scholarly journals Synthesis and Antimalarial Activities of Cyclen 4-Aminoquinoline Analogs

2009 ◽  
Vol 53 (4) ◽  
pp. 1320-1324 ◽  
Author(s):  
M. O. Faruk Khan ◽  
Mark S. Levi ◽  
Babu L. Tekwani ◽  
Shabana I. Khan ◽  
Eiichi Kimura ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
High Selectivity ◽  
Antimalarial Activity ◽  
New Class ◽  
Antimalarial Agents ◽  
Sensitive Clone ◽  
Resistant Strains ◽  
Incorporation Assay

ABSTRACT In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn2+ complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities. It displays 50% inhibitory concentrations (IC50s) of 7.5 nM against the D6 (chloroquine-sensitive) clone of Plasmodium falciparum and 19.2 nM against the W2 (chloroquine-resistant) clone, which are comparable to those of artemisinin (10.6 and 5.0 nM, respectively) and lower than those of chloroquine (10.7 and 87.2 nM, respectively), without any evidence of cytotoxicity to mammalian cells, indicating a high selectivity index (>1,333 against D6 clone and >521 against W2 clone). Potent antimalarial activities of the bisquinoline against chloroquine- and mefloquine-resistant strains of P. falciparum were also confirmed by in vitro [3H]hypoxanthine incorporation assay. The in vivo antimalarial activity of the bisquinoline, as determined in P. berghei-infected mice, is comparable to that of chloroquine (50% effective dose, ≤1.1 mg/kg when given orally); no apparent toxicity has been observed up to the highest dose tested (3 × 30 mg/kg). The bisquinoline inhibits in vitro hemozoin (β-hematin) formation with an IC50 of 1.1 μM, which is about 10-fold more potent than chloroquine (IC50 9.5 μM). Overall, this article describes the discovery of a new class of cyclen 4-aminoquinoline analogs as potent antimalarial drugs.

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.

Synthesis and antimalarial activity of new 4-aminoquinolines active against drug resistant strains

RSC Advances ◽  
2016 ◽  
Vol 6 (107) ◽  
pp. 105676-105689 ◽  
Author(s):  
Srinivasarao Kondaparla ◽  
Awakash Soni ◽  
Ashan Manhas ◽  
Kumkum Srivastava ◽  
Sunil K. Puri ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Drug Resistant ◽  
New Class ◽  
Resistant Strains ◽  
Drug Resistant Strains

In the present study we have synthesized a new class of 4-aminoquinoline derivatives and bioevaluated them for antimalarial activity against theP. falciparum in vitro(3D7 & K1) andP. yoelii in vivo(N-67 strain).

scholarly journals Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes

2007 ◽  
Vol 51 (4) ◽  
pp. 1463-1472 ◽  
Author(s):  
Françoise Benoit-Vical ◽  
Joël Lelièvre ◽  
Antoine Berry ◽  
Caroline Deymier ◽  
Odile Dechy-Cabaret ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Mice Model ◽  
Additional Advantage ◽  
Antimalarial Agents ◽  
Hybrid Molecules ◽  
Resistant Strains ◽  
Antimalarial Chemotherapy

ABSTRACT Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.

Inhibition of Hemoglobin Degrading Protease Falcipain-2 as a Mechanism for Anti-Malarial Activity of Triazole-Amino Acid Hybrids

2020 ◽  
Vol 20 (5) ◽  
pp. 377-389 ◽  
Author(s):  
Vigyasa Singh ◽  
Rahul Singh Hada ◽  
Amad Uddin ◽  
Babita Aneja ◽  
Mohammad Abid ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cysteine Protease ◽  
Mammalian Cells ◽  
Antimalarial Activity ◽  
Docking Studies ◽  
Dependent Manner ◽  
Trophozoite Stage ◽  
Hemoglobin Degradation

Background: Novel drug development against malaria parasite over old conventional antimalarial drugs is essential due to rapid and indiscriminate use of drugs, which led to the emergence of resistant strains. Methods: In this study, previously reported triazole-amino acid hybrids (13-18) are explored against Plasmodium falciparum as antimalarial agents. Among six compounds, 15 and 18 exhibited antimalarial activity against P. falciparum with insignificant hemolytic activity and cytotoxicity towards HepG2 mammalian cells. In molecular docking studies, both compounds bind into the active site of PfFP-2 and block its accessibility to the substrate that leads to the inhibition of target protein further supported by in vitro analysis. Results: Antimalarial half-maximal inhibitory concentration (IC50) of 15 and 18 compounds were found to be 9.26 μM and 20.62 μM, respectively. Blood stage specific studies showed that compounds, 15 and 18 are effective at late trophozoite stage and block egress pathway of parasites. Decreased level of free monomeric heme was found in a dose dependent manner after the treatment with compounds 15 and 18, which was further evidenced by the reduction in percent of hemoglobin hydrolysis. Compounds 15 and 18 hindered hemoglobin degradation via intra- and extracellular cysteine protease falcipain-2 (PfFP-2) inhibitory activity both in in vitro and in vivo in P. falciparum. Conclusion: We report antimalarial potential of triazole-amino acid hybrids and their role in the inhibition of cysteine protease PfFP-2 as its mechanistic aspect.

