Exploring the Boundaries of “Practical”: De Novo Syntheses of Complex Natural Product-Based Drug Candidates

Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrowspectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

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“…A detailed summary of the historical context and synthetic efforts has been compiled nicely in Harran’s recent review. 51 …”

Section: Strategies Toward Analog Developmentmentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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“…These compounds demonstrate several important biological activities such as anti-COX-2, anti-complement, and immunosuppressive. 79 In 2018, Inoue and coworkers 80 reported a new procedure for establishing the isoryanodane ABCDE-ring structure of 148 for the first time. They synthesized the 6/5/7-membered isoryanodane BCD-ring system of 148 from the 5/6-membered ryanodane BD-ring system of 146 in 7 steps.…”

Section: Applications Of Smi 2 -Mediated Reactions...mentioning

confidence: 99%

Samarium(ii) iodide-mediated reactions applied to natural product total synthesis

Heravi

Nazari

2022

RSC Adv.

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“…It was developed by Tetraphase and displays broad activity against Gram-positive and Gramnegative bacteria, including multidrug-resistant strains, Fig. 48 The first multi-kilogram synthesis of omadacycline i.e., methicillin-resistant Staphylococcus aureus and carbapenem-resistant Entereobacteriacae [149].…”

Section: Eravacyclinementioning

confidence: 99%

Tetracycline antibiotics

Ramachanderan

Schaefer

2021

ChemTexts

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Tetracyclines belong to the first broad-spectrum, well-tolerated, and easy-to-administer antibiotics, which are effective against plague, cholera, typhoid, syphilis, Legionnaire’s disease, and anthrax. Some can also be used to treat malaria, Lyme disease, tuberculosis, Rocky Mountain spotted fever, and leprosy. Humans first encountered these chemical species involuntarily in ancient times, as evidenced from the analysis of bone samples dating back more than 1500 years. Shortly after World War II, they were “rediscovered” at Lederle Laboratories and Pfizer as a result of an intense search for new antibiotics. Their bacteriostatic action is based on the inhibition of protein biosynthesis. Since the structure elucidation by Robert Woodward, Lloyd Hillyard Conover, and others in the 1950s, tetracyclines have become preferred targets for natural product synthesis. However, on industrial scale, they became readily available by fermentation and partial synthesis. Their casual and thoughtless use in the initial decades after launch not only in humans but for veterinary purposes and as growth-enhancement agents in meat production rapidly led to the emergence of resistance. In an arms race for new antibiotics, more and more new drugs have been developed to deal with the threat. In this ongoing endeavor, a remarkable milestone was set by Andrew Myers in 2005 with the convergent total synthesis of (−)-doxycycline, as well as numerous azatetracyclines and pentacyclines, which has inspired chemists in the pharmaceutical industry to discover novel and highly active tetracyclines in recent years. Graphic abstract

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Exploring the Boundaries of “Practical”: De Novo Syntheses of Complex Natural Product-Based Drug Candidates

Cited by 64 publications

References 316 publications

Natural Products as Platforms To Overcome Antibiotic Resistance

Natural Products as Platforms To Overcome Antibiotic Resistance

Samarium(ii) iodide-mediated reactions applied to natural product total synthesis

Tetracycline antibiotics

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