Stereochemistry at the Forefront in the Design and Discovery of Novel Anti-tuberculosis Agents

Abstract

Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry.

Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives

“…For instance, if an inhibitor is a small compound and contains a stereogenic center in its chemical structure, such a chiral molecule can be exploited for synthesis of two enantiomers that are mirror images to each other. More often, the two enantiomers exhibit significant difference in their target selectivity and potency, in addition to difference in bioavailability, rate of metabolism, excretion and toxicity. , Therefore, a mechanistic characterization of the two enantiomers provides useful insights into developing more selective and more potent agents. Here we describe a mechanistic study of the enantiomers of the C-4-methyl 2,3-benzodiazepine derivatives, as part of our investigation of the structure–activity relationship of these compounds (Figure ).…”

Multi-drug resistant tuberculosis and HIV-infection

“…Кроме того, имеются сообщения о новых перс пективных химических соединениях ПТП, которые, вполне возможно, помогут человечеству в борьбе с ШЛУ туберкулезом [44][45][46][47][48].…”

Chiral Resolution of Racemic p-Methylsulfonylphenyl Serine Ethyl Ester with Lipases: The Mechanism of Side Reaction and Its Suppression

“…Because different enantiomers of a drug can exert different pharmacological and toxic effects to an organism, chirality is a crucial factor for the efficacy and safety of many drug products. Thus, production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. − Single enantiomers can be produced through both chemical and biocatalytic approaches. Compared to chemical methods, enzymatic methods are preferable because they are usually highly enantio- and regioselective.…”