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Synthesis and evaluation of diazaquinomycin derivatives as new anti-tuberculosis agents

Diaqing Sun headshot
Dianqing Sun

Research Summary: Tuberculosis (TB) is a contagious airborne disease caused by a deadly bacterium pathogen called Mycobacterium tuberculosis. TB is the second leading infectious disease in the world and even in the 21st century remains an intransigent health problem. The World Health Organization (WHO) estimates that about a third of the world’s population is latently infected with TB bacteria. In 2017, an estimated 1.6 million people died from this deadly disease and about 10 million became ill with TB. The number of infected cases are still rising rapidly because of human immunodeficiency virus (HIV) co-infection, multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. The challenges and problems regarding TB treatment regimens include its latency, long treatment regimen, HIV co-infection, and emerging drug resistance. Notably, only bedaquiline (SirturoTM), the first new antibiotic for the treatment of MDR-TB, has been approved by the US FDA in late 2012 since the introduction of Rifampin 50 years ago.3 Therefore, there is an urgent need to develop new anti-tuberculosis agents with distinct mechanisms of action and fewer cross resistance properties.

Among antibacterial discovery strategies, whole cell-based phenotypic screens of small molecule and/or natural product-like libraries, followed by target deconvolution and identification remain an attractive and efficient approach. Natural products represent one of the most valuable sources for novel bioactive molecules and chemical diversity in drug discovery. Historically, the majority of antimicrobial agents, including TB drugs, originate from natural products.8 Diazaquinomycins H and J were isolated from a freshwater-derived actinomycete in 2015 and reported to show potent anti-tuberculosis activity with minimum inhibitory activity of 0.04-0.07 µg/mL. Notably, this class of diazaquinomycin antibiotics also possessed favorable selectivity profile toward M. tuberculosis with low cytotoxicity. We previously evaluated the substrate scope and optimized the chemistry to access the tricyclic diazaquinomycin core. We very recently reported the first total synthesis of diazaquinomycins H and J via double Knorr cyclization in the presence of triisopropylsilane.

The specific objective of the proposed research is to synthesize, evaluate, and develop diazaquinomycin derivatives as new anti-tuberculosis agents, conduct structure-activity relationship (SAR) studies, and microbiological profiling of diazaquinomycin leads. The central hypothesis is diazaquinomycin analogs will show excellent anti-tuberculosis activity with desirable physiochemical properties and serve as valuable anti- tuberculosis leads for further development. The rationale is based on others’ along with our own preliminary data. We will achieve our goal through the following specific aim, and collaborate with Dr. Richard Lee (Medicinal Chemist at St. Jude Children’s Research Hospital) and apply a multidisciplinary collaborative approach with expertise in synthetic organic chemistry, medicinal chemistry, microbiology, and antimicrobial drug discovery and development.


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