Natural products: a continuing source of novel drug leads.

Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed.

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/265172/PMC3901206.pdf

A historical overview of natural products in drug discovery.

In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as "slow substrates" or inhibitors of β-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.

Carbapenems: Past, Present, and Future

Natural products to drugs: natural product derived compounds in clinical trials

Pharmaceutical cocrystals: along the path to improved medicines.

http://www.gbv.de/dms/bs/toc/226035883.pdf

Burger's medicinal chemistry and drug discovery

Pleuromutilins. Part 1: The identification of novel mutilin 14-carbamates

Preparation and properties of 7 alpha formamidocephalosporins

Heating (3R,4R)-1-[azido-(t-butoxycarbonyl)methyl]-4-(prop-2-ynylthio)-3-(triphenylmethylamino)azetidin-2-one (4) in refluxing toluene resulted in smooth intramolecular cycloaddition of the azido-group to the acetylenic function to afford (5aR,6R,9ξ,)-t-butyl 6,7-dihydro-7-oxo-6-triphenylmethylamino-4H,5aH-azeto[2,1-b]-v-triazolo[3,4-e][1,3,5]thiadiazepine-9-carboxylate (5).

Syntheses based on 1,2-secopenicillins. Part 4. A new tricyclic β-lactam derivative

The synthesis and antibacterial activity of 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl) carbonylamino] acetamido]-7 alpha-formamidocephalosporins with various substituents at the C-3 position of the cephalosporin nucleus is described. Inhibition of Gram-positive and Gram-negative bacteria including beta-lactamase producing strains was observed with phenyl as the aryl residue. The 3,4-dihydroxyphenyl group further enhanced the activity against Gram-negative organisms; in this series, the 3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl] and 3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl] analogues (2 and 12b) exhibited exceptional activity against Gram-negative bacteria, including Pseudomonas aeruginosa.

Studies on semi-synthetic 7 alpha-formamidocephalosporins. III. Synthesis and antibacterial activity of some 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl amino] acetamido]-7 alpha-formamidoceph-3-em-4-carboxylate derivatives.

Michael J. Pearson

Papers

Burger's medicinal chemistry and drug discovery

Pleuromutilins. Part 1: The identification of novel mutilin 14-carbamates

Preparation and properties of 7 alpha formamidocephalosporins

Syntheses based on 1,2-secopenicillins. Part 4. A new tricyclic β-lactam derivative

Studies on semi-synthetic 7 alpha-formamidocephalosporins. III. Synthesis and antibacterial activity of some 7 beta-[D-2-(aryl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl amino] acetamido]-7 alpha-formamidoceph-3-em-4-carboxylate derivatives.