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Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents.

ABSTRACT: Cancer is a major cause of deaths across the globe due to chemoresistance and lack of selective chemotherapy. Pyrido[2,3-d]pyrimidine is an emerging scaffold in medicinal chemistry having a broad spectrum of activities, including antitumor, antibacterial, CNS depressive, anticonvulsant, and antipyretic activities. In this study, we have covered different cancer targets, including tyrosine kinase, extracellular regulated protein kinases - ABL kinase, phosphatidylinositol-3 kinase, mammalian target of rapamycin, p38 mitogen-activated protein kinases, BCR-ABL, dihydrofolate reductase, cyclin-dependent kinase, phosphodiesterase, KRAS and fibroblast growth factor receptors, their signaling pathways, mechanism of action and structure-activity relationship of pyrido[2,3-d]pyrimidine derivatives as inhibitors of the above-mentioned targets. This review will represent the complete medicinal and pharmacological profile of pyrido[2,3-d]pyrimidines as anticancer agents, and will help scientists to design new selective, effective and safe anticancer agents.

SUBMITTER: Kumar A

PROVIDER: S-EPMC9972360 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Medicinal chemistry perspective of pyrido[2,3-<i>d</i>]pyrimidines as anticancer agents.

Kumar Adarsh A Bhagat Kuber Kumar KK Singh Ankit Kumar AK Singh Harshwardhan H Angre Tanuja T Verma Amita A Khalilullah Habibullah H Jaremko Mariusz M Jaremko Mariusz M Emwas Abdul-Hamid AH Kumar Pradeep P

RSC advances 20230228 10

Cancer is a major cause of deaths across the globe due to chemoresistance and lack of selective chemotherapy. Pyrido[2,3-<i>d</i>]pyrimidine is an emerging scaffold in medicinal chemistry having a broad spectrum of activities, including antitumor, antibacterial, CNS depressive, anticonvulsant, and antipyretic activities. In this study, we have covered different cancer targets, including tyrosine kinase, extracellular regulated protein kinases - ABL kinase, phosphatidylinositol-3 kinase, mammalia ...[more]

PMID: 36865574

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Project description:Recently, heterocyclic compounds such as pyrido [2,3-d] pyrimidinones, 1,2,4-triazolopyrimidines, pyrimidoquinazolines, and quinoline derivatives have gained attention from researchers due to their pharmacological and biological activities. To synthesize new compounds, quinoline-2-thioxopyrido [2,3-d] pyrimidinone (1) and methylthioquinoline-pyrido [2,3-d] pyrimidinones (2) were used as starting materials. The new compounds synthesized were quinoline-pyrido [2,3-d] (DeGoey et al., 2013; Gouda et al., 2020; Dangolani et al., 2018) [1, 2,4]triazolopyrimidinones (5a-d), 2-methylsulfonyl-quinoline-pyrido [2,3-d]pyrimidinone (6), pyrido [2,3-d]pyrimidine derivatives, pyridopyrimido (Gouda et al., 2020; DeGoey et al., 2013) 2,12,1-b] quinazoline (9), pyrido [(Khajouei et al., 2021; Gouda et al., 2020) 3,23,2-e]bis (1,2,4-triazole)pyrimidine (12a,b) and pyridopyrimido-diquinazoline-dione (16) derivatives. These compounds were synthesized with high efficiency, producing yields ranging from 69% to 90%, under moderate conditions, through treating (2) or (10) with various reagents such as anthranilic acid, phosphorus oxychloride, hydrazine hydrate, formic acid, glacial acetic acid, arylamine (aniline, 4-chloroaniline, or 4-methoxyaniline), and sec-amine (piperazine or morpholine). The new structures of the synthesized compounds were verified using various spectroscopic procedures, such as IR, NMR, and mass spectra. Molecular docking studies were carried out to investigate and discuss how the prepared compounds bind to amino acids such as Estrogen Receptor alpha, EGFR, and NADPH oxidase protein. Also, the synthesized products were tested for their anticancer and antioxidant activities against the (MCF-7) breast carcinoma cell line and human normal Retina pigmented epithelium cells (RPE-1). The study on the structure-activity relationship (SAR) established a correlation between the chemical structure of the newly synthesized compounds and their anticancer activity. The findings suggest that compounds 5a-d, 9,12a-b, and 16 exhibited promising anticancer activity and antioxidant effects as measured by DPPH inhibition.

Project description:The eight contributions here provide ample evidence that shape as a volume or as a surface is a vibrant and useful concept when applied to drug discovery. It provides a reliable scaffold for "decoration" with chemical intuition (or bias) for virtual screening and lead optimization but also has its unadorned uses, as in library design, ligand fitting, pose prediction, or active site description. Computing power has facilitated this evolution by allowing shape to be handled precisely without the need to reduce down to point descriptors or approximate metrics, and the diversity of resultant applications argues for this being an important step forward. Certainly, it is encouraging that as computation has enabled our intuition, molecular shape has consistently surprised us in its usefulness and adaptability. The first Aurelius question, "What is the essence of a thing?", seems well answered, however, the third, "What do molecules do?", only partly so. Are the topics covered here exhaustive, or is there more to come? To date, there has been little published on the use of the volumetric definition of shape described here as a QSAR variable, for instance, in the prediction or classification of activity, although other shape definitions have been successful applied, for instance, as embodied in the Compass program described above in "Shape from Surfaces". Crystal packing is a phenomenon much desired to be understood. Although powerful models have been applied to the problem, to what degree is this dominated purely by the shape of a molecule? The shape comparison described here is typically of a global nature, and yet some importance must surely be placed on partial shape matching, just as the substructure matching of chemical graphs has proved useful. The approach of using surfaces, as described here, offers some flavor of this, as does the use of metrics that penalize volume mismatch less than the Tanimoto, e.g., Tversky measures. As yet, there is little to go on as to how useful a paradigm this will be because there is less software and fewer concrete results.Finally, the distance between molecular shapes, or between any shapes defined as volumes or surfaces, is a metric property in the mathematical sense of the word. As yet, there has been little, if any, application of this observation. We cannot know what new application to the design and discovery of pharmaceuticals may yet arise from the simple concept of molecular shape, but it is fair to say that the progress so far is impressive.

Dataset Information

Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents.

Publications

Medicinal chemistry perspective of pyrido[2,3-<i>d</i>]pyrimidines as anticancer agents.

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