Synthesis and Antimalarial Activity of 1,4-Disubstituted Piperidine Derivatives

In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules—compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))—were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).

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A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01371-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 2

Author(s):

James S. McCarthy ◽

Thomas Rückle ◽

Suzanne L. Elliott ◽

Emma Ballard ◽

Katharine A. Collins ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Activity ◽

Plasma Concentrations ◽

Parasite Clearance ◽

Blood Stage ◽

Content Type ◽

Dose Combination ◽

Combination Study ◽

Study Support ◽

New Compounds

ABSTRACT Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.)

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Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline

Molecules ◽

10.3390/molecules25204858 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4858 ◽

Cited By ~ 1

Author(s):

Despina Palla ◽

Antonia I. Antoniou ◽

Michel Baltas ◽

Christophe Menendez ◽

Philippe Grellier ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Infectious Diseases ◽

Antimalarial Activity ◽

Biological Evaluation ◽

Antiplasmodial Activity ◽

Malaria Parasites ◽

Antimalarial Agents ◽

New Compounds

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively.

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In vitro and in vivo antimalarial activity of the volatile oil of Cyperus articulatus (Cyperaceae)

Acta Amazonica ◽

10.1590/1809-4392201804331 ◽

2019 ◽

Vol 49 (4) ◽

pp. 334-342 ◽

Cited By ~ 1

Author(s):

Nazaré Carneiro da SILVA ◽

Suellen Ferreira GONÇALVES ◽

Luciana Silva de ARAÚJO ◽

Aline Aparecida München KASPER ◽

Amanda Luisa da FONSECA ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Plant Species ◽

Plasmodium Berghei ◽

Preventive Measures ◽

Antimalarial Activity ◽

Volatile Oil ◽

In Vivo Assays ◽

New Compounds

ABSTRACT Malaria is a disease of global tropical distribution, being endemic in more than 90 countries and responsible for about 212 million cases worldwide in 2016. To date, the strategies used to eradicate this disease have been ineffective, without specific preventive measures such as vaccines. Currently, the existing therapeutic arsenal is limited and has become ineffective against the expansion of artemisinin-resistant Plasmodium, demonstrating the need for studies that would allow the development of new compounds against this disease. In this context, we studied the volatile oil obtained from rhizomes of Cyperus articulatus (VOCA), a plant species commonly found in the Amazon region and popularly used as a therapeutic alternative for the treatment of malaria, in order to confirm its potential as an antimalarial agent by in vitro and in vivo assays. We cultured Plasmodium falciparum W2 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) strains in erythrocytes and exposed them to VOCA at different concentrations in 96-well microplates. In vivo antimalarial activity was tested in BALB/c mice inoculated with approximately 106 erythrocytes infected with Plasmodium berghei. VOCA showed a high antimalarial potential against the two P. falciparum strains, with IC50 = 1.21 μg mL-1 for W2 and 2.30 μg mL-1 for 3D7. VOCA also significantly reduced the parasitemia and anemia induced by P. berghei in mice. Our results confirmed the antimalarial potential of the volatile oil of Cyperus articulatus.

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Plasmodium falciparum Knockout for the GPCR-Like PfSR25 Receptor Displays Greater Susceptibility to 1,2,3-Triazole Compounds That Block Malaria Parasite Development

Biomolecules ◽

10.3390/biom10081197 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1197

Author(s):

Benedito M. dos Santos ◽

Daniel T. G. Gonzaga ◽

Fernando C. da Silva ◽

Vitor F. Ferreira ◽

Celia R. S. Garcia

Keyword(s):

