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Article

The Antimicrobial and Cytotoxicity Properties of New Dibrominated 1,3-Dithiolium Flavonoids

by
Laura Gabriela Sarbu
1,
Ana Alexandra Dumitru
2,
Mihaela Savu
2,
Isabela Andreea Sandu
3,
Lucian Gabriel Bahrin
3,
Marius Stefan
2,* and
Mihail Lucian Birsa
1,*
1
Department of Chemistry, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania
2
Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania
3
Intelcenter, Petru Poni Institute of Macromolecular Chemistry, No. 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2026, 19(2), 259; https://doi.org/10.3390/ph19020259
Submission received: 30 December 2025 / Revised: 26 January 2026 / Accepted: 31 January 2026 / Published: 2 February 2026
(This article belongs to the Section Medicinal Chemistry)
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Versions Notes

Abstract

Background/Objectives: Antimicrobial resistance (AMR) presents a medical risk as well as a significant global socioeconomic challenge. Key contributors to AMR include the excessive use and incorrect application of antibiotics in humans and agriculture, nosocomial infections, and the absence of new classes of antibiotics. Methods: Novel dibrominated tricyclic flavonoids have been synthesized from the corresponding 3-dithiocarbamic flavanones and their antimicrobial and cytotoxicity properties have been investigated. Results: It has been found that these tricyclic flavonoids exhibit strong antimicrobial properties against clinically relevant pathogens such as Staphylococcus aureus, Acinetobacter baumannii, and Escherichia coli with MIC and MBC values against S. aureus ATCC 25923 as low as 0.12 µg/mL and 1.9 µg/mL, respectively. Conclusions: The synthetic tricyclic flavonoids exhibit strong antibacterial activity against selected WHO priority pathogens, including Staphylococcus aureus and Acinetobacter baumannii, surpassing the efficacy of both natural and synthetic flavonoids and several conventional antibiotics.

Graphical Abstract

1. Introduction

In 2019, approximately 4.95 million deaths were linked to antimicrobial resistance (AMR) [1], a phenomenon regarded by the World Health Organization (WHO) as one of the most significant threats to public health and development. Key contributors to AMR include the excessive use and incorrect application of antibiotics in humans and agriculture, nosocomial infections, and the absence of new antibiotic classes. Without sufficient measures, the worldwide burden of AMR will rise significantly, potentially resulting in around 10 million deaths annually by 2050 [2]. AMR presents a medical risk as well as a significant global socioeconomic challenge, resulting in an approximate loss of 3.8% of the worldwide gross domestic product anticipated by the World Bank until 2050 [3].
Microorganisms that are resistant can tolerate and even prosper despite the presence of antibiotics [4]. Consequently, antimicrobial medications grow progressively less effective and numerous infections become harder, if not impossible to manage, placing greater strain on healthcare systems globally [5]. Additionally, the rise and dissemination of multidrug-resistant (MDR) microbes or superbugs undermine the effectiveness of existing antibiotics, jeopardizing the management of infectious diseases and posing a significant challenge for contemporary medicine [6]. Pathogens such as Staphylococcus aureus, Acinetobacter baumannii, and Escherichia coli are developing resistance to multiple antibiotic classes, making the treatment of infections increasingly difficult and leading to higher morbidity, mortality, and healthcare costs.
This AMR crisis is further amplified by the lack of progress in new antibiotic development, largely due to economic and regulatory barriers [7]. A recent WHO report indicates that since 2017, just 13 new antibiotics have been approved, with only vaborbactam and lefamulin belonging to novel chemical classes [8]. However, the recently approved medications show no greater efficacy and do not present new mechanisms of action against current threats. This concerning trend, along with the increased incidence of superbugs, highlights the pressing necessity for creative strategies to produce new antimicrobials effective in combating infectious diseases.
In this perspective, flavonoids—an extensive category of naturally occurring heterocyclic organic substances—are likely effective candidates as antimicrobial agents. Linked to the various substitution patterns on the C6-C3-C6 framework, over 13,000 flavonoids are recognized [9]. The focus they garner is a direct result of the numerous biological actions that this group of compounds displays. Flavonoids exhibit a significant variety of chemical and biochemical traits that give them antimicrobial characteristics [10,11,12]. These substances are likewise recognized for their effective antioxidant properties [13,14,15,16,17,18]. Additionally, some research indicates that flavonoids may provide defense against cancer and heart diseases [19,20,21,22,23,24,25,26,27,28].
Despite their promising properties, natural flavonoids face challenges in medical applications due to limited bioavailability, poor solubility, and instability [29]. The flavonoid scaffold is highly amenable to chemical modification, allowing the design of derivatives with enhanced antimicrobial potency, selectivity, and pharmacokinetic properties. By combining natural bioactivity with rational synthetic optimization, flavonoids offer versatile solutions for developing new antibacterial agents capable of addressing the AMR crisis.
In the last twelve years, our research group has managed to design a new type of tricyclic flavonoids featuring a 1,3-dithiolium ring (Figure 1) with different substituents on the C6-C3-C6 framework. We have established that this new class of synthetic flavonoids displays significant antibacterial activity against both Gram-positive and Gram-negative strains, including ESKAPE pathogens [30], and investigated their mechanisms of action.
Based on these promising results, by changing the substituents’ nature on rings A and B, we are presenting herein an expansion of our research on the development of novel tricyclic flavonoids exhibiting strong antimicrobial properties against clinically relevant pathogens such as S. aureus, A. baumannii, and E. coli. The overarching goal is to identify highly potent antibacterial agents capable of addressing the growing threat of antimicrobial resistance.

