Orally Bioavailable 4(1H)-Quinolones with Multi-Stage Antimalarial Activity

具有多阶段抗疟活性的口服生物可利用 4(1H)-喹诺酮类药物

• 批准号: 9913468
• 负责人: DENNIS E KYLE
• 金额: $ 71.38万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913468
• 关键词: Affect; African; Aminoquinolines; Antimalarials; Area; Artemisinins; Avian Malaria; Bioavailable; Biological Availability; Blood; Cause of Death; Cessation of life; Child; Chloroquine resistance; Combined Modality Therapy; Contracts; Country; Culicidae; Cytochrome bc1 Complex; Data; Development; Disease; Dose; Drug resistance; Elements; Erythrocytes; Evaluation; Falciparum Malaria; Future; Glucosephosphate Dehydrogenase; Gold; In Vitro; Individual; Infection; Investigation; Lead; Liver; Macaca mulatta; Malaria; Mammals; Medicine; Modeling; Multi-Drug Resistance; New Agents; Oral; Parasite resistance; Parasites; Parasitic Diseases; Performance; Pharmaceutical Preparations; Phase; Plasmodium cynomolgi; Plasmodium falciparum; Plasmodium vivax; Population; Prevalence; Primaquine; Prodrugs; Property; Public Health; Pyridones; Quinolones; Regimen; Relapse; Reporting; Research; Research Personnel; Resistance; Resort; Rhesus; Risk; Series; Solubility; Southeastern Asia; Structure; Therapeutic Index; Toxic effect; Traditional Medicine; Work; World Health Organization; analog; aqueous; base; combat; drug development; improved; in vivo; inhibitor/antagonist; malaria infection; mouse model; novel therapeutics; phase 1 study; preclinical development; preclinical efficacy; preclinical safety; preclinical toxicity; prevent; prophylactic; resistant Plasmodium falciparum; scaffold; service member; transmission process

Project Summary / Abstract Malaria remains among the most significant public health problems in the world. Since 40% of the world’s population living in malaria endemic areas, malaria is one of the most devastating parasitic diseases. More than 200 million infections and over 0.4 million of deaths were reported in 2015. Importantly, commonly used antimalarials lose potency at an alarming rate due to widespread prevalence of drug resistant parasites. For example, resistance to chloroquine, one of the most commonly used antimalarials, has been confirmed in nearly all regions affected by malaria. Artemisinin combination therapies (ACTs) have arisen to combat malaria resistant to traditional medicines, and presently serve as a last-resort treatment. Unfortunately, a recent WHO report indicates that resistance to artemisinin has emerged in more than five countries of South-East Asia. Due to the limited number of antimalarial chemotypes and rising P. falciparum resistance to most available medicines, new drugs are urgently required to combat this deadly disease. Herein, we propose the evaluation and optimization of two 4(1H)-quinolone chemotypes, namely the phenoxyethoxy-4(1H)-quinolones (PEQs) and the 1,2,3,4- tetrahydroacridin-9(10H)-ones (THAs), for their activity against the blood, liver, and transmission stages of the parasite. The PEQs and THAs are structurally related to 4(1H)-quinolone ELQ-300, whose advancement towards Phase I studies was deferred due to poor oral bioavailability, limiting preclinical safety and toxicity studies. Our preliminary data demonstrate that a variety of structural elements, which we identified, render the PEQs and THAs a better aqueous solubility than ELQ-300 without significantly reducing the antimalarial activity. Furthermore, the use of a solubilizing prodrug moiety has also shown to improve the 4(1H)-quinolone’s antimalarial activity in vivo. Based on this preliminary data, we hypothesize that increase of PEQ’s and THA’s aqueous solubility will improve the overall performance of 4(1H)-quinolone antimalarials and possibly provide entrance to preclinical development. Specifically, we propose to further optimize our PEQs and THAs as we identified specific substituents, which significantly increase aqueous solubility, while also maintain or improve antimalarial activity. Furthermore, we will also continue the optimization of a general prodrug approach. The proposed research has potential to provide orally bioavailable 4(1H)-quinolone-based malaria prophylactic regimens that (a) target blood, liver, and transmitting stages of the malaria parasites, (b) act against relapsing malaria including P. vivax, (c) encourage higher compliance in deployed service members, and (d) possibly optimize the application of existing malaria drugs reducing the impact of artemisinin resistant P. falciparum.

项目摘要/摘要