**1. Introduction**

Flavonoids are a diverse group of polyphenolic plant secondary metabolites. Associated with the multitude of substitution patterns on the C-6–C-3–C-6 backbone, more than 9000 flavonoids are known [1]. The attention that they receive is a direct consequence of the many biological activities that this class of compounds displays. Studies performed on flavonoids found that they possess antioxidant, anti-inflammatory, antimicrobial, antitumoral, antiviral or cardioprotective properties [2–4]. The antimicrobial properties that some flavonoids display could be exploited for this purpose. In principle, flavonoids can act directly against the infectious microorganisms, they can be used in combination with other antibiotics (synergistic relationship), or they can act against bacterial virulence factors, such as the cell-binding ability or toxins released by the pathogens. Many flavonoids, such as quercetin and naringenin [5], apigenin [6] or epigallocathechin gallate [7], to name but a few, are known to possess antibacterial activity. More than that, epigallocathechin gallate was also shown to enhance the activity of other antibiotics against drug-resistant pathogens [8]. In the past few years, the subject of antibacterial research has often been related to semisynthetic and synthetic flavonoids, some of these compounds being more active than natural flavonoids [9]. Our recent review highlighted the synthetic flavonoids with antimicrobial activities known up to date in the literature [10].

The emergence of more and more nosocomial infections caused by multidrug-resistant organisms (MDROs) is one of the most worrying phenomena of recent years. The discovery of new and more efficient antimicrobial drugs is therefore a matter of high priority among scientists and clinicians worldwide. Ideally, antibacterial agents should belong to new classes, since the structural alteration of drugs to which resistance has already developed rarely provides a major solution [11]. Following the general interest for synthetic flavonoids, the synthesis of a new class of tricyclic flavonoids as a combination of a condensed benzopyran core and 1,3-dithiolium ring was reported [12]. Subsequently, this class of new synthetic flavonoids proved to exhibit good to excellent antibacterial activities against both Gram-positive and Gram-negative bacteria [13]. The tricyclic flavonoids developed by us inhibited and also killed bacterial cells at very low concentrations (up to 0.24 μg/mL MIC and MBC values) [14,15]. Moreover, some of these flavonoids exhibited a stronger inhibitory and bactericidal effect compared with some antibiotics and other natural or syn-

**Citation:** Birsa, M.L.; Sarbu, L.G. An Improved Synthetic Method for Sensitive Iodine Containing Tricyclic Flavonoids. *Molecules* **2022**, *27*, 8430. https://doi.org/10.3390/ molecules27238430

Academic Editor: Fawaz Aldabbagh

Received: 12 November 2022 Accepted: 25 November 2022 Published: 2 December 2022

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thetic flavonoids reported in the literature and inhibited to some degree the proliferation of cancer cells [16].

Recently, we reported a study on the influence of halogen substituents on the antibacterial properties of tricyclic flavonoids [17]. Upon going from fluorine to iodine, these compounds exhibited good to excellent antimicrobial properties against both Gram-positive and Gram-negative pathogens. The results suggested that halogen size was the main factor for the change in potency rather than polarity/electronics. Prompted by these findings, we decided to investigate the synthesis of sulphur-containing tricyclic flavonoids bearing two iodine substituents on the benzopyran moiety.