Plasmodium Falciparum ◽

Malaria Parasite ◽

Antimalarial Activity ◽

Parasite Development ◽

Embryonic Cells ◽

Hek 293 ◽

Parasite Plasmodium ◽

Parasite Plasmodium Falciparum ◽

Ic50 Values ◽

New Compounds

The search for new compounds with antimalarial activity is urgent, as resistance to ones in the classical drug, has already been described in more than one continent. Compounds derived from 1,2,3-triazoles are effective against parasites and bacteria. Here, we evaluated the potential antimalarial activity against the human malaria parasite Plasmodium falciparum in a culture of fifty-four triazole compounds derived from 1H-and 2H-1,2,3-triazole. We identified thirty-one compounds with potential antimalarial activity at concentrations in the micromolar order (µM) and IC50 values ranging from 2.80 µM (9) to 29.27 µM (21). Then, we selected some of these compounds to perform the same tests on the PfSR25- strain (knockout for P. falciparum G-protein coupled receptor-like, SR25). Our experiences with the PfSR25- strain showed that both compounds with higher antimalarial activity for the 3D7 strain and those with less activity resulted in lower IC50 values for the knockout strain. The cytotoxicity of the compounds was evaluated in human renal embryonic cells (HEK 293), using MTT assays. This demonstrated that the compounds with the highest activity (9, 13, 19, 22, 24, 29), showed no toxicity at the tested concentrations.

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Synthesis and Evaluation of Some New Isoquine Analogues for Antimalarial Activity

E-Journal of Chemistry ◽

10.1155/2009/693757 ◽

2009 ◽

Vol 6 (s1) ◽

pp. S381-S389

Author(s):

Chandra Nath Saha ◽

Sanjib Bhattacharya ◽

Dipak Chetia

Keyword(s):

Plasmodium Falciparum ◽

Side Effects ◽

Drug Toxicity ◽

Antimalarial Activity ◽

Haematological Toxicity ◽

Test Strain ◽

Side Chain ◽

Adverse Side Effects ◽

Step Procedure

Amodiaquine is a 4-aminoquinoline antimalarial that can cause adverse side effects including hepatic and haematological toxicity. The drug toxicity involves the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which binds to cellular macromolecules leading to hepatotoxicity and agranulocytosis. Interchange of the 3ʼ hydroxyl and the 4ʼ Mannich side-chain function of amodiaquine provides an amodiaquine regioisomer (isoquine) that cannot form toxic quinoneimine metabolites. By a simple two-step procedure, four isoquine analogues were synthesized and subsequently evaluated against the chloroquine sensitive RKL-2 strain ofPlasmodium falciparum in vitro. All synthesized analogues demonstrated differential level of antimalarial activity against the test strain. However, no compound was found to exhibit better antimalarial property as compared to chloroquine.

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Therapeutic Aspects of Squill; An Evidence-Based Review

Current Drug Discovery Technologies ◽

10.2174/1570163816666190125154745 ◽

2020 ◽

Vol 17 (3) ◽

pp. 318-324 ◽

Cited By ~ 1

Author(s):

Khadije Saket ◽

Jalil T. Afshari ◽

Ehsan Saburi ◽

Mahdi Yousefi ◽

Roshanak Salari

Keyword(s):

Side Effects ◽

Traditional Medicine ◽

Respiratory Diseases ◽

Low Cost ◽

Current Evidence ◽

Evidence Based ◽

Helminthic Infections ◽

Traditional Persian Medicine ◽

Healing Of Wounds ◽

Bioactive Agents

From ancient times, medicinal plants have been usually utilized to treat many disorders, but today, interest in these herbs is again aroused, because of their fewer side effects and low-cost. In traditional medicine, for many diseases, various medicinal herbs have been suggested so far. Drimia maritime, also named squill, is an important medicinal plant for the treatment of many diseases, especially respiratory diseases. In the current evidence-based study, we conducted a review of the general characteristics, ingredients, administration form, and side effects of squill in traditional medicine. For this purpose, traditional Persian medicine literatures and electronic databases were examined including PubMed, Scopus, and Google Scholar. Many compounds are isolated from D.maritima, including scillaren, scillirubroside, scillarenin, and bufadienolide glycosides. Oxymel is the most commonly used form of squill for various diseases, especially respiratory diseases. Besides, squill has been used in the treatment of cardiovascular, digestive, and dermatological disorders, it is also used against various cancer cells for its antioxidant and cytotoxic properties. Moreover, there is relatively reliable evidence of its benefits for bacterial and helminthic infections, rheumatism, edema, gout, abortion induction, healing of wounds and urine induction. It seems that supplementary studies are required to explore the bioactive agents and their effective mechanisms.

