Non-phosgene route to unsymmetrical ureas from N-Cbz-α-amino acid amides

A convenient method toward the synthesis of α-amino acid-derived unsymmetrical ureas 2 is described herein. This route involves an interesting rearrangement of amides of N-Cbz-α-amino acids 1, which presumably entails the intermediacy of hydantoins that is followed by hydrolysis to afford unsymmetrical ureas 2 in quantitative yields and high purity. © 2013 Elsevier Ltd. All rights reserved

Non-Phosgene Route To Unsymmetrical Ureas From N-Cbz-Α-Amino Acid Amides

A convenient method toward the synthesis of α-amino acid-derived unsymmetrical ureas 2 is described herein. This route involves an interesting rearrangement of amides of N-Cbz-α-amino acids 1, which presumably entails the intermediacy of hydantoins that is followed by hydrolysis to afford unsymmetrical ureas 2 in quantitative yields and high purity. © 2013 Elsevier Ltd. All rights reserved

Bridging the Gap in Malaria Parasite Resistance, Current Interventions, and the Way Forward from in Silico Perspective: A Review

The past decade has seen most antimalarial drugs lose their clinical potency stemming from parasite resistance. Despite immense efforts by researchers to mitigate this global scourge, a breakthrough is yet to be achieved, as most current malaria chemotherapies suffer the same fate. Though the etiology of parasite resistance is not well understood, the parasite’s complex life has been implicated. A drug-combination therapy with artemisinin as the central drug, artemisinin-based combination therapy (ACT), is currently the preferred malaria chemotherapy in most endemic zones. The emerging concern of parasite resistance to artemisinin, however, has compromised this treatment paradigm. Membrane-bound Ca2+-transporting ATPase and endocytosis pathway protein, Kelch13, among others, are identified as drivers in plasmodium parasite resistance to artemisinin. To mitigate parasite resistance to current chemotherapy, computer-aided drug design (CADD) techniques have been employed in the discovery of novel drug targets and the development of small molecule inhibitors to provide an intriguing alternative for malaria treatment. The evolution of plasmepsins, a class of aspartyl acid proteases, has gained tremendous attention in drug discovery, especially the non-food vacuole. They are expressed at multi-stage of the parasite’s life cycle and involve in hepatocytes’ egress, invasion, and dissemination of the parasite within the human host, further highlighting their essentiality. In silico exploration of non-food vacuole plasmepsin, PMIX and PMX unearthed the dual enzymatic inhibitory mechanism of the WM382 and 49c, novel plasmepsin inhibitors presently spearheading the search for potent antimalarial. These inhibitors impose structural compactness on the protease, distorting the characteristic twist motion. Pharmacophore modeling and structure activity of these compounds led to the generation of hits with better affinity and inhibitory prowess towards PMIX and PMX. Despite these headways, the major obstacle in targeting PM is the structural homogeneity among its members and to human Cathepsin D. The incorporation of CADD techniques described in the study at early stages of drug discovery could help in selective inhibition to augment malaria chemotherapy

Benzotriazole-Mediated Synthesis of Aza-peptides: En Route to an Aza-Leuenkephalin Analogue

Novel <i>N</i>-(<i>N</i>-Pg-azadipeptidoyl)­benzotriazoles <b>20a</b>–<b>e</b> couple efficiently with α-amino acids <b>21a</b>–<b>e</b>, dipeptides <b>22a</b>–<b>c</b>, aminoxyacetic acid <b>23a</b>, depsidipeptide <b>23b</b>, and α-hydroxy-β-phenylpropionic acid <b>27</b> yielding, respectively, azatripeptides <b>24a</b>–<b>g</b>, azatetrapeptides <b>25a</b>,<b>b</b>, a hybrid azatripeptide with an oxyamide bond <b>26a</b>, a hybrid azatetrapeptide with an ester bond <b>26b</b>, and a hybrid azatripeptide with an ester bond <b>28</b>. A new protocol for the synthesis of <i>N</i>-Pg-azatripeptides <b>33a</b>,<b>b</b> and <b>35a</b>,<b>b</b>, each containing a natural amino acid at the <i>N</i>-terminus, avoids the low coupling rates of the aza-amino acid residue and enables the solution-phase synthesis of an azaphenylalanine analogue of Leu-enkephalin <b>40</b>

Oxyazapeptides: Synthesis, Structure Determination, and Conformational Analysis

Herein we report the synthesis, X-ray structure determination, and conformational analysis of a novel class of heteroatom-modified peptidomimetics, which we shall call “oxyazapeptides”. Substituting the typical native N-C^α bond with an O-N^α bond creates a completely new, previously unknown family of peptidomimetics, which are hydrolytically stable and display very interesting conformational behavior. Force field calculations revealed that the barrier to rotation around the O-N^α bond in oxyazapeptides is five times lower than that around the N-N^α bond in azapeptides. Also, conformational analysis supported by X-ray suggests that the oxyaza moiety can effectively induce β-turns, which can make the newly discovered oxyazapeptide scaffold a useful tool for drug discovery and for design of biologics