Elemental exchange: Bioisosteric replacement of phosphorus by boron in drug design.

Continuous efforts are being directed toward the employment of boron in drug design due to its advantages and unique characteristics including a plethora of target engagement modes, lower metabolism, and synthetic accessibility, among others. Phosphates are components of multiple drug molecules as well as clinical candidates, since they play a vital role in various biochemical functions, being components of nucleotides, energy currency- ATP as well as several enzyme cofactors. This review discusses the unique chemistry of boron functionalities as phosphate bioisosteres - "the boron-phosphorus elemental exchange strategy" as well as the superiority of boron groups over other commonly employed phosphate bioisosteres. Boron phosphate-mimetics have been utilized for the development of enzyme inhibitors as well as novel borononucleotides. Both the boron functionalities described in this review-boronic acids and benzoxaboroles-contain a boron connected to two oxygens and one carbon atom. The boron atom of these functional groups coordinates with a water molecule in the enzyme site forming a tetrahedral molecule which mimics the phosphate structure. Although boron phosphate-mimetic molecules - FDA-approved Crisaborole and phase II/III clinical candidate Acoziborole are products of the boron-phosphorus bioisosteric elemental exchange strategy, this technique is still in its infancy. The review aims to promote the use of this strategy in future medicinal chemistry projects.

Anti-Tuberculosis Mur Inhibitors: Structural Insights and the Way Ahead for Development of Novel Agents.

Mur enzymes serve as critical molecular devices for the synthesis of UDP-MurNAc-pentapeptide, the main building block of bacterial peptidoglycan polymer. These enzymes have been extensively studied for bacterial pathogens such as Escherichia coli and Staphylococcus aureus. Various selective and mixed Mur inhibitors have been designed and synthesized in the past few years. However, this class of enzymes remains relatively unexplored for Mycobacterium tuberculosis (Mtb), and thus offers a promising approach for drug design to overcome the challenges of battling this global pandemic. This review aims to explore the potential of Mur enzymes of Mtb by systematically scrutinizing the structural aspects of various reported bacterial inhibitors and implications concerning their activity. Diverse chemical scaffolds such as thiazolidinones, pyrazole, thiazole, etc., as well as natural compounds and repurposed compounds, have been reviewed to understand their in silico interactions with the receptor or their enzyme inhibition potential. The structural diversity and wide array of substituents indicate the scope of the research into developing varied analogs and providing valuable information for the purpose of modifying reported inhibitors of other multidrug-resistant microorganisms. Therefore, this provides an opportunity to expand the arsenal against Mtb and overcome multidrug-resistant tuberculosis.

Atropisomerism transforming anti-cancer drug discovery.

Atropisomerism is a stereochemical phenomenon that describes how groups are arranged in space as a result of their impeded rotation around a single bond. It is one of the frequently underappreciated conformational kinds of chirality. A significant role for atropisomers in drug discovery and development has been established via substantial study on the characteristics of molecules exhibiting this form of chirality. According to studies on the target selectivity of anti-cancer drugs, it was identified that atropisomers of specific compounds could be examined to modulate the selectivity of promiscuous inhibitors, which are a key target in cancer therapy. Conversely, it was discovered that these deliberate rigidifications of possible molecules along an axis of chirality gave an abundant possibility of acquiring more tailored anti-cancer action. Atropisomerism plays a significant role in altering pharmacodynamic and pharmacokinetic properties and thereby the success of any proposed drug candidate. It is thus necessary to anticipate the impact of stereogenic centres in such compounds on cancer drug development. Hence, herein we review atropisomeric anti-cancer moieties which have been investigated based on their target proteins, origin and isomerism. The insights offered herein would be extremely useful in anti-cancer drug design, pave way for new avenues to development promising potent agents to combat this life-threatening disease.