Structural and PK-guided identification of indole-based non-acidic autotaxin (ATX) inhibitors exhibiting high in vivo anti-fibrosis efficacy in rodent model

Lei, Hongrui; Cao, Zhi; Wu, Huinan; Li, Tong; Wang, Xinyu; Chen, Yuxiang; Ma, Enlong; Sun, Lixin; Zhai, Xin

doi:10.1016/j.ejmech.2021.113951

Cited by 7 publications

(2 citation statements)

References 27 publications

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“…Various electrical and voluminal substituents in azole ring might influence the distribution of electron cloud, further altering the affinity with targets. Therefore, imidazoles with different substituents were incorporated into pyrimidine to explore the effects of different substituents on antibacterial performances. Diol fragment as a polar structure plays a significant role in improving water solubility and could exert the interaction with DNA, enzymes, and other receptors via hydrogen bonds. , It is also an important active component in some FDA-approved drugs such as dipyridamole and gilenya. However, the antibacterial item of such a fragment combined with pyrimidine is rarely reported.…”

Section: Introductionmentioning

confidence: 99%

“…Diol fragment as a polar structure plays a significant role in improving water solubility and could exert the interaction with DNA, enzymes, and other receptors via hydrogen bonds. , It is also an important active component in some FDA-approved drugs such as dipyridamole and gilenya. However, the antibacterial item of such a fragment combined with pyrimidine is rarely reported.…”

Section: Introductionmentioning

confidence: 99%

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Azolylpyrimidinediols as Novel Structural Scaffolds of DNA-Groove Binders against Intractable Acinetobacter baumannii

Tan

Wang

et al. 2023

J. Med. Chem.

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A unique class of antibacterial azolylpyrimidinediols (APDs) and their analogues were developed. Some synthesized compounds showed excellent bacteriostatic potency; especially, triazolylpyrimidinediol (triazolyl PD) 7a exhibited good anti-Acinetobacter baumannii potential with a low MIC of 0.002 mmol/ L. Triazolyl PD 7a with inconspicuous cytotoxicity and hemolytic activity could eradicate the established biofilm, showed low resistance, and exhibited favorable drug-likeness. Mechanistic explorations revealed that compound 7a without membrane-targeting ability could decrease metabolic activity, interact with DNA through groove binding action to block DNA replication rather than intercalate into and cleave DNA, and thus inhibit bacterial growth. Further computations displayed that the low E HOMO and large energy gap might help triazolyl PD 7a binding to biological targets more easily. Moreover, compound 7a gave appreciable in vivo pharmacokinetic properties and pharmacodynamics. These findings of azolylpyrimidinediols as novel structural scaffolds of DNA-groove binders might imply a large promise for the treatments of Acinetobacter baumannii infection.

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