Dihydroazolopyrimidines: Past, Present and Perspectives in Synthesis, Green Chemistry and Drug Discovery

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Abstract

Dihydroazolopyrimidines are an important class of heterocycles that are isosteric to natural purines and are therefore of great interest primarily as drug‐like molecules. In contrast to the heteroaromatic analogs, synthetic approaches to these compounds were developed much later, and their chemical properties and biological activity have not been studied in detail until recently. In the review, different ways to build dihydroazolopyrimidine systems from different building blocks are described – via the initial formation of a partially hydrogenated pyrimidine ring or an azole ring, as well as a one‐pot assembly of azole and azine fragments. Special attention is given to modern approaches: multicomponent reactions, green chemistry, and the use of non‐classical activation methods. Information on the chemical properties of dihydroazolopyrimidines and the prospects for their use in the design of drugs of various profiles are also summarized in this review.

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Escape from flatland: increasing saturation as an approach to improving clinical success.

Frank Lovering, Jack Bikker, Christine Humblet (2009)

The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp(3) (Fsp(3)) where Fsp(3) = (number of sp(3) hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp(3)) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting.

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Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

Dean G Brown, Jonas Boström (2016)

An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.

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Record: found
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NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy.

Yue Yang, Anthony A. Sauve (2016)

We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD(+) and NADP(+) which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD(+) has become reinvigorated by new understandings that dynamics within NAD(+) metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD(+) as an effector substrate. Cellular adaptations include stimulation of mitochondrial biogenesis, a process fundamental to adjusting cellular and tissue physiology to reduced nutrient availability and/or increased energy demand. Several mammalian metabolic pathways converge to NAD(+), including tryptophan-derived de novo pathways, nicotinamide salvage pathways, nicotinic acid salvage and nucleoside salvage pathways incorporating nicotinamide riboside and nicotinic acid riboside. Key discoveries highlight a therapeutic potential for targeting NAD(+) biosynthetic pathways for treatment of human diseases. A recent emergence of understanding that NAD(+) homeostasis is vulnerable to aging and disease processes has stimulated testing to determine if replenishment or augmentation of cellular or tissue NAD(+) can have ameliorative effects on aging or disease phenotypes. This experimental approach has provided several proofs of concept successes demonstrating that replenishment or augmentation of NAD(+) concentrations can provide ameliorative or curative benefits. Thus NAD(+) metabolic pathways can provide key biomarkers and parameters for assessing and modulating organism health.

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Author and article information

Contributors

Valentyn A. Chebanov: (View ORCID Profile)

Journal

Title: The Chemical Record

Abbreviated Title: The Chemical Record

Publisher: Wiley

ISSN (Print): 1527-8999

ISSN (Electronic): 1528-0691

Publication date (Electronic): September 05 2023

Affiliations

[1 ] Department of Organic and Bioorganic Chemistry State Scientific Institution “Institute for Single Crystals” NAS of Ukraine Nauky ave. 60 Kharkiv Ukraine 61072

[2 ] Faculty of Chemistry V.N. Karazin Kharkiv National University Svobody sq. 4 Kharkiv Ukraine 61022

[3 ] Department of Medicinal Chemistry State Institution “V. Ya. Danilevsky Institute for Endocrine Pathology Problems” NAMS of Ukraine Alchevskikh St. 10 Kharkiv Ukraine 61002

Article

DOI: 10.1002/tcr.202300244

SO-VID: f247cb3d-0e0c-41ae-86bf-73ee25b7641d

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http://onlinelibrary.wiley.com/termsAndConditions#vor

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