Natural Products Inspired Novel Antimalarial Agents
Many natural products have provided inspiration and templates toward the design and development of various drugs that are currently in clinical use or under development stage. Approximately one-third of the top-selling drugs in the world are natural products or their derivatives. Indeed, natural products have played an important role in the treatment of the malaria, such as Quinine, derived from the bark of the South American cinchona tree, and Artemisinin, extracted from the leaves of sweet wormwood (Artemisia annua). Over time the parasite which causes malaria develops resistance to drugs, and so we need to find new structures which operate by a different mechanism. Over the past few years, our research has focused on the discovery and development of novel antimalarials from the natural sources. To that end, we have developed prodiginine and tambjamine natural products as novel antimalarials that are effective against multiple life-cycle stages of malaria parasite. Prodiginines (PGs) and tambjamines (TAs) belong to a family of intriguing pyrrolylpyrromethane alkaloid antibiotics isolated from various bacteria, marine and terrestrial sources. 4-Methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC) is the common precursor in the biosynthetic pathway of both PGs and TAs. The key structural difference between PGs and TAs is that TAs constitute an alkylamine moiety in the place of alkyl-pyrrole (ring-C) of PGs. Our prodiginine and tambjamine scaffolds are the unique chemotypes as compared to existing antimalarials, and potentially operate by a novel mode of action. Further lead optimization studies are currently underway, and additional structure activity relationships will be established toward the selection of the late lead candidate(s) to be advanced for future preclinical evaluations.
Development of Novel Natural Product Inspired Antileishmanial Drugs
Leishmania and other kinetoplastid parasites cause devastating diseases that afflict millions of people, yet current antileishmanial therapies are woefully inadequate, suffering from toxicity, difficulty of delivery, development of drug resistance, poor efficacy, etc. Hence, there is a widely recognized and urgent need for development of novel therapies that represent improvements over current drugs. This project will explore the potential of the natural product-derived tambjamines as potential novel drug leads against leishmaniasis. Our preliminary results demonstrated that the tambjamine molecules exhibit remarkable antileishmanial properties and the potency was greater than the reference drug miltefosine. Notably, our study presented the first account of antileishmanial activity in the tambjamine family, and may lead to the generation of new antileishmanial chemotypes. We have established robust structural activity relationships, identified multiple potent analogues, and demonstrated partial efficacy in controlling leishmaniasis in a murine model. Further lead optimizations of these tambjamine compounds are currently underway to produce antileishmanial oral drugs.
Novel Liver Stage Active Antimalarials
We have developed a novel antimalarial acridone chemotype with dual stage efficacy against both liver stage and blood stage malaria, as well as single-dose cure ability and potential to prevent relapsing infection. The ability to combat multiple stages of the infection represents a powerful tool, and one ideally suited to achieve the broadest possible benefit as the malaria eradication effort proceeds. A rigorous optimization process has produced a series of second-generation acridones with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. Our overarching goal is to develop a novel antimalarial that is safe in individuals with G6PD deficiency, and in the most vulnerable populations–pregnant women and children, thus supporting world-wide elimination of the disease. Further antimalarial and animal toxicity studies are currently underway toward the selection of a promising acridone analog to be advanced for future preclinical evaluations.
(Bio)synthesis and Antimalarial Activity of Novel Marineosin Natural Products
We have elucidated the first and complete biosynthetic pathway of marineosin natural products that are similar to the prodiginines, containing an unusual spiro-tetrahydropyran-aminal core fused with a 12-membered macrocyclic pyrrole. Our study unequivocally disproved previously published biosynthetic hypotheses by other researchers, and generated a novel class of antimalarial chemotype. Currently, there are no practical synthetic routes toward the generation of marineosin derivatives, nor reported comprehensive biological activities. Therefore, our efforts also focused on the development of new synthetic methods toward the generation of derivatives, and their testing for antimalarial and other activities.
Development of Pyrrolylpyrromethene Alkaloids as Novel Antibacterial Agents
Antibiotic resistance is one of the serious problems, describing a significant health complication globally. Therefore, there is an urgent need to discover and develop novel antibiotics with new mechanisms of action. To that end, we established a new collaborative research project with Walter Reed Army Institute of Research toward the development of novel pyrrolylpyrromethene alkaloids, specifically the prodiginines and tambjamines, as novel antibacterial agents. Our preliminary results demonstrated that a number of our synthetic tambjamines and prodiginines have remarkable antibacterial properties against ESKAPEE panel consists of 17 bacterial strains from 2 gram-positive (E. faecium, S. aureus) and 5 gram-negative (K. pneumoniae, A. baumannii, P. aeruginosa, E. cloacae, and E. coli) bacterial species. Further optimizations and SAR studies are currently underway to produce novel antibacterial agents.