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 affect millions worldwide. Unfortunately, current antileishmanial therapies remain highly inadequate, hampered by issues such as toxicity, poor efficacy, complex administration, and the rapid emergence of drug resistance. Consequently, there is an urgent and widely recognized need to develop new, safer, and more effective therapeutics. This project investigates the potential of natural product–derived tambjamines as promising new leads for the treatment of leishmaniasis. Our preliminary studies revealed that tambjamine analogs possess remarkable antileishmanial potency, exceeding that of the reference drug miltefosine. Notably, this work represents the first report of antileishmanial activity within the tambjamine family, opening the door to an entirely new class of therapeutic chemotypes. Through systematic structure–activity relationship (SAR) studies, we have identified several highly potent analogs and demonstrated partial efficacy in controlling leishmaniasis in a murine model. Ongoing lead optimization efforts aim to enhance pharmacological properties and advance these tambjamine derivatives as orally active antileishmanial drug candidates.
Novel Liver Stage Active Antimalarials
We have developed a novel acridone-based antimalarial chemotype that exhibits potent dual-stage efficacy against both the liver and blood stages of malaria, demonstrating single-dose curative potential and the capacity to prevent relapsing infections. The ability to target multiple stages of the Plasmodium life cycle represents a major therapeutic advance, ideally positioned to contribute to global malaria eradication efforts. Through a rigorous lead optimization campaign, we have generated a series of second-generation acridone analogs with markedly improved efficacy, metabolic stability, pharmacokinetic properties, and safety profiles. Our overarching objective is to develop a novel antimalarial that is safe for individuals with G6PD deficiency and suitable for use in pregnant women and children, the populations most vulnerable to malaria. Ongoing antimalarial efficacy and animal toxicity studies are focused on identifying a lead acridone candidate for advancement into preclinical development.
(Bio)synthesis and Antimalarial Activity of Novel Marineosin Natural Products
We have elucidated, for the first time, the complete biosynthetic pathway of the marineosin family of natural products, which are structurally related to the prodiginines but distinguished by an unusual spiro-tetrahydropyran–aminal core fused to a 12-membered macrocyclic pyrrole. Our findings unequivocally refuted earlier biosynthetic hypotheses proposed by other researchers and established a new class of antimalarial chemotypes with significant therapeutic potential. Currently, no practical synthetic routes exist for the preparation of marineosin derivatives, and their biological activities remain largely unexplored. Consequently, our ongoing efforts are directed toward the development of efficient synthetic methodologies to access novel marineosin analogs and to evaluate their antimalarial and broader biological 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.
Development of Tambjamines As Next-Generation Antifungal Agents
Fungal infections represent a major global health challenge, highlighting the urgent need for new chemotypes active against multidrug-resistant fungal pathogens such as Candida auris. Recently, we developed a series of tambjamine analogs that exhibited potent antifungal activity against both Candida albicans and Candia auris strains. This discovery offers a new avenue for developing improved medicines to treat fungal infections. Further in vivo efficacy studies and comprehensive SAR investigations on an expanded tambjamine library are currently underway.