2. Results and Discussion

2.1. Tricyclic Flavonoids

As previously reported, flavanone derivatives of type 4 have been synthesized by the reactions of phenacyl dithiocarbamates with aminals 3 [31]. Thus, by reacting 2-bromo-1-(3,5-bromo-2-hydroxyphenyl)ethan-1-one (1) [32] with sodium N,N-diethyldithiocarbamate in acetone, 1-(3,5-dibromo-2-hydroxyphenyl)ethan-1-oxoethan-2-yl N,N-diethylaminocarbodithioate (2) has been successfully synthesized in good yield (85%) [33]. 3-Dithiocarbamic flavanones 4a-d have been prepared through the reaction of phenacyl N,N-diethylaminocarbodithioate 2 with aminals 3 derived from unsubstituted and methyl, ethyl, and methoxy substituted benzaldehydes (Scheme 1) [34].
NMR spectroscopy has confirmed the benzopyran ring closure. The 1H NMR spectra indicated the disappearance of the singlet provided by the methylene group from dithiocarbamate 2 (4.84 ppm) and the appearance of the two pairs of signals between 5.8 and 6.3 ppm corresponding to the vicinal hydrogen atoms at the C-2 and C-3 positions of the benzopyran ring. Mass spectrometry also provided evidence for the ring closure to the benzopyran ring.
Due to the relative orientation of H-2 and H-3 hydrogen atoms of the flavanones 4, two diastereoisomers are obtained as a mixture. They originate from the position of the mentioned hydrogen atoms that can be oriented either to the same side (syn) or to opposite (anti) sides of the benzopyrane core (Figure 2). The relative positions of these two atoms are reflected in the size of the 3J coupling constants. According to the basic rules of stereochemistry, the most stable isomer should be that with an anti orientation of the two hydrogen atoms 4′ as opposed to the syn diastereoisomer 4″. The diastereoisomeric ratio and coupling constants of flavanones 4a-d, presented in Table 1, support the above assumption, the anti diastereoisomer being the major one for all 3-dithiocarbamic flavanones.
2-N,N-Dialkylamino-1,3-dithiolium-2-yl cations are easily synthesized from phenacyl dithiocarbamates [35,36]. Under acidic conditions, the latter undergo cyclocondensation to the corresponding 1,3-dithiolium ring [37]. The cyclocondensation of flavanones 4 to 1,3-dithiolium flavonoids 5 has been demonstrated by analytical and spectral data.
Thus, the carbonyl absorption bands from the infrared spectra (1682–1698 cm−1) disappeared, while at the same time new broad absorption bands (ca. 1010–1090 cm−1) characteristic of the tetrafluoroborate anion were identified. The 1H NMR spectra of 1,3-dithiolium flavonoids 5 indicated the absence of C-3 hydrogens from the benzopyran moiety. Simultaneously, new singlets belonging to the C-2 hydrogens appeared at approximately 6.99 ppm. The 13C NMR spectra indicated the disappearance of the signals for carbonyl and thiocarbonyl and the presence of a new signal (ca. 185 ppm) corresponding to the carbenium atom of the 1,3-dithiol-2-ylium ring.

