quassia Amara ◽  
Plasmodium Vinckei

ABSTRACT We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amara L. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparum cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteri by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.

Potential Antimalarials. XV. Di-Mannich Bases of 2-(7'-Chloroquinolin-4'-ylamino)phenol and 2-[7'-Bromo( and trifluoromethyl)-1',5'-naphthyridin-4'-ylamino]phenol

1992 ◽  
Vol 45 (10) ◽  
pp. 1651 ◽  
Author(s):  
GB Barlin ◽  
TMT Nguyen ◽  
B Kotecka ◽  
KH Rieckmann
Keyword(s):  
Mannich Base ◽  
Antimalarial Activity ◽  
Mannich Bases ◽  
In Vitro Tests ◽  
In Vivo Tests ◽  
Methyl Derivatives ◽  
Derivatives Of ◽  
Plasmodium Vinckei

A total of 26 di-Mannich base derivatives of 2-(7'-chloroquinolin-4'-ylamino)phenol and 2-[7'- bromo (and trifluoromethyl )-1',5'-naphthyridin-4'-ylino]phenol, such as 2-(7'-chloroquinolin- 4'-ylamino)-4,6-bis( piperidin-1″-ylmethyl )phenol, together with some 3- and 5-methyl derivatives and mono-Mannich analogues, have been prepared by condensation of the 4-chloro heterocycle with the appropriate Mannich base derivatives of 2-aminophenols. In in vitro tests against Plasmodium falciparum, many of the di-Mannich base derivatives of 2-(7'-chloroquinolin-4'-ylarnino)phenol exhibited activity comparable to or superior to chloroquine against the chloroquine -sensitive (FCQ-27) isolate, and vastly superior activity compared with chloroquine against the chloroquine -resistant (K-1) isolate. Strong antimalarial activity was also revealed in in vivo tests against Plasmodium vinckei vinckei in mice.

Antimalarial Activity of a Riboflavin Analog against Plasmodium vinckei in Vivo and Plasmodium falciparum in Vitro

1987 ◽  
Vol 37 (3) ◽  
pp. 495-500 ◽  
Author(s):  
William B. Cowden ◽  
Geoffrey A. Butcher ◽  
Fumio Yoneda ◽  
Nicholas H. Hunt ◽  
Ian A. Clark
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Plasmodium Vinckei

scholarly journals In Vitro and In Vivo Synergy of Fosmidomycin, a Novel Antimalarial Drug, with Clindamycin

2002 ◽  
Vol 46 (9) ◽  
pp. 2889-2894 ◽  
Author(s):  
Jochen Wiesner ◽  
Dajana Henschker ◽  
David B. Hutchinson ◽  
Ewald Beck ◽  
Hassan Jomaa
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
High Rate ◽  
In Vitro Experiments ◽  
Nonmevalonate Pathway ◽  
Recent Clinical Study ◽  
Key Enzyme ◽  
Plasmodium Vinckei

ABSTRACT Fosmidomycin acts through inhibition of 1-deoxy-d-xylulose 5-phosphate (DOXP) reductoisomerase, a key enzyme of the nonmevalonate pathway of isoprenoid biosynthesis. It possesses potent antimalarial activity in vitro and in murine malaria. In a recent clinical study, fosmidomycin was effective and well tolerated in the treatment of patients with acute uncomplicated Plasmodium falciparum malaria but resulted in an unacceptably high rate of recrudescence. In order to identify a potential combination partner, the interaction of fosmidomycin with a number of antimalarial drugs in current use was investigated in a series of in vitro experiments. Synergy was observed between fosmidomycin and the lincosamides, lincomycin and clindamycin. The efficacy of a combination of fosmidomycin and clindamycin was subsequently demonstrated in the Plasmodium vinckei mouse model.

