Synthesis and inhibitory activity of machaeridiol- based novel anti-MRSA and anti-VRE compounds and their profiling for cancer- related signaling pathways

Authors: KUMARIHAMY, MALLIKA - University Of Mississippi; TRIPATHI, SIDDHARTH - University Of Mississippi; BALACHANDRAN, PREMALATHA - University Of Mississippi; AVULA, BHARATHI - University Of Mississippi; ZHAO, JIANPING - University Of Mississippi; Wang, Mei; BENNETT, MARIA - University Of Mississippi; CARR, MARY - University Of Mississippi; MICHEAL, LOVELL - University Of Mississippi; OCEAN, WELLINGTON - University Of Mississippi; MARQUART, MARY - University Of Mississippi; NANAYAKKARA, DHAMMIKA - University Of Mississippi; MUHAMMAD, ILIAS - University Of Mississippi

Submitted to: Molecules
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/26/2022
Publication Date: 10/5/2022
Citation: Kumarihamy, M., Tripathi, S., Balachandran, P., Avula, B., Zhao, J., Wang, M., Bennett, M., Carr, M.A., Micheal, L., Ocean, W.I., Marquart, M.E., Nanayakkara, D., Muhammad, I. 2022. Synthesis and inhibitory activity of machaeridiol- based novel anti-MRSA and anti-VRE compounds and their profiling for cancer- related signaling pathways. Molecules. https://doi.org/10.3390/molecules27196604.
DOI: https://doi.org/10.3390/molecules27196604

Interpretive Summary: There are currently considerable challenges with the treatment of infections caused by strains of clinically relevant bacteria showing multidrug-resistance (MDR), such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci faecalis (VRE), as well as the recently emerged and extremely drug-resistant Mycobacterium tuberculosis XDR-TB . According to the Center for Disease Control (CDC), the number of nosocomial VRE isolates increased in the United States by 20-fold, between 1989 and 1993, and now are the second to third most common cause of nosocomial infections in the USA. Considering the urgency of newly emerging MRSA infection due to the Covid-19 pandemic and BSI of cancer patient, novel antibacterial leads focused on anti-MRSA and anticancer dual effects from natural and synthetic sources are, therefore, urgently warranted. In this paper, we report the synthesis, of a series of new and diverse stemofuran, pinosylvin and resveratol type aralkyl compounds and geraniol substituted pinosylvin analogs, like cannabigerol (CBG) analogs, together with the profiling of their antimicrobial and anticancer activities.

Technical Abstract: Three unique 5,6-seco-hexahydrodibenzopyrans (seco-HHDBP) machaeridiol 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 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-(-)-a-phellandrene, (-)-p-mentha-2,8-diene-1-ol and geraniol, and their inhibitory activities profiled against MRSA ATCC 1708, VRE ATCC 700221, and cancer signaling pathways. Compounds 5 and 11 showed strong in vitro activity with MIC values of 2.5 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). Reduction of the double bonds of the monoterpene unit of compound 5 resulted in 17, which had same antibacterial potency (MIC 1.25 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 4- fold decrease in MIC 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 the compounds were not efficacious under these conditions. Finally, compounds 1-17 were profiled against a panel of luciferase genes that assessed the activity of a complex cancer-related signaling pathways (i.e., (IC50 3.7, 3.5, and 1.2, 1.3 µg/mL, respectively), with no cytotoxicity to mammalian Vero cells. transcription factors), using T98G glioblastoma multiforme cells. Among the compounds tested, the geranyl- substituted analog 14 was found to be very active against several signaling pathways, notably Smad, Myc, and Notch with IC50 values of 2.17, 1.86 and 2.15 µM, respectively, while the anti-MRSA actives 5 and 17 were found inactive (IC50 >20 µM) against the panel of cancer signaling pathways.