2.2. Antimicrobial Activity of Tricyclic Flavonoids

All novel flavonoids exhibited notable antibacterial activity against the tested strains, as summarized in Table 2. The 5b and 5c derivatives exhibited superior potency against the Gram-positive strain S. aureus ATCC 25923, reaching a minimum inhibitory concentration (MIC) as low as 0.12 µg/mL. Gram-negative bacteria were less susceptible to the tested compounds than Gram-positive strains, with MIC values ranging from 3.9 to 31.25 µg/mL. Among the tricyclic flavonoids, compounds 5b and 5c displayed the highest activity (3.9 µg/mL) against E. coli ATCC 25922 and A. baumannii medbio3 2013, respectively. The synthetic flavonoids also showed significant inhibitory effects against antibiotic resistant isolates. Specifically, 5d was the most active compound against the methicillin-resistant S. aureus (MRSA) clinical isolate (MIC = 0.9 µg/mL), whereas 5c exhibited the strongest activity against the A. baumannii strain (MIC = 3.9 µg/mL).
Significant bactericidal activity was observed for flavonoids 5a and 5b against S. aureus ATCC 25923, with minimum bactericidal concentration (MBC) values as low as 1.9 µg/mL (Table 3). The synthetic flavonoids exhibited higher MBCs against Gram-negative strains (7.8–62.5 µg/mL). A. baumannii medbio3-2013 was the least susceptible strain, showing the highest MBC value for 5d, indicating a milder bactericidal efficacy compared to Gram-positive strains.
Our results indicate that the novel flavonoids, particularly 5b and 5c, exhibit strong inhibitory and bactericidal effects, especially against Gram-positive bacteria. The tested Gram-negative strains were generally less susceptible to the novel flavonoids compared to Gram-positive bacteria, a finding that is consistent with known differences in bacterial cell envelope architecture. In particular, the presence of an outer membrane in the Gram-negative bacteria wall is widely recognized as an intrinsic permeability barrier that can limit the activity of many antimicrobial compounds. Nevertheless, the low MIC values recorded against E. coli suggest that these synthetic tricyclic flavonoids may possess enhanced membrane permeation properties, potentially contributing to their antibacterial activity. However, direct experimental evaluation of membrane permeability or integrity was beyond the scope of the present study, and future investigations will be required to validate this hypothesis.
The antibacterial potency of the synthetic tricyclic flavonoids appears higher than that reported for many natural flavonoids, including flavones, flavonols, and flavanones, which typically exhibit MIC values in the range of 250–1000 μg/mL against common bacterial strains such as Staphylococcus aureus and Escherichia coli [38]. Literature reports further indicate that natural flavonoids such as quercetin or kaempferol often display MIC values in the range of 25–125 μg/mL against S. aureus [39]. In comparison with highly potent natural flavonoids such as Panduratin A—previously reported as one of the most active flavonoids with MIC values of 0.5–1 μg/mL—compounds 5a–d nonetheless exhibit notable inhibitory activity against MRSA [40]. Moreover, the tested compounds demonstrate relevant antibacterial activity relative to active natural compounds such as isobavachalcone, particularly against E. coli, for which reported MIC values often exceed 256 μg/mL [41].
Compounds 5a–d exhibit antibacterial activity comparable to, or exceeding that of previously reported halogenated tricyclic flavonoids, underscoring the effectiveness of rational scaffold modification (particularly halogenation and methoxy/alkyl substitution) in enhancing antibacterial potency relative to both natural and synthetic flavonoids. Relative to synthetic chalcones containing diphenyl ether moieties, tricyclic flavonoids 5a–d show 2–5-fold greater activity against E. coli (MICs = 10–33 μg/mL) and markedly superior inhibition of S. aureus (MICs between 7.5 and 25 μg/mL) [42]. Moreover, our tested synthetic flavonoids outperform nitrogen-containing synthetic flavonoids, which typically display MIC values > 32 μg/mL [43]. The synthetic flavonoids exhibited remarkable activity against A. baumannii medbio3 2013 strain, with 5c achieving an MIC of 3.9 µg/mL. This potency surpasses that of other synthetic scaffolds, including halogenated nitrochromenes (8–32 µg/mL) [44], and markedly exceeds the activity of natural flavonoids such as quercetin (256 µg/mL) [45] and norwogonin (128 µg/mL) [46]. While these comparisons provide a useful contextual reference, direct quantitative comparisons should be interpreted with caution, as MIC values reported across different studies may vary due to differences in experimental conditions.
For most of the tested flavonoids, the MBC/MIC ratio was ≤4, indicating significant bactericidal activity. Notably, for 5b, the MIC was equal to the MBC against antibiotic-resistant strains such as S. aureus MedBio1-2012 and A. baumannii MedBio3-2013, underscoring its exceptional antimicrobial potential. Collectively these findings position the tricyclic flavonoids 5a–d as highly promising candidates for the treatment of infections caused by multidrug-resistant priority pathogens, including S. aureus and A. baumannii. Nonetheless, the antibacterial activity observed against resistant bacterial strains should be regarded as preliminary, as it was evaluated using only two clinical isolates. Further studies involving a larger and more diverse collection of clinical strains will be required to assess the reproducibility and spectrum of activity of these compounds against clinically important pathogens.
The pronounced inhibitory and bactericidal activities of synthetic flavonoids 5a–d are further confirmed by comparison with the antibiotics employed as reference controls. Notably, all tested compounds exhibited considerably enhanced inhibitory activity against S. aureus ATCC 25923, surpassing ampicillin by up to 16-fold and chloramphenicol by up to 65-fold. Comparable trends were observed against the MRSA strain, where compounds 5c and 5d displayed MIC values up to ninefold lower than those of chloramphenicol. Against E. coli, the synthetic flavonoids demonstrated moderate yet significant activity, with compound 5b showing up to 16-fold lower potency than ampicillin, while exhibiting activity comparable to kanamycin. In contrast, all tested compounds were less active against A. baumannii than gentamicin.
The strong antimicrobial activity is likely attributable to a donor–acceptor interaction between nucleophilic moieties of wall and/or membrane constituents (e.g., peptides, peptidoglycans) and the electrophilic C(2) atom of the 1,3-dithiolium ring. The lower MICs and MBCs may suggest that the inhibitory and bactericidal activity are related to the impairment of the cell membrane integrity, as our previous studies showed for similar halogenated sulfur containing tricyclic flavonoids [47]. The potential of the novel flavonoids reported here is underscored by their synthetic, non-natural nature, making them excellent candidates for antimicrobial development. Their synthetic structures allow them to circumvent existing resistance mechanisms and act via novel modes of action, enhancing their efficacy against multidrug-resistant strain. Nevertheless, further investigations are required to elucidate the precise mechanisms of action.

