Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review.
TL;DR: The role of modification of the core structure of CQ and its effects on the biological activities are described and the attempt has been made to predict the future prospects of such drugs to reemerge as antimalarial agents.
About: This article is published in European Journal of Medicinal Chemistry.The article was published on 2015-01-27. It has received 74 citations till now. The article focuses on the topics: Antimalarial Agent.
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TL;DR: This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquines, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases.
Abstract: Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases.
343 citations
TL;DR: The range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine.
Abstract: Great progress has been made in recent years to reduce the high level of suffering caused by malaria worldwide. Notably, the use of insecticide-treated mosquito nets for malaria prevention and the use of artemisinin-based combination therapy (ACT) for malaria treatment have made a significant impact. Nevertheless, the development of resistance to the past and present anti-malarial drugs highlights the need for continued research to stay one step ahead. New drugs are needed, particularly those with new mechanisms of action. Here the range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine. A number of new potential anti-malarial drugs currently in development are outlined, along with a description of the hit to lead campaign from which it originated. Finally, promising novel mechanisms of action for these and future anti-malarial medicines are outlined.
254 citations
TL;DR: The underlying mechanisms behind the antimalarial, anticancer and antiviral effects of CQ are reviewed and the clinical evidence for the use of C Q and hydroxychloroquine (HCQ) against COVID-19 is discussed.
48 citations
TL;DR: The importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) Plasmodium falciparum clone strain and in vivo against Plas modium berghei-infected mouse model is demonstrated.
Abstract: Based on medicinal chemistry tools, new compounds for malaria treatment were designed. The scaffolds of the drugs used to treat malaria, such as chloroquine, primaquine, amodiaquine, mefloquine and sulfadoxine, were used as inspiration. We demonstrated the importance of quinoline and non-quinoline derivatives in vitro with activity against the W2 chloroquine-resistant (CQR) Plasmodium falciparum clone strain and in vivo against Plasmodium berghei-infected mouse model. Among the quinoline derivatives, new hybrids between chloroquine and sulfadoxine were designed, which gave rise to an important prototype that was more active than both chloroquine and sulfadoxine. Hybrids between chloroquine–atorvastatin and primaquine–atorvastatin were also synthesized and shown to be more potent than the parent drugs alone. Additionally, among the quinoline derivatives, new mefloquine derivatives were synthesized. Among the non-quinoline derivatives, we obtained excellent results with the triazolopyrimidine nucleus, which gave us prototype I that inspired the synthesis of new heterocycles. The pyrazolopyrimidine derivatives stood out as non-quinoline derivatives that are potent inhibitors of the P. falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. We also examined the pyrazolopyridine and pyrazolopyrimidine nuclei.
47 citations
TL;DR: Fifteen 7-arylpyrazolo[1,5-a]pyrimidine derivatives are designed and synthesized using ring bioisosteric replacement and molecular hybridization of functional groups based on the highly active 5-methyl-N-(naphthalen-2-yl)-2-(trifluoromethyl)- [1,2,4]triazolo-7-amine and showed increased drug activity.
45 citations
References
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TL;DR: There are multiple channels by which malaria impedes development, including effects on fertility, population growth, saving and investment, worker productivity, absenteeism, premature mortality and medical costs.
Abstract: Where malaria prospers most, human societies have prospered least. The global distribution of per-capita gross domestic product shows a striking correlation between malaria and poverty, and malaria-endemic countries also have lower rates of economic growth. There are multiple channels by which malaria impedes development, including effects on fertility, population growth, saving and investment, worker productivity, absenteeism, premature mortality and medical costs.
2,320 citations
"Reemergence of chloroquine (CQ) ana..." refers background in this paper
...Besides, it is also known th at both malarial DV and cancerous cells share a common resemblance of low pH [50-55]....
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TL;DR: The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7 that harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America.
1,358 citations
TL;DR: This review centers on these beneficial secondary metabolites, the discovery of which goes back 80 years to the time when penicillin was discovered by Alexander Fleming.
Abstract: Microbes have made a phenomenal contribution to the health and well-being of people throughout the world. In addition to producing many primary metabolites, such as amino acids, vitamins and nucleotides, they are capable of making secondary metabolites, which constitute half of the pharmaceuticals on the market today and provide agriculture with many essential products. This review centers on these beneficial secondary metabolites, the discovery of which goes back 80 years to the time when penicillin was discovered by Alexander Fleming.
852 citations
"Reemergence of chloroquine (CQ) ana..." refers background in this paper
...Introduction Protozoan parasites are among the most common patho gens in the world and are recognized as causative agent of various tropical d iseases in both man and animals [1, 2]....
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TL;DR: Recent field studies suggest chloroquine resistance arose in > or = 4 distinct geographic foci and substantiate an important role of immunity in the outcomes of resistant infections after chlorquine treatment.
Abstract: The development of chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains had major impacts on global public health in the 20th century. In P. falciparum, the cause of the most lethal human malaria, chloroquine resistance is linked to multiple mutations in PfCRT, a protein that likely functions as a transporter in the parasite's digestive vacuole membrane. Rapid diagnostic assays for PfCRT mutations are already employed as surveillance tools for drug resistance. Here, we review recent field studies that support the central role of PfCRT mutations in chloroquine resistance. These studies suggest chloroquine resistance arose in > or = 4 distinct geographic foci and substantiate an important role of immunity in the outcomes of resistant infections after chloroquine treatment. P. vivax, which also causes human malaria, appears to differ from P. falciparum in its mechanism of chloroquine resistance. Investigation of the resistance mechanisms and of the role of immunity in therapeutic outcomes will support new approaches to drugs that can take the place of chloroquine or augment its efficiency.
705 citations
"Reemergence of chloroquine (CQ) ana..." refers background in this paper
...Everything was going smooth until the reports of de velopment of resistance against this brilliant drug [6-9]....
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TL;DR: Verapamil, a calcium channel blocker, completely reversed chloroquine resistance in two chlorquine-resistant P. falciparum clones from Southeast Asia and Brazil and fitted the criteria for the multidrug-resistant phenotype.
Abstract: The parasite Plasmodium falciparum, like neoplastic cells, develops resistance to multiple structurally unrelated drugs. If the mechanisms by which P. falciparum and neoplastic cells become resistant are similar, then it may be possible to reverse the resistance in the two types of cells by the same pharmacological agents. Verapamil, a calcium channel blocker, completely reversed chloroquine resistance in two chloroquine-resistant P. falciparum clones from Southeast Asia and Brazil. Verapamil reversed chloroquine resistance at the same concentration (1 X 10(-6)M) as that at which it reversed resistance in multidrug-resistant cultured neoplastic cells. This same concentration of verapamil had no effect on chloroquine-sensitive parasites. Hence, chloroquine resistance in P. falciparum may fit the criteria for the multidrug-resistant phenotype.
570 citations