This review is an updated and expanded version of the five prior reviews that were published in this journal in 1997, 2003, 2007, 2012, and 2016. For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of January 1981 to the 30th of September 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of September 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irrespective of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small molecules, 40, or 53.3%, are N or ND. In the 1981 to date time frame the equivalent figures for the N* compounds of the 185 small molecules are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compounds (one of which is a little speculative) approved as drugs in this 39-year time frame, though there is also one drug that was developed using the "fragment-binding methodology" and approved in 2012. We have also added a discussion of candidate drug entities currently in clinical trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the absolute requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated"; thus we consider that this area of natural product research should be expanded significantly.

Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019.

Summary: Nitroaromatic compounds are relatively rare in nature and have been introduced into the environment mainly by human activities. This important class of industrial chemicals is widely used in the synthesis of many diverse products, including dyes, polymers, pesticides, and explosives. Unfortunately, their extensive use has led to environmental contamination of soil and groundwater. The nitro group, which provides chemical and functional diversity in these molecules, also contributes to the recalcitrance of these compounds to biodegradation. The electron-withdrawing nature of the nitro group, in concert with the stability of the benzene ring, makes nitroaromatic compounds resistant to oxidative degradation. Recalcitrance is further compounded by their acute toxicity, mutagenicity, and easy reduction into carcinogenic aromatic amines. Nitroaromatic compounds are hazardous to human health and are registered on the U.S. Environmental Protection Agency's list of priority pollutants for environmental remediation. Although the majority of these compounds are synthetic in nature, microorganisms in contaminated environments have rapidly adapted to their presence by evolving new biodegradation pathways that take advantage of them as sources of carbon, nitrogen, and energy. This review provides an overview of the synthesis of both man-made and biogenic nitroaromatic compounds, the bacteria that have been identified to grow on and completely mineralize nitroaromatic compounds, and the pathways that are present in these strains. The possible evolutionary origins of the newly evolved pathways are also discussed.

Nitroaromatic Compounds, from Synthesis to Biodegradation

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme.

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Exploiting bacterial DNA gyrase as a drug target: current state and perspectives.

Many fungi, lichens, and bacteria produce xanthones (derivatives of 9H-xanthen-9-one, “xanthone” from the Greek “xanthos”, for “yellow”) as secondary metabolites. Xanthones are typically polysubstituted and occur as either fully aromatized, dihydro-, tetrahydro-, or, more rarely, hexahydro-derivatives. This family of compounds appeals to medicinal chemists because of their pronounced biological activity within a notably broad spectrum of disease states, a result of their interaction with a correspondingly diverse range of target biomolecules. This has led to the description of xanthones as “privileged structures”.(1) Historically, the total synthesis of the natural products has mostly been limited to fully aromatized targets. Syntheses of the more challenging partially saturated xanthones have less frequently been reported, although the development in recent times of novel and reliable methods for the construction of the (polysubstituted) unsaturated xanthone core holds promise for future endeavors. In particular, the fascinating structural and biological properties of xanthone dimers and heterodimers may excite the synthetic or natural product chemist.

Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis

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Plant pathogenicity in the genus streptomyces.

Biosynthesis of Tetracyclines. I. The Halide Metabolism of Streptomyces aureofaciens Mutants. The Preparation and Characterization of Tetracycline, 7-Chloro36 -tetracycline and 7-Bromotetracycline

LL-F42248.ALPHA., a novel chlorinated pyrrole antibiotic.

A new antibacterial antibiotic, designated LL-E19085 alpha, was isolated from the fermentation broth of an actinomycete strain. Based on cultural, physiological, morphological and chemical characteristics, culture LL-E19085 was identified as a new subspecies of Micromonospora citrea. Antibiotic LL-E19085 alpha demonstrated potent activity against a spectrum of Gram-positive aerobic and anaerobic bacteria.

LL-E19085 alpha, a novel antibiotic from Micromonospora citrea: taxonomy, fermentation and biological activity

A new antibacterial antibiotic, designated simaomicin α (LL-D42067 α) was isolated from the fermentation broth of an actinomycete strain. Based on cultural, physiological, morphological and chemical characteristics, culture LL-D42067 was identified as a new subspecies of Actinomadura madurae. Simaomicin α demonstrated potent activity against Gram-positive bacteria and was active in vivo against a variety of Eimeria species causing coccidiosis in chickens.

Simaomicin (LL-D42067), a novel antibiotic from Actinomadura madurae. I. Taxonomy, fermentation and biological activity.

Bromide and thiocyanate have been shown to be effective inhibitors of the chlorination process leading to chlortetracycline formation by certain strains of Streptomyces aureofaciens Duggar (Gourevitch et al., 1955; Doerschuk, et at., 1956). Sekizawa (1955) reported thiourea, 2-thiouracil, 2-mercaptobenzothiazole, and thioglycolic-f3-aminonaphthalide (thionalide) to inhibit chlorination by this organism leading to the production of tetracycline rather than chlortetracyline. The present paper summarizes the work in our laboratories on the effectiveness of a number of compounds, some of which have antithyroid activity (Astwood et al., 1945) as chlorination inhibitors in an S. aureofaciens chlortetracycline synthesizing system.'

Joseph J. Goodman

Papers

Biosynthesis of Tetracyclines. I. The Halide Metabolism of Streptomyces aureofaciens Mutants. The Preparation and Characterization of Tetracycline, 7-Chloro36 -tetracycline and 7-Bromotetracycline

LL-F42248.ALPHA., a novel chlorinated pyrrole antibiotic.

LL-E19085 alpha, a novel antibiotic from Micromonospora citrea: taxonomy, fermentation and biological activity

Simaomicin (LL-D42067), a novel antibiotic from Actinomadura madurae. I. Taxonomy, fermentation and biological activity.

Inhibition of the incorporation of chloride into the tetracycline molecule