2.3. Cytotoxicity Study

In order to evaluate the effect of tricyclic flavonoids 5a–d on human cells, the MTS assay was used. The tested derivatives were found to have little negative effect on HDF-Ad cells at concentrations up to 7.8 µg/mL. However, when tested at a concentration of 15.6 µg/mL, cell viability was significantly reduced to approximately 60% for 5b and 5d and plummeted to 20% and 0% for 5a and 5c, respectively (Figure 3). When compared to the MIC and MBC values presented in Table 2 and Table 3, it is worth noting that all four tested derivatives are active against S. aureus ATCC 25923 at concentrations lower than those found to induce cytotoxicity in HDF-Ad cells. For E. coli ATCC 25922, three of the four tested flavonoids, namely 5a, 5b, and 5d, were determined to have MIC values lower than or equal to 7.8 µg/mL, at which HDF-Ad cell viability is arguably unaffected. However, all four derivatives present MBC values of 31.25 µg/mL, a 4-fold increase when compared to 7.8 µg/mL. In the case of S. aureus medbio1-2012, all four flavonoids presented MIC values lower than 7.8 µg/mL, but only three of them, derivatives 5b–d, had MBC values lower than or equal to 7.8 µg/mL. Finally, for A. baumannii medbio3 2013, flavonoids 5b and 5c have MIC values of 7.8 and 3.9 µg/mL, while 5b also has an MBC value of 7.8 µg/mL.

3. Materials and Methods

Melting points were obtained on a KSPI melting-point meter (A. KRÜSS Optronic, Hamburg, Germany) and are uncorrected. IR spectra were recorded on a Bruker Tensor 27 instrument (Bruker Optik GmbH, Ettlingen, Germany). NMR spectra were recorded on a Bruker 500 MHz spectrometer (Bruker BioSpin, Rheinstetten, Germany). Chemical shifts are reported in ppm downfield from TMS. Mass spectra were recorded on a Thermo Scientific ISQ LT instrument (Thermo Fisher Scientific Inc., Waltham, MA, USA). All reagents were commercially available and used without further purification. Elemental analyses (Table S1), 1H NMR and 13C NMR spectra are presented in the Supplementary Materials.

3.1. Chemistry

3.1.1. 6,8-Dibromo-2-phenyl-4-oxochroman-3-yl N,N-diethyldithiocarbamate (4a); General Procedure

To a solution of 1-(2,5-dibromo-2-hydroxyphenyl)-1-oxoethan-2-yl N,N-diethyldithiocarbamate (2) (0.441 g, 1 mmol) in a mixture of CHCl3/MeOH (14 mL, 1:1 v/v) aminal 3a (0.276 g, 1 mmol) was added and the reaction mixture was heated under reflux for 4 h. After cooling, the solid material was filtered off, dried and recrystallized from ethanol to give 4a (0.365 g, 69%) as colorless crystals. M.p. 148–149 °C. IR (ATR, cm−1) 2972, 1683, 1488, 1423, 1262, 1188, 811, 714, 637, 562. 1H NMR (CDCl3, selected data for the major anti isomer) δ 7.97 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.59–7.50 (m, 2H), 7.39–7.35 (m, 3H), 6.05 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 3.97 (q, J = 6.6 Hz, 2H), 3.69 (q, J = 7.1 Hz, 2H), 1.23 (m, 6H). 13C NMR (CDCl3, selected data for the major anti isomer) δ 191.0, 186.2, 156.0, 141.5, 135.7, 129.3, 128.9, 128.6, 127.2, 123.2, 114.3, 113.1, 83.1, 58.2, 50.6, 47.3, 12.6, 11.4. MS (EI) m/z: 526.9 (M+, 12%) for C20H1979Br2NO2S2.

