Tuberculosis (TB) remains a serious threat to global public health, responsible for an estimated 1.5 million mortalities in 2018. While there are available therapeutics for this infection, slow-acting drugs, poor patient compliance, drug toxicity, and drug resistance require the discovery of novel TB drugs. Discovering new and more potent antibiotics that target novel TB protein targets is an attractive strategy towards controlling the global TB epidemic. In silico strategies can be applied at multiple stages of the drug discovery paradigm to expedite the identification of novel anti-TB therapeutics. In this paper, we discuss the current TB treatment, emergence of drug resistance, and the effective application of computational tools to the different stages of TB drug discovery when combined with traditional biochemical methods. We will also highlight the strengths and points of improvement in in silico TB drug discovery research, as well as possible future perspectives in this field.
Even better than the real thing? As host molecules, long synthetic nanotubes may be reasonable alternatives to single‐walled nanotubes. For example, calixarene‐based nanotubes effectively pack into infinite tubular bundles in the solid state (see picture), and they can be easily filled with guest molecules to form stable, but reversible, encapsulation complexes.
Novel nickel(II) complexes of pyridine-azamacrocycles (PyMACs) with pendant arms have been synthesized using simple, direct, and selective mono-N-functionalization of PyMACs. These complexes have been characterized by spectroscopy and X-ray crystallography. Nickel(II)-PyMAC complexes with a flexible pendant arm bearing a tertiary amine, a carboxylic acid, or an amide group exhibit structural and color changes due to "on-off" arm coordination to the metal center. Five- or six-coordinate complexes with the arm bound to the nickel(II) center are high-spin, while their four-coordinate "arm-off" counterparts are low-spin. Synergistic axial coordination of acetonitrile and the amide group from the pendant arm was observed. Coordination to the nickel(II) center lowers the pK(a) of the functional group attached to the macrocycle via a propylene linker by up to 4-5 orders of magnitude. Varying hydrogen bonding and proton-donating properties of the pendant arm affects the peroxidase-like activity of Ni(II)-PyMAC complexes in the oxidation of ABTS with hydrogen peroxide.
We report the synthesis and encapsulation properties of long (up to 5 nm) molecular nanotubes 1-4, which are based on calix[4]arenes and can be filled with multiple nitrosonium (NO(+)) ions upon reaction with NO(2)/N(2)O(4) gases. These are among the largest nanoscale molecular containers prepared to date and can entrap up to five guests. The structure and properties of tubular complexes 1(NO(+))(2)-4(NO(+))(5) were studied by UV/Vis, FTIR, and (1)H NMR spectroscopy in solution, and also by molecular modeling. Entrapment of NO(+) in 1(NO(+))(2)-4(NO(+))(5) is reversible, and addition of [18]crown-6 quickly recovers starting tubes 1-4. The FTIR and titration data revealed enhanced binding of NO(+) in longer tubes, which may be due to cooperativity. The described nanotubes may serve as materials for storing and converting NO(x) and also offer a promise to further develop supramolecular chemistry of molecular containers. These findings also open wider perspectives towards applications of synthetic nanotubes as alternatives to carbon nanotubes.
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