scholarly journals In VivoAntimalarial Activity of the 80%Methanolic Root Bark Extract and Solvent Fractions ofGardenia ternifoliaSchumach. & Thonn. (Rubiaceae) againstPlasmodium berghei

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Dejen Nureye ◽  
Solomon Assefa ◽  
Teshome Nedi ◽  
Ephrem Engidawork
Keyword(s):  
Crude Extract ◽  
Antimalarial Activity ◽  
Standard Procedure ◽  
New Drugs ◽  
Bark Extract ◽  
Root Bark ◽  
Antimalarial Agents ◽  
Loss Of Weight

Background. Evolution of antimalarial drug resistance makes the development of new drugs a necessity. Important source in search of such drugs is medicinal plants.Gardenia ternifoliaplant is used in Ethiopian traditional medicine for the treatment of malaria and is endowed within vitroantimalarial activity. Herein, thein vivoantimalarial activity of the plant was investigated.Methods. Acute toxicity was carried out using a standard procedure. A 4-day suppressive test was employed to evaluate the antimalarial effect of methanolic crude extract and solvent fractions of the plant. The curative and prophylactic effect of crude extract was further tested by Ranes’s test and residual infection procedure, respectively, usingPlasmodium berghei(ANKA strain) in Swiss albino mice.Results. The chemosuppressive effect exerted by the crude extract and fractions ranged between 30-59% and 14-51%, respectively. Curative and prophylactic effects of the crude extract were in the range of 36-63% and 24-37%, respectively. All dose levels of the crude extract prevented loss of weight, reduction in temperature, and anemia on early and established infection. Butanol and chloroform fractions also did reverse reduction in temperature, body weight, and packed cell volume.Conclusions. The results indicated that the plant has a promising antiplasmodial activity and it could be considered as a potential source to develop new antimalarial agents.

scholarly journals Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Tae Sung Kim ◽  
Jin Ho Choe ◽  
Young Jae Kim ◽  
Chul-Su Yang ◽  
Hyun-Jin Kwon ◽  
...  
Keyword(s):  
Similar Efficacy ◽  
Mycobacterium Abscessus ◽  
Sequencing Analysis ◽  
Highly Pathogenic ◽  
Content Type ◽  
New Class ◽  
Nucleotide Insertion ◽  
Resistant Strains

ABSTRACT Mycobacterium abscessus is a highly pathogenic drug-resistant rapidly growing mycobacterium. In this study, we evaluated the in vitro, intracellular, and in vivo activities of LCB01-0371, a novel and safe oxazolidinone derivative, for the treatment of M. abscessus infection and compared its resistance to that of other oxazolidinone drugs. LCB01-0371 was effective against several M. abscessus strains in vitro and in a macrophage model of infection. In the murine model, a similar efficacy to linezolid was achieved, especially in the lungs. We induced laboratory-generated resistance to LCB01-0371; sequencing analysis revealed mutations in rplC of T424C and G419A and a nucleotide insertion at the 503 position. Furthermore, LCB01-0371 inhibited the growth of amikacin-, cefoxitin-, and clarithromycin-resistant strains. Collectively, our data indicate that LCB01-0371 might represent a promising new class of oxazolidinones with improved safety, which may replace linezolid for the treatment of M. abscessus.

scholarly journals Novel Antimalarial Aminoquinolines: Heme Binding and Effects on Normal or Plasmodium falciparum-Parasitized Human Erythrocytes

2009 ◽  
Vol 53 (10) ◽  
pp. 4339-4344 ◽  
Author(s):  
Fausta Omodeo-Salè ◽  
Lucia Cortelezzi ◽  
Nicoletta Basilico ◽  
Manolo Casagrande ◽  
Anna Sparatore ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Heme Binding ◽  
Human Red Blood Cells ◽  
Rbc Membrane ◽  
Alkyl Derivatives ◽  
Resistant Strains ◽  
Dose Dependent