3.1.2. 6,8-Dibromo-2-(4′-methylphenyl)-4-oxochroman-3-yl N,N-diethyldithiocarbamate (4b)

Colorless crystals, m.p. 157–158 °C, 0.390 g, 72%. IR (ATR, cm−1) 2978, 2728, 1690, 1494, 1416, 1273, 1200, 809, 723, 644, 551. 1H NMR (CDCl3, selected data for the major anti isomer) δ 7.96 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.01 (d, J = 6.8 Hz, 1H), 5.78 (d, J = 6.8 Hz, 1H), 3.98 (q, J = 7.0 Hz, 2H), 3.70 (q, J = 7.7 Hz, 2H), 2.35 (s, 3H), 1.25 (t, J = 7.1 Hz, 6H). 13C NMR (CDCl3, selected data for the major anti isomer) δ 191.1, 186.3, 156.0, 141.4, 138.8, 132.8, 129.3, 129.1, 127.1, 123.2, 114.2, 113.1, 83.0, 58.1, 50.5, 47.3, 21.2, 12.6, 11.4. MS (EI) m/z: 540.9 (M+, 17%) for C21H2179Br2NO2S2.

3.1.3. 6,8-Dibromo-2-(4′-ethylphenyl)-4-oxochroman-3-yl N,N-diethyldithiocarbamate (4c)

Colorless crystals, m.p. 145–146 °C, 0.400 g, 72%. IR (ATR, cm−1) 2983, 2714, 1682, 1484, 1402, 1269, 1156, 809, 714, 632, 541. 1H NMR (CDCl3, selected data for the major anti isomer) δ 7.96 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 6.02 (d, J = 7.0 Hz, 1H), 5.79 (d, J = 7.0 Hz, 1H), 3.98 (q, J = 7.6 Hz, 2H), 3.69 (q, J = 6.2 Hz, 2H), 2.64 (d, J = 7.6, Hz, 2H), 1.37–1.24 (m, 6H), 1.23 (m, 3H). 13C NMR (CDCl3, selected data for the major anti isomer) δ 191.1, 186.3, 156.0, 145.0, 141.4, 133.0, 129.3, 128.1, 127.2, 123.2, 114.2, 113.1, 83.1, 58.1, 50.5, 47.3, 28.5, 15.3, 12.6, 11.4. MS (EI) m/z: 554.9 (M+, 18%) for C22H2379Br2NO2S2.

3.1.4. 6,8-Dibromo-2-(4′-methoxyphenyl)-4-oxochroman-3-yl N,N-diethyldithiocarbamate (4d)

Colorless crystals, m.p. 164–165 ° C, 0.390 g, 70%. IR (ATR, cm−1) 2964, 1685, 1471, 1439, 1244, 1213, 798, 723, 614, 564. 1H NMR (CDCl3, selected data for the major anti isomer) δ 7.97 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.96 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 7.7 Hz, 1H), 4.09–3.98 (m, 1H), 3.98–3.88 (m, 1H), 3.81 (s, 3H), 3.69 (q, J = 7.3 Hz, 2H), 1.24 (m, 6H). 13C NMR (CDCl3, selected data for the major anti isomer) δ 191.1, 186.5, 160.0, 156.0, 141.4, 129.3, 128.7, 127.8, 123.1, 114.2, 113.9, 113.1, 82.9, 58.4, 55.3, 50.6, 47.3, 12.6, 11.4. MS (EI) m/z: 556.9 (M+, 14%) for C21H2179Br2NO3S2.

