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Synthesis and Inhibitory Activity of Machaeridiol-Based Novel Anti-MRSA and Anti-VRE Compounds and Their Profiling for Cancer-Related Signaling Pathways.
Kumarihamy, Mallika; Tripathi, Siddharth; Balachandran, Premalatha; Avula, Bharathi; Zhao, Jianping; Wang, Mei; Bennett, Maria M; Zhang, Jin; Carr, Mary A; Lovell, K Michael; Wellington, Ocean I; Marquart, Mary E; Nanayakkara, N P Dhammika; Muhammad, Ilias.
  • Kumarihamy M; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Tripathi S; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Balachandran P; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Avula B; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Zhao J; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Wang M; Natural Products Utilization Research Unit, Agricultural Research Service, USA Department of Agriculture, University City, MS 38677, USA.
  • Bennett MM; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Zhang J; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Carr MA; Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
  • Lovell KM; Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
  • Wellington OI; Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
  • Marquart ME; Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
  • Nanayakkara NPD; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
  • Muhammad I; National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University City, MS 38677, USA.
Molecules ; 27(19)2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-2066284
ABSTRACT
Three unique 5,6-seco-hexahydrodibenzopyrans (seco-HHDBP) machaeridiols A-C, reported previously from Machaerium Pers., have displayed potent activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and E. faecalis (VRE). In order to enrich the pipeline of natural product-derived antimicrobial compounds, a series of novel machaeridiol-based analogs (1-17) were prepared by coupling stemofuran, pinosylvin, and resveratrol legends with monoterpene units R-(-)-α-phellandrene, (-)-p-mentha-2,8-diene-1-ol, and geraniol, and their inhibitory activities were profiled against MRSA ATCC 1708, VRE ATCC 700221, and cancer signaling pathways. Compounds 5 and 11 showed strong in vitro activities with MIC values of 2.5 µg/mL and 1.25 µg/mL against MRSA, respectively, and 2.50 µg/mL against VRE, while geranyl analog 14 was found to be moderately active (MIC 5 µg/mL). The reduction of the double bonds of the monoterpene unit of compound 5 resulted in 17, which had the same antibacterial potency (MIC 1.25 µg/mL and 2.50 µg/mL) as its parent, 5. Furthermore, a combination study between seco-HHDBP 17 and HHDBP machaeriol C displayed a synergistic effect with a fractional inhibitory concentrations (FIC) value of 0.5 against MRSA, showing a four-fold decrease in the MIC values of both 17 and machaeriol C, while no such effect was observed between vancomycin and 17. Compounds 11 and 17 were further tested in vivo against nosocomial MRSA at a single intranasal dose of 30 mg/kg in a murine model, and both compounds were not efficacious under these conditions. Finally, compounds 1-17 were profiled against a panel of luciferase genes that assessed the activity of complex cancer-related signaling pathways (i.e., transcription factors) using T98G glioblastoma multiforme cells. Among the compounds tested, the geranyl-substituted analog 14 exhibited strong inhibition against several signaling pathways, notably Smad, Myc, and Notch, with IC50 values of 2.17 µM, 1.86 µM, and 2.15 µM, respectively. In contrast, the anti-MRSA actives 5 and 17 were found to be inactive (IC50 > 20 µM) across the panel of these cancer-signaling pathways.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Biological Products / Methicillin-Resistant Staphylococcus aureus / Anti-Infective Agents / Neoplasms Limits: Animals Language: English Journal subject: Biology Year: 2022 Document Type: Article Affiliation country: Molecules27196604

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Biological Products / Methicillin-Resistant Staphylococcus aureus / Anti-Infective Agents / Neoplasms Limits: Animals Language: English Journal subject: Biology Year: 2022 Document Type: Article Affiliation country: Molecules27196604