ABSTRACT Two new quinolizidinyl-alkyl derivatives of 7-chloro-4-aminoquinoline, named AM-1 and AP4b, which are highly effective in vitro against both the D10 (chloroquine [CQ] susceptible) and W2 (CQ resistant) strains of Plasmodium falciparum and in vivo in the rodent malaria model, have been studied for their ability to bind to and be internalized by normal or parasitized human red blood cells (RBC) and for their effects on RBC membrane stability. In addition, an analysis of the heme binding properties of these compounds and of their ability to inhibit beta-hematin formation in vitro has been performed. Binding of AM1 or AP4b to RBC is rapid, dose dependent, and linearly related to RBC density. Their accumulation in parasitized RBC (pRBC) is increased twofold compared to levels in normal RBC. Binding of AM1 or AP4b to both normal and pRBC is higher than that of CQ, in agreement with the lower pKa and higher lipophilicity of the compounds. AM1 or AP4b is not hemolytic per se and is less hemolytic than CQ when hemolysis is accelerated (induced) by hematin. Moreover, AM-1 and AP4b bind heme with a stoichiometry of interaction similar to that of CQ (about 1:1.7) but with a lower affinity. They both inhibit dose dependently the formation of beta-hematin in vitro with a 50% inhibitory concentration comparable to that of CQ. Taken together, these results suggest that the antimalarial activity of AM1 or AP4b is likely due to inhibition of hemozoin formation and that the efficacy of these compounds against the CQ-resistant strains can be ascribed to their hydrophobicity and capacity to accumulate in the vacuolar lipid (elevated lipid accumulation ratios).

scholarly journals Novel Inhibitor of Plasmodium Histone Deacetylase That Cures P. berghei-Infected Mice

2009 ◽  
Vol 53 (5) ◽  
pp. 1727-1734 ◽  
Author(s):  
S. Agbor-Enoh ◽  
C. Seudieu ◽  
E. Davidson ◽  
A. Dritschilo ◽  
M. Jung
Keyword(s):  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Hdac Inhibitors ◽  
High Drug ◽  
Lead Compounds ◽  
Drug Concentrations

ABSTRACT Histone deacetylases (HDAC) are potential targets for the development of new antimalarial drugs. The growth of Plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent HDAC inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. Furthermore, most established HDAC inhibitors concurrently show broad toxicities against parasites and human cells and high drug concentrations are required for effective antimalarial activity. Here, we report on HDAC inhibitors that are potent against P. falciparum at subnanomolar concentrations and that have high selectivities; the lead compounds have mean 50% inhibitory concentrations for the killing of the malaria parasite up to 950 times lower than those for the killing of mammalian cells. These potential drugs improved survival and completely and irreversibly suppressed parasitemia in P. berghei-infected mice.

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.

Design, Synthesis, Antimalarial Activity and Docking Study of 7-Chloro-4- (2-(substituted benzylidene)hydrazineyl)quinolines

2020 ◽  
Vol 16 (7) ◽  
pp. 928-937 ◽  
Author(s):  
Jahnabi Kalita ◽  
Dipak Chetia ◽  
Mithun Rudrapal
Keyword(s):  
Antimalarial Drug ◽  
Disease Burden ◽  
Antimalarial Activity ◽  
Docking Study ◽  
Molecular Scaffold ◽  
Design Synthesis ◽  
Antimalarial Agents ◽  
Drug Molecules ◽  
Resistant Strains

Background: Malaria is a growing infectious disease burden due to the increasing emergence of resistant strains of Plasmodium falciparum. Because of the limited therapeutic efficacy of available antimalarial drugs, the development of potent antimalarial drug agents is therefore an urgent requirement to fight against resistant malaria. Objective: The objective of this work was to develop novel quinoline-baed antimalarial agents that would be active against resistant P. falciparum malaria. Methods: Some 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines were synthesized for the evaluation of their potential as possible antimalarial agents, particularly against resistant malaria. The antimalarial activity of synthesized compounds was evaluated in vitro against bloodstage parasites of P. falciparum. Further, molecular docking and drug-likeness including ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity) studies were also carried out using in silico tools. Results: Results reveal the in vitro antimalarial activity of synthesized 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines against P. falciparum. The docking study investigates the antimalarial effectiveness of synthesized quinolines as novel plasmepsin 2 inhibitors. Drug-likeness prediction exhibits acceptable drug-likeness and ADMET properties. Conclusion: Based upon our findings, it is concluded that the molecular scaffold of 7-chloro-4-(2- (substituted benzylidene)hydrazineyl)quinolines may be used as a lead structure for further modifications in the search of more potent antimalarial drug molecules.

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