Over
the past 2000 years, tuberculosis (TB) has claimed more lives
than any other infectious disease. In 2020 alone, TB was responsible
for 1.5 million deaths worldwide, comparable to the 1.8 million deaths
caused by COVID-19. The World Health Organization has stated that
new TB drugs must be developed to end this pandemic. After decades
of neglect in this field, a renaissance era of TB drug discovery has
arrived, in which many novel candidates have entered clinical trials.
However, while hundreds of molecules are reported annually as promising
anti-TB agents, very few successfully progress to clinical development.
In this Perspective, we critically review those anti-TB compounds
published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally,
we highlight the main challenges and strategies for developing new
TB drugs and the current global pipeline of drug candidates in clinical
studies to foment fresh research perspectives.
This review covers the application of heptamethine cyanine dye (HMCD) mediated drug delivery. A relatively small number of HMCDs possess tumor targeting abilities, and this has spurred interest from research groups to explore them as drug delivery systems. Their tumor selectivity is primarily attributed to their uptake by certain isoforms of organic anion transporting polypeptides (OATPs) which are overexpressed in cancer tissues, although there are other possible mechanisms for the observed selectivity still under investigation. This specificity is confirmed using various cancer cell lines and is accompanied by moderate cytotoxicity. Their retention in tumor tissue is facilitated by the formation of albumin adducts as revealed by published mechanistic studies. HMCDs are also organelle selective dyes with specificity toward mitochondria and lysosomes, and with absorption and emission in the near-infrared region. This makes them valuable tools for biomedical imaging, especially in the field of fluorescenceguided tumor surgery. Furthermore, conjugating antitumor agents to HMCDs is providing novel drugs that await clinical testing. HMCD development as theranostic agents with dual tumor targeting and treatment capability signals a new approach to overcome drug resistance (mediated through evasion of efflux pumps) and systemic toxicity, the two parameters which have long plagued drug discovery.
Small cyclic peptides possess a wide range of biological properties and unique structures that make them attractive to scientists working in a range of areas from medicinal to materials chemistry. However, cyclic tetrapeptides (CTPs), which are important members of this family, are notoriously difficult to synthesize. Various synthetic methodologies have been developed that enable access to natural product CTPs and their rationally designed synthetic analogues having novel molecular structures. These methodologies include the use of reversible protecting groups such as pseudoprolines that restrict conformational freedom, ring contraction strategies, onresin cyclization approaches, and optimization of coupling reagents and reaction conditions such as temperature and dilution factors. Several fundamental studies have documented the impacts of amino acid configurations, N-alkylation, and steric bulk on both synthetic success and ensuing conformations. Carefully executed retrosynthetic ring dissection and the unique structural features of the linear precursor sequences that result from the ring dissection are crucial for the success of the cyclization step. Other factors that influence the outcome of the cyclization step include reaction temperature, solvent, reagents used as well as dilution levels. The purpose of this review is to highlight the current state of affairs on naturally occurring and rationally designed cyclic tetrapeptides, including strategies investigated for their syntheses in the literature, the conformations adopted by these molecules, and specific examples of their function. Using selected examples from the literature, an in-depth discussion of the synthetic techniques and reaction parameters applied for the successful syntheses of 12-, 13-, and 14-membered natural product CTPs and their novel analogues are presented, with particular focus on the cyclization step. Selected examples of the three-dimensional structures of cyclic tetrapeptides studied by NMR, and X-ray crystallography are also included.
CONTENTSSpecial Issue: Macrocycles
A published
study of structural features associated with the aerobic
and anaerobic activities of 4- and 5-nitroimidazoles had found that
the 3-nitro isomer of pretomanid, 8, displayed interesting
potencies, including against nitroreductase mutant Mycobacterium
tuberculosis. However, recent nuclear magnetic resonance
analyses of two trace byproducts, isolated from early process optimization
studies toward a large-scale synthesis of pretomanid, raised structural
assignment queries, particularly for 8, stimulating further
investigation. Following our discovery that the reported compound
was a 6-nitroimidazooxazole derivative, we developed a de
novo synthesis of authentic 8 via nitration
of the chiral des-nitro imidazooxazine alcohol 26 in
trifluoroacetic or acetic anhydride, and verified its identity through
an X-ray crystal structure. Unfortunately, 8 displayed
no antitubercular activity (MICs > 128 μM), whereas the second
byproduct (3′-methyl pretomanid) was eight-fold more potent
than pretomanid in the aerobic assay. These findings further clarify
target specificities for bicyclic nitroimidazoles, which may become
important in the event of any future clinical resistance.
The presence of “hypoxic” tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.
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