3.1.5. 2-N,N-Diethylamino-6,8-dibromo-4-phenyl-4H-1,3-dithiol[4,5-c]chromen-2-ylium tetrafluoroborate (5a); General Procedure

To a mixture of sulfuric acid (1 mL) and acetic acid (3 mL), flavanone 4a (0.264 g, 0.5 mmol) was added and the resulting solution was heated to 70 °C for 30 min. The reaction mixture was then left to cool to room temperature and a solution of sodium tetrafluoroborate (0.3 g) in water (10 mL) was added dropwise, under vigorous stirring. The resulting precipitate was then filtered, washed thoroughly with water and recrystallized from ethanol, yielding the desired tetrafluoroborate 5a in the form of colorless crystals (0.23 g, 76%). M.p. 203–204 °C. IR (ATR, cm−1) 1562, 1444, 1202, 1050, 721, 523. 1H NMR (DMSO-d6) δ 7.91 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 6.9, 3.2 Hz, 2H), 7.47 (q, J = 3.0 Hz, 3H), 6.99 (s, 1H), 4.00–3.82 (m, 4H), 1.41 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (DMSO-d6) δ 184.9, 147.7, 136.9, 136.7, 130.6, 130.0, 129.6, 127.9, 127.1, 126.8, 119.7, 115.0, 112.4, 76.3, 54.8, 54.7, 10.8, 10.5. MS (EI) m/z: 509.9 (M+-BF4, 6%) for C20H1879Br2NOS2]+.

3.1.6. 2-N,N-Diethylamino-6,8-dibromo-4-(4′-methylphenyl)-4H-1,3-dithiol[4,5-c]chromen-2-ylium tetrafluoroborate (5b)

Colorless crystals, m.p. 209–210 °C (0.274 g, 91%). IR (ATR, cm−1) 2981, 1556, 1441, 1217, 1046, 741, 506. 1H NMR (DMSO-d6) δ 7.89 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 6.93 (s, 1H), 4.00–3.82 (m, 4H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (DMSO-d6) δ 184.9, 147.8, 140.4, 136.8, 133.7, 130.3, 130.1, 127.9, 127.0, 126.7, 119.7, 114.9, 112.4, 76.3, 54.8, 54.7, 21.3, 10.8, 10.5. MS (EI) m/z: 523.9 (M+-BF4, 5%) for C21H2079Br2NOS2]+.

3.1.7. 2-N,N-Diethylamino-6,8-dibromo-4-(4′-ethylphenyl)-4H-1,3-dithiol[4,5-c]chromen-2-ylium tetrafluoroborate (5c)

Colorless crystals, m.p. 211–212 °C (0.26 g, 85%). IR (ATR, cm−1) 2973, 1549, 1433, 1225, 1049, 757, 584, 530. 1H NMR (DMSO-d6) δ 7.89 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 3.98–3.80 (m, 4H), 2.62 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H). 13C NMR (DMSO-d6) δ 184.8, 147.7, 146.5, 136.8, 134.0, 130.2, 129.0, 128.0, 127.0, 126.7, 119.6, 114.9, 112.4, 76.3, 54.8, 54.7, 28.3, 15.8, 10.8, 10.5. MS (EI) m/z: 537.9 (M+-BF4, 7%) for C22H2279Br2NOS2]+.

3.1.8. 2-N,N-Diethylamino-6,8-dibromo-4-(4′-methoxyphenyl)-4H-1,3-dithiol[4,5-c]chromen-2-ylium tetrafluoroborate (5d)

Colorless crystals, m.p. 219–220 °C (0.27 g, 79%). IR (ATR, cm−1) 1550, 1493, 1251, 1230, 1178, 1046, 820, 708, 563, 518. 1H NMR (DMSO-d6) δ 7.89 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.88 (s, 1H), 3.98–3.81 (m, 4H), 3.77 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H). 13C NMR (DMSO-d6) δ 184.8, 161.0, 147.8, 136.8, 130.5, 129.8, 128.5, 127.0, 126.7, 119.7, 114.9, 114.8, 112.4, 76.2, 55.8, 54.8, 54.6, 10.8, 10.5. MS (EI) m/z: 539.9 (M+-BF4, 8%) for C21H2079Br2NO2S2]+.

3.2. Bacterial Susceptibility Assays

3.2.1. Strains and Culture Conditions

The strains selected for antimicrobial testing included Staphylococcus aureus ATCC 25923 (methicillin-sensitive, MSSA) and Escherichia coli ATCC 25922, both obtained from the culture collection of the Microbiology Laboratory, Alexandru Ioan Cuza University of Iași. Additionally, the clinical isolate S. aureus medbio1-2012 (methicillin-resistant, MRSA; resistant to cefoxitin, clindamycin, erythromycin, moxifloxacin, penicillin, and tetracycline) was provided by PhD Simona Matiut from Praxis Clinical Laboratory, Iași, Romania; Acinetobacter baumannii medbio3-2013 (resistant to cefotaxime and ceftazidime) was isolated from a local wastewater treatment plant and identified via MALDI-TOF/MS.
Strains were maintained as glycerol stocks at −80 °C. Prior to testing, frozen cultures were streaked onto Mueller–Hinton agar (MHA; Accumix, Belgium) and incubated overnight at 37 °C under aerobic conditions to ensure viability and purity. A single, morphologically typical colony from each strain was used to inoculate 10 mL of Mueller–Hinton broth (MHB; Roth, Germany). Pre-cultures were incubated for 24 h at 37 °C with agitation at 190 rpm to obtain inoculum for subsequent assays.