Synthesis and In Vivo Antimalarial Activity of Quinoline/Mercaptopurine Conjugates

2012 ◽  
Vol 9 (4) ◽  
pp. 361-366 ◽  
Author(s):  
Nicolli Bellotti de Souza ◽  
Rafael Carvalhaes ◽  
Arturene Maria Lino do Carmo ◽  
Marcio Jose Martins Alves ◽  
Elaine Soares Coimbra ◽  
...  
Keyword(s):  
Antimalarial Activity

Synthesis and In Vivo Antimalarial Activity of Novel Derivatives of 6- Mercaptopurine

2013 ◽  
Vol 10 (8) ◽  
pp. 741-747 ◽  
Author(s):  
Roberta Soares ◽  
Roberta Corrales ◽  
Fernanda Lopes ◽  
Marcio Alves ◽  
Adilson Silva ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Derivatives Of

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Haicheng Liu ◽  
Yushi Futamura ◽  
Honghai Wu ◽  
Aki Ishiyama ◽  
Taotao Zhang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimalarial Activity ◽  
In Vitro Assays ◽  
Compound Library ◽  
Antimalarial Agents ◽  
Phenotypic Screen ◽  
Ic50 Values ◽  
Substituted Benzamides

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3-cinnamamido-N-substituted benzamides. Method: In this study, a screening of our compound library was carried out against the multidrug-sensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, phenotypic screen of our compound library resulted in the first report of 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

Preparation of Chloro and Sulfanyl Derivatives of 1-(2-Deoxy-4-C-hydroxymethyl-α-L-threo-Pentofuranosyl)uracil

1997 ◽  
Vol 62 (7) ◽  
pp. 1114-1127 ◽  
Author(s):  
Hubert Hřebabecký ◽  
Jan Balzarini ◽  
Antonín Holý
Keyword(s):  
Nucleophilic Substitution ◽  
Hydrogen Chloride ◽  
Thionyl Chloride ◽  
Sodium Methoxide ◽  
Thioacetic Acid ◽  
Uracil Derivatives ◽  
Derivatives Of ◽  
Hiv 1

3'-Chloro and 3'-acetylsulfanyl derivatives of 1-(2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil were prepared by reaction of 2,3'-anhydro-1-{5'-O-benzoyl-4'-C-[(benzoyloxy)methyl]-2'-deoxy-α-L-erythro-pentofuranosyl}uracil (3) with hydrogen chloride and thioacetic acid, respectively. The reaction with hydrogen chloride gave a mixture of N-1 and N-3 substituted uracil derivatives 12 and 14. Reaction of 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-α-L-threo-pentofuranosyl}uracil (7) with thionyl chloride and subsequent debenzoylation afforded 1-(4-C-chloromethyl-2-deoxy-β-D-erythro-pentofuranosyl)uracil (19). Nucleophilic substitution with lithium thioacetate, followed by deacylation, converted 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (9) into 1-(2-deoxy-4-C-sulfanylmethyl-β-D-erythro-pentofuranosyl)uracil (21). The obtained thiols were oxidized with iodine or air to give 1,1'-[disulfandiylbis(2,3-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-3,1-diyl]di(pyrimidine-2,4-(1H,3H)-dione) (17) and 1,1'-[disulfandiylbis(2,5-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-5,1-diyl]di(pyrimidine-2,4(1H,3H)-dione) (22). Reaction of 1-{3-acetylsulfanyl-5-O-methanesulfonyl-4-C-[(benzoyloxy)methyl]-2,3-dideoxy-α-L-threo-pentofuranosyl)}uracil (24) with methanolic sodium methoxide afforded 1-(3,5-anhydro-2,3-dideoxy-4-C-hydroxymethyl-3-sulfanyl-α-L-threo-pentofuranosyl)uracil (25). The same reagent was used in the preparation of 1-(3,5-anhydro-2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil (26) from 1-{4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (8). From the series of 4'-substituted 2'-deoxyuridine derivatives, synthesized in this study, solely the 4'-chloromethyl derivative 19 and the oxetane derivative 26 exhibited an appreciable activity against HIV-1 and HIV-2.

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