Pharmacophore Modeling, Synthesis, and Antibacterial Evaluation of Chalcones and Derivatives

Mingming Zhang, Allan M. Prior, Marcus M. Maddox, Wan Jou Shen, Kirk Hevener, David F. Bruhn, Robin B. Lee, Aman P. Singh, Justin Reinicke, Charles J. Simmons, Julian G. Hurdle, Richard E. Lee, Dianqing Sun

Research output: Contribution to journalArticle

Abstract

A series of novel chalcone and thiol-Michael addition analogues was synthesized and tested against Mycobacterium tuberculosis and other clinically significant bacterial pathogens. Previously reported chalcone-like antibacterials (1a-c and 2) were used as a training set to generate a pharmacophore model. The chalcone derivative hit compound 3 was subsequently identified through a pharmacophore-based virtual screen of the Specs library of >200 000 compounds. Among the newly synthesized chalcones and thiol-Michael addition analogues, chalcones 6r and 6s were active (minimum inhibitory concentrations (MICs) = 1.56-6.25 μg/mL) against Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus [methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA)]. The chalcone thiol-Michael addition derivatives 7j-m showed good to excellent antibacterial activities (MICs = 0.78-6.25 μg/mL) against Enterococcus faecalis, B. anthracis, and S. aureus. Interestingly, the amine-Michael addition analogue 12a showed promising anti-MRSA activity (MIC = 1.56 μg/mL) with a selectivity index of 14 toward mammalian Vero cells. In addition, evaluation of selected compounds against biofilm and planktonic S. aureus (MSSA and MRSA) revealed that 12a exhibited bactericidal activities in these assays, which was overall superior to vancomycin. These properties may result from the compounds dissipating the proton motive force of bacterial membranes.

Original languageEnglish (US)
Pages (from-to)18343-18360
Number of pages18
JournalACS Omega
Volume3
Issue number12
DOIs
StatePublished - Dec 26 2018

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Chalcones
Methicillin
Pathogens
Chalcone
Derivatives
Sulfhydryl Compounds
Biofilms
Bacilli
Amines
Assays
Protons
Membranes
Vancomycin

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Zhang, M., Prior, A. M., Maddox, M. M., Shen, W. J., Hevener, K., Bruhn, D. F., ... Sun, D. (2018). Pharmacophore Modeling, Synthesis, and Antibacterial Evaluation of Chalcones and Derivatives. ACS Omega, 3(12), 18343-18360. https://doi.org/10.1021/acsomega.8b03174

Pharmacophore Modeling, Synthesis, and Antibacterial Evaluation of Chalcones and Derivatives. / Zhang, Mingming; Prior, Allan M.; Maddox, Marcus M.; Shen, Wan Jou; Hevener, Kirk; Bruhn, David F.; Lee, Robin B.; Singh, Aman P.; Reinicke, Justin; Simmons, Charles J.; Hurdle, Julian G.; Lee, Richard E.; Sun, Dianqing.

In: ACS Omega, Vol. 3, No. 12, 26.12.2018, p. 18343-18360.

Research output: Contribution to journalArticle

Zhang, M, Prior, AM, Maddox, MM, Shen, WJ, Hevener, K, Bruhn, DF, Lee, RB, Singh, AP, Reinicke, J, Simmons, CJ, Hurdle, JG, Lee, RE & Sun, D 2018, 'Pharmacophore Modeling, Synthesis, and Antibacterial Evaluation of Chalcones and Derivatives', ACS Omega, vol. 3, no. 12, pp. 18343-18360. https://doi.org/10.1021/acsomega.8b03174
Zhang, Mingming ; Prior, Allan M. ; Maddox, Marcus M. ; Shen, Wan Jou ; Hevener, Kirk ; Bruhn, David F. ; Lee, Robin B. ; Singh, Aman P. ; Reinicke, Justin ; Simmons, Charles J. ; Hurdle, Julian G. ; Lee, Richard E. ; Sun, Dianqing. / Pharmacophore Modeling, Synthesis, and Antibacterial Evaluation of Chalcones and Derivatives. In: ACS Omega. 2018 ; Vol. 3, No. 12. pp. 18343-18360.
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