Isolation and Antimalarial Activity of Small Molecules from Ocimum sanctum

圣罗勒小分子的分离及其抗疟活性

• 批准号: 7392525
• 负责人: Shuren Zhu
• 金额: $ 30万
• 依托单位: RADIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392525
• 关键词: Acute; Adsorption; Adult; Adverse effects; Affect; African; Animal Model; Animals; Antimalarials; Appetite Depressants; Attention; Biological Availability; Biological Factors; Cell Line; Cessation of life; Characteristics; Chemical Structure; Chemicals; Chloroquine; Chloroquine resistance; Clinical Research; Clinical Trials; Communicable Diseases; Condition; Cyclic GMP; Data; Development; Dose; Drug Formulations; Drug Kinetics; Drug resistance; Epidemic; Epithelial Cells; Evaluation; Excipients; Excretory function; Exhibits; Falciparum Malaria; Generations; Goals; Growth; Guanosine Monophosphate; Health; Hepatocyte; Human; Immunocompromised Host; Investigational Drugs; Investigational New Drug Application; Kinetics; Laboratories; Left; Lethal Dose 50; Liver; Macaca mulatta; Malaria; Mefloquine; Metabolism; Mus; New Drug Approvals; Numbers; Ocimum; Parasite resistance; Parasites; Parasitic infection; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plant Roots; Plasmodium; Plasmodium falciparum; Preparation; Process; Rattus; Recrudescences; Research; Research Design; Resistance; Rodent; Rodent Model; Route; Schedule; Sprague-Dawley Rats; Swiss Mice; Testing; Thailand; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicity Tests; Tuberculosis; United States Food and Drug Administration; Work; albino mouse; analytical method; base; capsule; day; efficacy evaluation; hemozoin; in vivo; killings; male; mortality; neurotoxicity; novel; pre-clinical; preclinical study; prophylactic; scale up; small molecule

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a new drug (new chemical entity [NCE]) that is inexpensive, orally active, non-toxic and can provide cure for P. falciparum malaria. Radix Pharmaceuticals has isolated and purified two natural products from the dried root barks of Ocimum sanctum Linn. The chemical structures of both compounds were determined. These compounds showed equally potent inhibitory activity against both chloroquine sensitive malaria strain (D-6) and chloroquine resistant malaria strain (W-2). The IC50's (concentration of compound that affords 50% of inhibition) were superior to the positive controls, chloroquine and mefloquine. These compounds also demonstrated low toxicity in human adult liver epithelial cells and freshly isolated rat hepatocytes. Additionally, these compounds were found to possess desirable ADME (adsorption, distribution, metabolism, and excretion) characteristics. These compounds possess the potential to interfere hemozoin synthesis, an indispensable process for the malaria parasite. Based on these preliminary studies, the overall goal of this Phase I project is to establish pre-clinical profiles for the candidates. Under Phase I support, we will perform the scale up isolation and purification of these compounds and begin pre-clinical studies in rodent models to obtain efficacy, pharmacokinetics and toxicity data. The following interactive studies will be performed to obtain rodent pre-clinical profiles efficiently and effectively: (I) The two natural products will be isolated and purified in a larger scale (1-2 kg per compound). (II) Antimalarial efficacy data will be obtained in immunocompromised BXN mice infected with human malaria strains and male Swiss albino mice infected with rodent malaria strain P. berghei. (III) Test compounds will be administered intraperitoneally, subcutaneously, or orally to rats and pharmacokinetic parameters will be calculated. (IV) Test compounds will be tested in rodent models to obtain acute and sub- acute toxicity, fetotoxicity, anorectic toxicity, and neurotoxicity information. On completion of the Phase I studies, compound(s) that are orally active and possess good therapeutic index will be selected for further development in Phase II. The efforts in Phase II would include pre-clinical studies in Rhesus monkey, followed by GMP isolation/purification and GLP evaluation. Investigational new drug (IND) application will then be filed with FDA. Project Narrative: Malaria is one of the most common infectious diseases in the world. It affects approximately 300 million people and leads to more than 2 million death a year. Discovering new and effective anti-malarial drugs possesses potential to contribute significantly to the economy of the nation and to the health of her people.

描述（由申请人提供）：本项目的长期目标是开发一种廉价、口服活性、无毒且可治愈恶性疟原虫疟疾的新药（新化学实体[NCE]）。Radix Pharmaceuticals从圣罗勒（Ocimum sanctum Linn）的干燥根皮中分离纯化了两种天然产物。确定了两种化合物的化学结构。这些化合物对氯喹敏感疟疾株（D-6）和氯喹抗性疟疾株（W-2）显示出同等有效的抑制活性。IC 50（提供50%抑制的化合物浓度）上级于阳性对照氯喹和甲氟喹。这些化合物在成人肝上皮细胞和新鲜分离的大鼠肝细胞中也显示出低毒性。此外，发现这些化合物具有理想的ADME（吸附、分布、代谢和排泄）特性。这些化合物具有干扰疟原虫色素合成的潜力，而疟原虫色素合成是疟疾寄生虫不可或缺的过程。基于这些初步研究，该I期项目的总体目标是为候选人建立临床前特征。在第一阶段支持下，我们将对这些化合物进行放大分离和纯化，并开始在啮齿动物模型中进行临床前研究，以获得功效、药代动力学和毒性数据。将进行以下交互研究，以高效和有效地获得啮齿动物临床前特征：（I）将以较大规模（每种化合物1-2 kg）分离和纯化两种天然产物。(II)将在感染人疟疾菌株的免疫受损BXN小鼠和感染啮齿类疟疾菌株伯氏疟原虫的雄性瑞士白化病小鼠中获得抗疟疗效数据。(III)将向大鼠腹膜内、皮下或经口给予测试化合物，并计算药代动力学参数。(IV)将在啮齿动物模型中测试供试化合物，以获得急性和亚急性毒性、胎儿毒性、厌食毒性和神经毒性信息。在I期研究完成后，将选择具有口服活性且具有良好治疗指数的化合物用于II期的进一步开发。第II阶段的工作将包括在恒河猴中进行临床前研究，然后进行GMP分离/纯化和GLP评价。研究性新药（IND）申请将提交给FDA。 项目简介：疟疾是世界上最常见的传染病之一。它影响到大约3亿人，每年导致200多万人死亡。发现新的和有效的抗疟疾药物具有为国家经济和人民健康做出重大贡献的潜力。