3.2.2. Minimum Inhibitory and Bactericidal Concentration Assays

Minimum inhibitory concentration (MIC) values were determined using the broth microdilution method using 96-well microplates, following CLSI guidelines, as we previously described [14]. Serial two-fold dilutions of each flavonoid were prepared in Mueller–Hinton broth (MHB) with dimethyl sulfoxide (DMSO, Roth, Germany) as solvent, yielding final concentrations ranging from 0.12 to 250 µg/mL. Final cell density in the well was approximately 1 × 105 CFU (colony-forming units)/mL for all strains tested. Growth controls consisted of inoculated MHB, and solvent controls included DMSO at concentrations up to 24.87% (v/v). No inhibitory effect of DMSO was observed at concentrations up to 3.10%, corresponding to the highest MIC value recorded (31.25 µg/mL). Reference antibiotics (ampicillin, chloramphenicol, kanamycin, and gentamicin) were included as positive controls. After incubation at 37 °C for 24 h, MIC values were determined using a resazurin assay, based on visual evaluation of the distinct color change (blue to pink) indicating bacterial growth. MIC values were determined in triplicate and are reported as modal values. Variability between replicates did not exceed one two-fold dilution.
To determine the minimum bactericidal concentration (MBC), 5 µL aliquots from wells exhibiting no visible growth were serially diluted and subsequently plated onto Mueller–Hinton agar. The MBC was recorded as the lowest concentration at which no colony formation occurred after incubation at 37 °C. All assays were performed in biological triplicate.

3.3. Cytotoxicity Assay

The cytotoxicity of tricyclic flavonoids 5a–d was evaluated using human dermal fibroblasts in culture, taken from an adult (HDF-Ad). HDF-Ad cells were cultured in dishes treated for cell cultures with complete MEM Eagle alpha culture medium containing 10% fetal bovine serum and 1% antibiotic-antimycotic mixture at 37 °C in a humidified atmosphere with 5% CO2. TrypLETM Express Dissociation Reagent was used for cell passage, when the cells reached 80% confluence, to avoid contact inhibition. Solutions of 5a–d were investigated by first preparing stock solutions in DMSO, followed by diluting them 100-fold in the culture medium, so that the final percentage of DMSO was 1% in the cell plate. The control group also contained 1% DMSO. To investigate the cytotoxicity of 5a–d we used the CellTiter 96® AQueous One Solution (MTS) assay, according to the manufacturer’s instructions. Briefly, cells were seeded in 96-well plates at a density of 5 × 103 wells in 100 μL complete culture medium/well and incubated overnight. After 24 h, the culture medium was replaced with test solutions at different concentrations, and the plates were incubated for 48 h. After this incubation period, 20 μL MTS was added in each well, and the plates were incubated for 3 h. Finally, the absorbance at 490 nm was measured with a microplate reader. The relative cell viability is expressed as a percentage of the control group viability. Graphical data were expressed as means ± standard deviation (SD).

4. Conclusions

The synthetic tricyclic flavonoids 5a–d exhibited strong antibacterial activity against selected WHO priority pathogens, including Staphylococcus aureus and Acinetobacter baumannii, surpassing the efficacy of both natural and synthetic flavonoids and several conventional antibiotics. MIC and MBC values against S. aureus ATCC 25923 as low as 0.12 µg/mL and 1.9 µg/mL, respectively, have been recorded for 5b and 5c. The tested derivatives were found to induce little to no cytotoxicity on HDF-Ad cells at concentrations up to 7.8 µg/mL, a value at which most of them are active against the four tested bacterial strains, further confirming their potential use as antibacterial agents. These findings underscore the promise of tricyclic flavonoid scaffolds as lead compounds for the development of new therapeutic agents targeting multidrug-resistant bacterial infections. Nevertheless, further investigations are needed to evaluate their antimicrobial spectrum against a broader panel of multidrug-resistant clinical isolates and to assess the potential for resistance development against these novel flavonoids.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ph19020259/s1, Table S1: Elemental analysis data; Copies of 13C NMR and 1H NMR spectra.

