Design, synthesis, and applications of ring-functionalized histidines in peptide-based medicinal chemistry and drug discovery.

Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.

Direct Access to α,ß-Alkynylamides via Pd-Catalyzed Carbonylation of Terminal Alkynes with Amines Using Chloroform as the CO Surrogate.

We describe the first-time use of a palladium-di(1-adamantyl)-n-butylphosphine catalytic system for the synthesis of alk-2-ynamides from terminal alkynes via aminocarbonylation reaction. This method avoids the direct use of toxic CO gas by utilizing chloroform as an in situ CO source. The aminocarbonylation of both aromatic and aliphatic electron-rich alkyne nucleophiles is reported for the first time. The mild condition provides alk-2-ynamides within 50 min under microwave irradiation at 80 °C.

Palladium-Catalyzed Aminocarbonylation of (Hetero)aryl Iodides with α-Amino Acid Esters as Nucleophiles.

We report palladium-catalyzed aminocarbonylation of (hetero)aryl iodides with α-amino acid esters as nucleophiles. The synthesized N-capped α-amino acids are biologically important building blocks. The mild conditions provide products with high enantioselectivity at 80 °C in 35 min. The reactions are performed under air in a sealed vessel using chloroform as an in situ CO source. For the first time, regioselective carbonylation of histidine is also presented.

New structural classes of antimalarials.

Malaria remains a major vector borne disease claiming millions of lives worldwide due to infections caused by Plasmodium sp. Discovery and development of antimalarial drugs have previously been dominated majorly by single drug therapy. The malaria parasite has developed resistance against first line and second line antimalarial drugs used in the single drug therapy. This has drawn attention to find ways to alleviate the disease burden supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has now mandated the revision of the current antimalarial pharmacotherapy. Research efforts of the past decade led to the discovery and identification of several new structural classes of antimalarial agents with improved biological attributes over the older ones. The following is a comprehensive review, addressed to the new structural classes of heterocyclic and natural compounds that have been identified during the last decade as antimalarial agents. Some of the classes included herein contain one or more pharmacophores amalgamated into a single bioactive scaffold as antimalarial agents, which act upon the conventional and novel targets.