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

Medicinal Chemistry ◽

10.2174/1573406416666200817160708 ◽

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.

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Natural Phytochemicals and Their Therapeutic Role in Management of Several Diseases: A Review

Current Traditional Medicine ◽

10.2174/2215083805666190807111817 ◽

2020 ◽

Vol 6 (1) ◽

pp. 43-53 ◽

Cited By ~ 2

Author(s):

Nitin R. Shirsath ◽

Ajaygiri K. Goswami

Keyword(s):

Side Effects ◽

Low Cost ◽

Herbal Medicines ◽

Biological Source ◽

Natural Medicine ◽

Synthetic Chemicals ◽

Alternative Approach ◽

Health Related ◽

Activity Mechanism ◽

Natural Medicines

Introduction: These days, a lot of people face some health-related problems in day to day life. The conventional synthetic medicine is not effective enough to cure them alone. The conventional therapy for the management of these health-related issues involves the use of hazardous synthetic chemicals and surgical diagnosis, which have lots of serious side effects. It is necessary to conduct research on herbal medicines, this is an alternative approach to avoid the side effects of synthetic medicines to achieve high effectiveness, low cost and improve patient compliance. Methods: The present survey is an analysis of some of the available data on the use of plants with their biological source, active phytochemicals constituents and a probable activity/ mechanism of action of several classes of drugs. This work also focused on highlighting the advantages of natural medicines for maximum utilization. Results: This article aims to increase awareness about natural medicine and help people find a suitable herbal medicine for the treatment of specific diseases. Conclusion: This article also exhibits the scope for further process in the development of new natural substance for the management of several diseases.

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Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽

10.1182/blood.v76.6.1250.1250 ◽

1990 ◽

Vol 76 (6) ◽

pp. 1250-1255 ◽

Cited By ~ 36

Author(s):

S Whitehead ◽

TE Peto

Keyword(s):

Plasmodium Falciparum ◽

Growth Inhibition ◽

Antimalarial Activity ◽

Clinical Malaria ◽

Inhibitory Effect ◽

Parasite Development ◽

And Control ◽

Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

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In vitro activities of novel catecholate siderophores against Plasmodium falciparum.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.9.2094 ◽

1996 ◽

Vol 40 (9) ◽

pp. 2094-2098 ◽

Cited By ~ 13

Author(s):

B Pradines ◽

F Ramiandrasoa ◽

L K Basco ◽

L Bricard ◽

G Kunesch ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Mechanism Of Action ◽

Ribonucleotide Reductase ◽

Antimalarial Activity ◽

Iron Chelators ◽

Resistant Clone ◽

Iron Deprivation ◽

Level Of Activity ◽

Susceptible Clone

The activities of novel iron chelators, alone and in combination with chloroquine, quinine, or artemether, were evaluated in vitro against susceptible and resistant clones of Plasmodium falciparum with a semimicroassay system. N4-nonyl,N1,N8-bis(2,3-dihydroxybenzoyl) spermidine hydrobromide (compound 7) demonstrated the highest level of activity: 170 nM against a chloroquine-susceptible clone and 1 microM against a chloroquine-resistant clone (50% inhibitory concentrations). Compounds 6, 8, and 10 showed antimalarial activity with 50% inhibitory concentrations of about 1 microM. Compound 7 had no effect on the activities of chloroquine, quinine, and artemether against either clone, and compound 8 did not enhance the schizontocidal action of either chloroquine or quinine against the chloroquine-resistant clone. The incubation of compound 7 with FeCI3 suppressed or decreased the in vitro antimalarial activity of compound 7, while no effect was observed with incubation of compound 7 with CuSO4 and ZnSO4. These results suggest that iron deprivation may be the main mechanism of action of compound 7 against the malarial parasites. Chelator compounds 7 and 8 primarily affected trophozoite stages, probably by influencing the activity of ribonucleotide reductase, and thus inhibiting DNA synthesis.

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