Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment

Chen, Pengqin; Duan, Yongli; Xiong, Hehua; Li, Hongmin; Zeng, Yao; Liang, Guang; Tang, Qidong; Wu, Di

doi:10.1016/j.ejmech.2021.113273

“…As an extension of previous research, much effort had been made on optimizing peripheral chemical groups of carbazole-oxadiazoles to further improve the drug’s properties in this research (Figure ). It is well known that alkyl chains, unsaturated alkenes, and halogen-containing phenyl moieties could exert large effects on biological potency by regulating the lipid-water partition coefficient and binding affinity or cell membrane permeability, which might influence the rate of absorption and transport of drugs. , Therefore, various alkyl chains, alkenes, and halogen-containing phenyl groups were incorporated into the 4-OH position of carbazole scaffold to investigate the influence on antibacterial activities. Moreover, the 1,3,4-oxadiazole-2-thiol ring at the N -1 position and the corresponding substituents at the C-4 position were swapped to explore the effect of position on bioactivity.…”

Section: Introductionmentioning

confidence: 99%

Unique Carbazole-Oxadiazole Derivatives as New Potential Antibiotics for Combating Gram-Positive and -Negative Bacteria

Xie

¹

,

Nagarajan

²

,

Meng

³

et al. 2022

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Novel carbazole-oxadiazoles were developed as new potential antibacterial agents to combat dreadful resistance. Some target compounds displayed predominant inhibitory effects on the tested Gram-positive and -negative bacteria, and carbazole-oxadiazoles 5g, 5i–k, 16a–c, and tetrazole analogues 23b–c were found to be efficient in impeding the growth of MRSA and Pseudomonas aeruginosa ATCC 27853 (MICs = 0.25–4 μg/mL). Furthermore, compounds 5g and 23b–c not only possessed rapid bactericidal ability and low tendency to develop resistance but also exhibited low cytotoxic effects toward Hek 293T, HeLa, and red blood cells (RBCs), especially molecule 5g also showed low toxicity in vivo, which showed the therapeutic potential of these compounds. Further exploration indicated that compounds 5g, 5i, and 23b–c could disintegrate the integrity of bacterial cell membranes to leak the cytoplasmic contents, thus exerting excellent antibacterial effects. These facts mean that carbazole-based antibacterial agents might have bright prospects in confronting bacterial infections.

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“…A series of pyrrolo[2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one analogs 90 were designed, synthesized, and their cytotoxic potency against three cancer cell lines (A549, Hela, and MCF-7) was examined [ 86 ]. Compound 90a emerged as the most potent compound with IC 50 values of 0.66, 0.38 and, 0.44 µM against A549, HeLa and MCF-7 cell lines, respectively.…”

Section: Six-membered Heterocyclic Compoundsmentioning

confidence: 99%

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Ebenezer

¹

,

Jordaan

²

,

Carena

³

et al. 2022

IJMS

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Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring.

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“…Globally, cancer kills about 10 million people every year and its mortality rate will reach 16.3 million deaths in 2040 1 . Conventional chemotherapeutic drugs can raise the survival rate of cancer patients but they have negative impact on patients’ quality of life because of their severe adverse effects 2 . With growing knowledge of chemistry and function of cellular molecular targets, tyrosine kinase (TK) inhibitors become the main arm of chemotherapeutic arsenal 3 .…”

Section: Introductionmentioning

confidence: 99%

“…With growing knowledge of chemistry and function of cellular molecular targets, tyrosine kinase (TK) inhibitors become the main arm of chemotherapeutic arsenal 3 . Compared to conventional chemotherapy, TK inhibitors afford good anticancer activity with few and tolerable adverse effects 2 .…”

Section: Introductionmentioning

confidence: 99%

Design and biological evaluation of 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors

Hassan

¹

,

Mubarak

²

,

Shehadi

³

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1 H ,3 H )-dione 2a – g , in addition to the preparation of some new derivatives namely, 3 and 4a – j . Three compounds namely, 2c , 4b , and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC 50 range 0.052–0.084 µM). Both compounds 4b , 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1 H ,3 H )-dione derivatives are promising antiproliferative candidates that require further optimisation. Highlights New 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives were synthesised and characterised. Compounds 4b and 4e showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines. Both compounds 4b and 4e showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line. Compound 4b was superior to cabozantinib in VEGFR-2 inhibition while compound 2c was equipotent to cabozantinib. Compounds 4b and 4e showed remarkable c-Met inhibitory activity. Compounds 4b and 4e arrested cell cycle and induced significant levels of apoptosis. In silico ADME prediction revealed high oral bioavailability and enhanced water solubility of target compounds as compared to cabozantinib. Target compounds interacted with both c-Met and VEGFR-2 active site in similar way to ca...

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Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment

Cited by 12 publications

References 35 publications

Unique Carbazole-Oxadiazole Derivatives as New Potential Antibiotics for Combating Gram-Positive and -Negative Bacteria

Unique Carbazole-Oxadiazole Derivatives as New Potential Antibiotics for Combating Gram-Positive and -Negative Bacteria

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Design and biological evaluation of 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors

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