Diversity-Oriented Synthesis and Chemoinformatic Analysis of the Molecular Diversity of sp3-Rich Morpholine Peptidomimetics

Abstract

Diversity-Oriented Synthesis (DOS) consists of generating structurally diverse compounds from a complexity-generating reaction followed by cyclization steps and appendage diversity. DOS has gathered interest to systematically explore the chemical space by generating high-quality small-molecule collections as probes to investigate biological pathways. The generation of heterocycles using amino acid and sugar derivatives as building blocks is a powerful approach to access chemical and geometrical diversity thanks to the high number of stereocenters and the polyfunctionality of such compounds. Our efforts in this field are focused on the generation of diversity-oriented molecules of peptidomimetic nature as a tool addressing protein-protein interactions, taking advantage of amino acid- and sugar-derived polyfunctional building blocks to be applied in couple-pair synthetic approaches. In this paper, the combination of diversity-oriented synthesis and chemoinformatics analysis of chemical space and molecular diversity of heterocyclic peptidomimetics are reported, with particular interest toward carbohydrate- and amino acid-derived morpholine scaffolds with a higher fraction of sp3 carbon atoms. Also, the chemoinformatic analysis of chemical space and molecular diversity of 186 morpholine peptidomimetics is outlined.

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…[20] The conventional Staudinger reaction was also applied in the synthesis of four peptidomimetic spiroβ-lactams 24 (Scheme 6). [21] The molecules were obtained from the reaction between ketenes, generated from serine and threonine-derived morpholine derivatives 22 and aromatic imines 23. The morpholinederived spiro-β-lactams were obtained in low to moderate yields (15-52%).…”

Smart Design of Small‐Molecule Libraries: When Organic Synthesis Meets Cheminformatics

“…Quaternary stereocenters are present in many biologically active compounds and pharmaceutical agents, and their presence can increase the three‐dimensional character of a molecule, which is generally associated with a more successful outcome in drug discovery . Because our efforts in this field are focused in the DOS of structurally complex morpholine compounds, we recently installed quaternary carbon atoms into selected morpholin‐3‐ones, to evaluate their different positions in the chemical space with reference to a set of 176 morpholine‐derived small molecules previously synthesized in our laboratories . Specifically, as case studies, we selected methyl 5‐oxomorpholine‐3‐carboxylates 23 , which were obtained from serine and threonine derivatives 22 a – b , and methyl 5‐oxomorpholine‐2‐carboxylate 26 , which was derived by application of the Castagnoli–Cushman reaction (Scheme ).…”

Recent applications of aminouracil in multicomponent reactions

“…This synthetic route uses 6-amino-1,3-dimethyluracil (1), N,N-dimethylformamide dimethyl acetal ( 46), 1phenyl-3-(4-substituted-phenyl)-4-formyl-1H-pyrazoles (45) and aromatic aniline (44), as starting materials for rapid access of the diverse pyrazolo-pyrimido [4,5-d]pyrimidines (47) in ionic liquid conditions by Chandramouli and co-workers (Scheme 24). 78 An efficient, four-component sequential protocol, the reaction proceeded in the presence of [Bmim]FeCl4 as a "green" reaction medium to promote eco-friendly transformations with unique reactivity and selectivity and both of recyclability and reusability without any loss.…”

“…This method proved to be of considerable utility to researchers to obtain desired complex heterocyclic frameworks by condensation of more than two reactants in a single operational step. [41][42][43][44][45][46][47][48] Herein, in continuation of studies towards the synthesis of heterocyclic scaffolds via multicomponent reactions, [49][50][51][52] and because the 6-aminouracil is frequently used as a starting material in synthesizing these compounds. This review is devoted to recent applications of 6-aminouracil and its derivatives in synthesizing diverse heterocyclic compounds based on MCRs from 2015 to 2020.…”