Background/Objectives: The rise of multidrug-resistant bacteria and fungi, or “superbugs”, makes the development of new antimicrobial compounds of continued importance. In this context, we have explored structural variants of the plant-derived phytocompound berberine, seeking higher antimicrobial activity and selectivity. Our prior work prepared fourteen protoberberine variants (B1–B14), and found that a partially reduced dihydroprotoberberine (B14) was significantly more active against Gram-positive bacteria. To further investigate this trend, we prepared a series of protoberberines and related dihydroprotoberberines, with the goal of better understanding the effects of the partial reduction of the protoberberine core. Methods: Protoberberines were prepared from a cyclization between glyoxal and substituted N-benzyl-phenethylamines, prepared by reductive amination. Dihydro-derivatives were obtained via NaBH4 reduction. Biological activity was assessed with a Kirby–Bauer assay to determine zones of inhibition against a panel of twelve microorganisms. Cytotoxicity was also assessed using an MTT assay against a T84 human colon carcinoma cell line. Results: The majority of the prepared compounds showed greater Gram-positive antibacterial activity compared to original berberine, and nearly all dihydro-protoberberines had improved Gram-positive antibacterial activity over their unreduced form. Additionally, the reduced variants were less active against fungi, indicating a step towards higher microbial selectivity. All variants showed greater potency against cancer cells. Conclusions: The present work highlights a significant improvement in antibacterial activity and selectivity for this set of dihydro-protoberberines over their unreduced counterparts.
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