Author Contributions

Conceptualization, L.G.S., M.S. (Marius Stefan), and M.L.B.; methodology, L.G.S.; validation, L.G.S., L.G.B. and M.S. (Marius Stefan); investigation, L.G.S., I.A.S., M.S. (Mihaela Savu), and A.A.D.; writing—review and editing, L.G.B., M.S. (Marius Stefan), and M.L.B.; visualization, L.G.S. and L.G.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Acknowledgments

This work was supported by a grant from the Ministry of Research, Innovation, and Digitization, CNCS/CCCDI—UEFISCDI, project number PN-IV-P7-7.1-PED-2024-1393, within PNCDI IV. Thanks to the CERNESIM Center, within the Interdisciplinary Research Institute at the “Alexandru Ioan Cuza” University of Iasi, for recording the NMR experiments.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Molecular structure of tricyclic 1,3-dithiolium flavonoids.
Figure 1. Molecular structure of tricyclic 1,3-dithiolium flavonoids.
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Scheme 1. Synthesis of 3-dithiocarbamic flavanones 4a–d and tricyclic flavonoids 5a–d.
Scheme 1. Synthesis of 3-dithiocarbamic flavanones 4a–d and tricyclic flavonoids 5a–d.
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Figure 2. Diastereoisomers of flavanones 4.
Figure 2. Diastereoisomers of flavanones 4.
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Figure 3. Graphical representation of cell viability for tricyclic flavonoids treated HDF-Ad cells, relative to untreated ones. The data are expressed as mean ± SD.
Figure 3. Graphical representation of cell viability for tricyclic flavonoids treated HDF-Ad cells, relative to untreated ones. The data are expressed as mean ± SD.
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Table 1. Coupling constants and diastereoisomeric ratio of flavanones 4.
Table 1. Coupling constants and diastereoisomeric ratio of flavanones 4.
Flavanones 4abcd
3JH2-H3 anti (Hz)7.66.87.07.7
3JH2-H3syn (Hz)4.14.44.44.5
anti:syn ratio69:3185:1581:1974:26
Table 2. In vitro antibacterial activity (MIC) of tricyclic flavonoids 5a–d against selected bacterial strains.
Table 2. In vitro antibacterial activity (MIC) of tricyclic flavonoids 5a–d against selected bacterial strains.
Microbial StrainsMIC (µg/mL)
5a5b5c5dDMSO (%)Control
Staphylococcus aureus ATCC 259230.240.120.120.4824.871.95 a/7.81 chl
Escherichia coli ATCC 259227.83.915.67.812.4362.50 a/7.81 k
S. aureus medbio1-20123.93.91.90.924.877.81 chl
Acinetobacter baumannii medbio3 201315.67.83.931.2524.87<0.9 g
a—ampicillin; chl—chloramphenicol; g—gentamicin; k—kanamycin. The values are means for at least three replicates.
Table 3. Minimum bactericidal concentrations of flavonoids 5a–d against tested bacterial strains.
Table 3. Minimum bactericidal concentrations of flavonoids 5a–d against tested bacterial strains.
Microbial StrainsMBC (µg/mL)
5a5b5c5dControl
Staphylococcus aureus ATCC 259231.91.97.83.97.8 a
Escherichia coli ATCC 2592231.2531.2531.2531.25125 a
S. aureus medbio1-201231.253.93.97.831.25 chl
Acinetobacter baumannii medbio3 201331.257.815.662.5<0.9 g
a—ampicillin; chl—chloramphenicol; g—gentamicin. The values are means for at least three replicates.
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MDPI and ACS Style

Sarbu, L.G.; Dumitru, A.A.; Savu, M.; Sandu, I.A.; Bahrin, L.G.; Stefan, M.; Birsa, M.L. The Antimicrobial and Cytotoxicity Properties of New Dibrominated 1,3-Dithiolium Flavonoids. Pharmaceuticals 2026, 19, 259. https://doi.org/10.3390/ph19020259

AMA Style

Sarbu LG, Dumitru AA, Savu M, Sandu IA, Bahrin LG, Stefan M, Birsa ML. The Antimicrobial and Cytotoxicity Properties of New Dibrominated 1,3-Dithiolium Flavonoids. Pharmaceuticals. 2026; 19(2):259. https://doi.org/10.3390/ph19020259

Chicago/Turabian Style

Sarbu, Laura Gabriela, Ana Alexandra Dumitru, Mihaela Savu, Isabela Andreea Sandu, Lucian Gabriel Bahrin, Marius Stefan, and Mihail Lucian Birsa. 2026. "The Antimicrobial and Cytotoxicity Properties of New Dibrominated 1,3-Dithiolium Flavonoids" Pharmaceuticals 19, no. 2: 259. https://doi.org/10.3390/ph19020259

APA Style

Sarbu, L. G., Dumitru, A. A., Savu, M., Sandu, I. A., Bahrin, L. G., Stefan, M., & Birsa, M. L. (2026). The Antimicrobial and Cytotoxicity Properties of New Dibrominated 1,3-Dithiolium Flavonoids. Pharmaceuticals, 19(2), 259. https://doi.org/10.3390/ph19020259

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