Design, synthesis and evaluation of hybrid of tetrahydrocarbazole with 2,4-diaminopyrimidine scaffold as antibacterial agents

Su, Liqiang; Li, Jiahui; Zhou, Zhen; Huang, Dan; Zhang, Yuanjin; Pei, Haixiang; Guo, Weikai; Wu, Haigang; Wang, Xin; Liu, Mingyao; Yang, Cai‐Guang; Chen, Yi Hua

doi:10.1016/j.ejmech.2018.11.016

Cited by 14 publications

(4 citation statements)

References 22 publications

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“…The herein described THCz compound class was one of the most active identified in the screen. Related THCz analogs with antimicrobial activity have been reported, but few targets have been proposed (13,20,28). Our mode of action studies revealed that THCz analogs stalled cell wall biosynthesis by targeting lipid II and other undecaprenyl pyrophosphate-containing lipid precursors involved in teichoic acid and capsule synthesis.…”

Section: Discussionmentioning

confidence: 85%

“…Moreover, the substance displayed activity against an Escherichia coli strain with a defective outer membrane, but not against wildtype E. coli or Pseudomonas aeruginosa, indicating that the outer membrane of certain gram-negative species may provide protection against THCz-1. Interestingly, Su et al (13) have previously recorded activity against an E. coli strain of a related THCz analog but with a 2,4-diaminopyrimidine substituent in position R 2 .…”

Section: Resultsmentioning

confidence: 99%

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THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates

Reithuber

Wixe

Ludwig

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate–containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II–binding antibiotics, makes THCz promising scaffolds for development of cell wall–targeting antimicrobials.

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Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates

Reithuber

Wixe

Ludwig

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Due to dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), which play key roles in the folate biosynthetic pathway that generates the cofactors necessary for continued DNA and RNA synthesis, proven targets for antimicrobial drugs, [72] it is proposed that diaminopyrimidine derivatives 12b and 17a can interfere with the folic acid metabolism by binding dihydrofolate reductase on B. subtilis and S. aureus, which eventually leads to the prevention of bacterial reproduction. [71,73]…”

Section: Antimicrobial Activitymentioning

confidence: 99%

Divergent Synthesis, Antiproliferative and Antimicrobial Studies of 1,3‐Aminoalcohol and 3‐Amino‐1,2‐Diol Based Diaminopyrimidines

Raji

Huỳnh

et al. 2022

Chemistry & Biodiversity

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A series of novel diaminopyrimidines containing pinane moieties were synthesized via an efficient methodology starting from pinane‐based aminoalcohols, aminodiols and 2,4‐dichloropyrimidines. Bioassay tests demonstrated that compound 18a displayed much stronger antiproliferative activities against four human cancer cell lines (HeLa, Siha, MDA‐MB‐231, MCF‐7 and A2780) than positive control cisplatin. In particular, compound 22a was found to be selective in inhibiting HeLa cell proliferation with cancer cell growth inhibition values higher than 95 %. Moreover, the in vitro screening of prepared compounds against different bacterial and fungal strains is reported. The results revealed that 12b and 17a, the most promising compounds, displayed selective inhibition for the Gram‐positive bacteria (B. subtilis and S. aureus) with percent inhibition values ranging from 75 to 95 % at 10 μg/mL concentration. Both selective inhibition and the in vitro activity values demonstrated that these compounds have the potential to be developed into clinically important therapeutic choices for the treatment of infections caused by B. subtilis and S. aureus.

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“…It focused on the synthesis and antimicrobial activity of compounds produced by combining two biologically active compounds (NSAIDS and THCZ). THCZ and Carbazole ring scaffolds are present in some alkaloids [2], they have a variety of biological effects such as antiviral (3) , antitumor (4) , antibacterial (5,6) and broad-spectrum antifungal activity [7,8]. NSAIDs are considered as non-antibiotic drugs reported to display antibacterial activity [9], Some NSAIDs such as indomethacin and diclofenac have been shown to have synergistic effect with particular antimicrobial drugs [10].…”

Section: Introductionmentioning

confidence: 99%

Untitled

2022

J. Med. Chem. Sci.

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New 6-chloro-1,2,3,4-tetrahydrocarbazole compounds were prepared from the reaction of cyclohexanone with 4-chlorophenylhydrazine. The synthesis of heterocyclic compounds was carried out through the reaction of cyclohexanone with 4-chlorophenylhydrazine, then the produced compound was treated with two NSAIDs (indomethacin, diclofenac) by amide bond formation to form N-substituted THCZ by NSAIDs. The characterization of prepared compounds was identified using the 1 H, 13 C NMR and FT-IR spectroscopies. The antimicrobial activity of the synthesized compounds was tested in vitro to discover a good activity as antifungal and moderate as antibacterial, which was confirmed by the docking study of the compounds.

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Design, synthesis and evaluation of hybrid of tetrahydrocarbazole with 2,4-diaminopyrimidine scaffold as antibacterial agents

Cited by 14 publications

References 22 publications

THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates

THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates

Divergent Synthesis, Antiproliferative and Antimicrobial Studies of 1,3‐Aminoalcohol and 3‐Amino‐1,2‐Diol Based Diaminopyrimidines

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