Recent progress toward the asymmetric synthesis of carbon-substituted piperazine pharmacophores and oxidative related heterocycles

The important requirement for approval of a new drug, in case it happens to be chiral, is that both enantiomers of the drug should be studied in detail, which has led synthetic organic and medicinal chemists to focus their attention on the development of new methods for asymmetric synthesis especial...

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Published inMedChemComm Vol. 11; no. 7; pp. 745 - 759
Main Author Magriotis, Plato A
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 01.07.2020
Subjects
Asymmetric synthesis
Asymmetry
Bioactive compounds
Biological activity
Carbon
Chemistry
Chemists
Enantiomers
Imatinib
Pharmacophores
Piperazine
Sildenafil
Substitutes
Synthesis
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Summary:The important requirement for approval of a new drug, in case it happens to be chiral, is that both enantiomers of the drug should be studied in detail, which has led synthetic organic and medicinal chemists to focus their attention on the development of new methods for asymmetric synthesis especially of relevant saturated N-heterocycles. On the other hand, the piperazine ring, besides defining a major class of saturated N-heterocycles, has been classified as a privileged structure in medicinal chemistry, since it is more than frequently found in biologically active compounds including several marketed blockbuster drugs such as Glivec (imatinib) and Viagra (sildenafil). Indeed, 13 of the 200 best-selling small molecule drugs in 2012 contained a piperazine ring. Nevertheless, analysis of the piperazine substitution pattern reveals a lack of structural diversity, with almost every single drug in this category (83%) containing a substituent at both the N1- and N4-positions compared to a few drugs having a substituent at any other position (C2, C3, C5, and C6). Significant chemical space that is closely related to that known to be biologically relevant, therefore, remains unexplored. In order to explore this chemical space, efficient and asymmetric syntheses of carbon-substituted piperazines and related heterocycles must be designed and developed. Initial, recent efforts toward the implementation of this particular target are in fact the subject of this review. The piperazine drugs are mostly N-substituted compared to only a few C-substituted drugs. To explore this unknown chemical space, asymmetric syntheses of C-substituted piperazines is the subject of this review.
Bibliography:Since 2006, Plato A. Magriotis, Ph.D., has been an Associate Professor of Medicinal Chemistry in the Department of Pharmacy at the University of Patras in Greece and a Research Affiliate with the Department of Chemistry at New York University. Magriotis received his Ph.D. in Chemical Biology with Professor Francis Johnson at Stony Brook University in 1983 and did postdoctoral work at Harvard University with Nobel Laureate Professor E. J. Corey. His career started at West Virginia University and continued at Merck & Co. as well as New York University in the U.S., prior to his return to Greece. Magriotis' research program focuses on the development of new methodology for the synthesis of relevant pharmacophores applied in drug discovery.
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This review is dedicated to Professor Francis Johnson (Stony Brook University) on the occasion of his ninetieth birthday and in acknowledgement of his immense contributions to Medicinal Chemistry.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d0md00053a