March Editorial Focus: Tuberculosis

With World Tuberculosis Day coming on the 24th of March, we take a look at medicinal chemistry research in the area of tuberculosis

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Future Medicinal Chemistry is the home for the latest research in medicinal chemistry and with the theme of tuberculosis, we bring you five of the latest publications in the field


Utilizing diversity-oriented synthesis in antimicrobial drug discovery

The development of resistance to existing antimicrobials has created a threat to human health that is not being addressed through our current drug pipeline. Limitations with the use of commercial vendor libraries and natural products have created a need for new types of small molecules to be screened in antimicrobial assays. Diversity oriented synthesis (DOS) is a strategy for the efficient generation of compound collections with a high degree of structural diversity. Diversity-oriented synthesis molecules occupy the middle ground of both complexity and efficiency of synthesis between natural products and commercial libraries. In this review we focus upon the use of diversity-oriented synthesis compound collections for the discovery of new antimicrobial agents.


Gold(III) complexes in medicinal chemistry

A number of gold(III) compounds has been designed with the objective of overcoming the disadvantages associated with the platinum-based drugs for cancer treatment. Compounds of a remarkable structural manifold show significant antiproliferative effects in vitro against a number of cancer cells, including cisplatin resistant ones. The target of most of them is, unlike that of cisplatin, not the DNA. Although the mechanisms of action displayed by the gold compounds in biological media are still under investigation, many studies show evidence that the cellular targets are mitochondria-based. Recent advances in gold(III) medicinal chemistry also recommend such compounds for other pharmacological applications such as the treatment of viral or parasitic diseases. The radioactive isotopes 198Au and 199Au present potential in radiotherapy.


Lessons learned in TB drug discovery: an industrial chemist's perspective

TB, caused by Mycobacterium tuberculosis (Mtb), is an airborne infectious disease that infects almost a third of the world's human population [1]. The emergence of multidrug-resistant (MDR) TB is threatening the current standard of care and new drugs are urgently needed. MDR TB is caused by Mtb that is resistant at least to isoniazid and rifampicin, the two most potent anti-TB drugs. Current treatment for MDR TB consists of lengthy regimens that are less effective, more expensive and less well tolerated [2]. Therefore, new TB drugs are needed that are not only able to shorten the longer treatment regimens, but also to control drug-resistant forms of TB and can be used along with the current AIDS/HIV retroviral treatments [3]. Despite an increase in research activities in TB, few novel chemical entities have been identified for preclinical/clinical development and only two new drugs (bedaquiline and delamanid) have been approved in the past 40 years [4,5].


The discovery of medicines for rare diseases

There is a pressing need for new medicines (new molecular entities; NMEs) for rare diseases as few of the 6800 rare diseases (according to the NIH) have approved treatments. Drug discovery strategies for the 102 orphan NMEs approved by the US FDA between 1999 and 2012 were analyzed to learn from past success: 46 NMEs were first in class; 51 were followers; and five were imaging agents. First-in-class medicines were discovered with phenotypic assays (15), target-based approaches (12) and biologic strategies (18). Identification of genetic causes in areas with more basic and translational research such as cancer and in-born errors in metabolism contributed to success regardless of discovery strategy. In conclusion, greater knowledge increases the chance of success and empirical solutions can be effective when knowledge is incomplete.


Medicinal applications of perfluoroalkylated chain-containing compounds

Compounds with polyfluorinated molecular fragments possess unique properties associated with the presence of a large number of fluorine atoms that affect lipophilicity and conformational rigidity of the parent molecule along with other effects. The aim of this review is to provide an overview of synthesized compounds possessing perfluoroalkylated or polyfluorinated chains that have been tested for bioactivity or as potential drug candidates for the treatment of various diseases. As far as the length of the perfluoroalkylated chain is concerned the focus is centered on the compound bearing perfluoroethyl or tetrafluoroethyl as well as longer chains. The perfluoroalkylated compounds discussed are classified according to their biological activity.


Cormer E, Duval JR, DuPont Lee M IV. Utilizing diversity-oriented synthesis in antimicrobial drug discovery. Future Medicinal Chemistry. 6(17), 1927-1942 (2014)

Da Silva Maia PI, Deflon VM, Abram U. Gold(III) complexes in medicinal chemistry. Future Medicinal Chemistry. 6(13), 1515-1536 (2014).

Jiricek J. Lessons learned in TB drug discovery: an industrial chemist's perspective. Future Medicinal Chemistry. 6(12), 1377-1380 (2014).

Swinney DC, Xia S. The discovery of medicines for rare diseases. Future Medicinal Chemistry. 6(9), 987-1002 (2014).

Prchalová E, Štěpánek O, Smrček S, Kotora M. Medicinal applications of perfluoroalkylated chain-containing compounds. Future Medicinal Chemistry. 6(10), 1201-1229 (2014)

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Gerald PJ Clarke

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