Development of Potent Antibacterial Chalcone Derivatives Containing 2,4-Thiazolidinedione for Fighting Multidrug-Resistant Staphylococcus Aureus
Kavitha Baburao1,2, Naresh Kumar Panigrahi1*
1Dept of Pharmaceutical Chemistry, GITAM School of Pharmacy, Vishakapatnam, India.
1,2Sarojini Naidu Vanita Pharmacy Maha Vidyalaya, Tarnaka, Hyderabad.
*Corresponding Author E-mail: npanigra@gitam.edu
ABSTRACT:
The emergence of methicillin and vancomycin resistant Staphylococcus aureus infections is a growing global health concern that is causing increasing illness and death. The growing problem of drug resistance has emphasized the need to discover and develop new antibacterial agents that work through different mechanisms to address this issue. To address this issue, a number of chalcone derivatives of Thiazolidine-2,4-dione were designed and synthesized as potential antibacterial agents. When evaluated against a panel of bacteria known as ESKAP, compounds 7a, 7h, and 7d were found to have highly selective inhibitory activity against Staphylococcus aureus at a concentration of 25μg/mL. This result suggests that these compounds have specific and powerful activity against S. aureus and have no effect against gram-negative bacteria.
KEYWORDS: Thiazolidine 2,4-dione, Anti-bacterial, Chalcones, ESKAP pathogen.
INTRODUCTION:
Medicinal chemistry research plays a vital role focusing on the discovery of new compounds with antimicrobial activity or new mechanisms of action for known compounds1. It is essential to continue research in this area to keep pace with the development of resistance and to find new ways to fight against the pathogenic microorganisms. 4-Thiazolidinone derivatives, particularly thiazolidine-2,4-diones (TZDs), have attracted significant attention in the scientific community, as seen in numerous reviews2-6. This interest is a result of not only the wide range of chemical modifications that can be made to these derivatives, but also their diverse pharmacological properties and specific biological targets. As a result, TZD derivatives are highly sought-after as potential sources of novel drug candidates.
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Received on 30.12.2024 Revised on 07.04.2025 Accepted on 13.06.2025 Published on 02.08.2025 Available online from August 08, 2025 Research J. Pharmacy and Technology. 2025;18(8):3739-3741. DOI: 10.52711/0974-360X.2025.00538 © RJPT All right reserved
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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License. |
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The versatility of these derivatives and their ability to target multiple disease states make them a promising area of research to develop new drugs.
Figure 1: Thiazolidine 2,4-dione, a multi-functional nucleus
One of the most promising strategies in drug discovery is the design of new compounds based on preferential scaffolds. This approach involves identifying and utilizing specific structural fragments that have the potential to exhibit desired biological activity. In our research, we have focused on the thiazolidine 2,4-dione scaffold, which has been found to display antimicrobial properties at low non-toxic concentrations. This makes it a valuable target for the development of new drugs to combat bacterial and fungal infections. By utilizing this scaffold, we aim to discover and develop new compounds that can effectively target and neutralize harmful microorganisms while minimizing toxicity to the host organism.
RESULTS AND DISCUSSION:
The synthesis of the chalcone derivatives began with the preparation of thiazolidine‑2,4‑dione (3) via a previously reported method using green chemistry principles. Subsequently, (Z)-4-((2,4-dioxothiazolidin-5-ylidene) methyl) benzaldehyde (5) was synthesized through a Knoevenagel condensation reaction between compound 3 and biphenyl aldehyde (4), a strategy widely adopted for the efficient formation of exocyclic double bonds. In the final step, a C–N bond was constructed between intermediate 5 and a variety of aryl and alkyl halides (6a–d), yielding the desired (Z)-5-(4-((E)-3-oxo-3-phenylprop-1-en-1-yl) benzylidene) thiazolidine-2,4-dione derivatives (7a–d), using known N-alkylation protocols for thiazolidinedione systems.
Anti-bacterial activity:
To evaluate the potential antibacterial activity of the newly synthesized Thiazolidine chalcones, they were tested against a panel of pathogens known as ESKAP7-9. The Minimum Inhibitory Concentration (MIC) of each compound was determined by performing antibiotic susceptibility testing in accordance with standard CLSI guidelines10. The compounds were tested at a concentration range of 75-25μg/mL, and Ceftriaxone was used as a reference compound. The results of these tests are summarized in Table 1.
It was observed that only compounds 7a and 7h demonstrated moderate activity against the ESKAP pathogens, as seen in the supplementary data. This suggests that these compounds may have potential as antimicrobial agents and can be further studied for their ability to combat bacterial infections. The study of these compounds can provide new tools for the management of drug-resistance and the development of new antibiotics. The results showed that these compounds have potential as new antimicrobial agents and needs further optimization and characterization.
Scheme 1. Synthetic scheme for the synthesis of compounds 5a and 5b.
Scheme 2. Synthetic scheme for the synthesis of compounds 7a-7o.
Table 1: MIC values (μg/mL) of the tested compounds against panel of bacterial and fungal.
|
S. No |
Compound |
S. aureus ATCC 25923 |
Salmonella typhi ATCC-14028 |
K. pneumoniae ATCC-33495 |
Candida albicans ATCC-66027 |
|
1 |
7a |
25 |
- |
75 |
75 |
|
2 |
7b |
50 |
- |
- |
- |
|
3 |
7c |
50 |
- |
- |
- |
|
4 |
7d |
75 |
25 |
25 |
- |
|
5 |
7e |
50 |
50 |
50 |
- |
|
6 |
7f |
- |
- |
50 |
75 |
|
7 |
7g |
- |
25 |
- |
- |
|
8 |
7h |
25 |
25 |
75 |
75 |
|
9 |
7i |
50 |
- |
- |
- |
|
10 |
7j |
- |
- |
- |
50 |
|
11 |
7k |
25 |
- |
75 |
75 |
|
12 |
7l |
50 |
- |
- |
- |
|
13 |
7m |
50 |
- |
- |
- |
|
14 |
7n |
75 |
- |
- |
- |
|
15 |
7o |
- |
- |
- |
50 |
|
6 |
Ceftriaxone |
50 |
50 |
50 |
50 |
|
7 |
Fluconazole |
- |
- |
- |
25 |
An initial in vitro assay revealed that the intermediate esters 7f did not display any significant anti-bacterial activity when tested at a concentration of 75mg/mL. However, among the desired compounds, 7a, 7b, and 7c were found to have potent anti-bacterial activity against Gram-positive strains, particularly Staphylococcus aureus ATCC-25923, with MIC values in the range of 75-25μg/mL. These results were comparable to those of the control drugs (Table 1). This suggests that compounds 7a, 7b, and 7c have the potential to be developed as new anti-bacterial agents, particularly against Gram-positive strains, and further studies are needed to determine their efficacy, safety, and potential for use in the treatment of bacterial infections.
Figure 2: MIC bar graph showing the antibacterial and antifungal activity of the synthesized compounds
CONCLUSION:
Further, a preliminary in-vitro assay was conducted to assess the anti-bacterial activity of the intermediate esters 7f. It was found that at a concentration of 75 mg/mL, these compounds did not exhibit any anti-bacterial activity. Among the desired compounds, 7a, 7b, and 7c showed potent anti-bacterial activity against the Gram-positive strain of Staphylococcus aureus ATCC-25923. Their MIC values were found to be in the range of 75-25μg/mL, which were comparable to the control drugs as per the data in Table 1. The results suggest that these newly synthesized Thiazolidine chalcones may have potential as antibacterial agents, particularly against Gram-positive strains, and further studies are warranted to confirm their efficacy. We have successfully synthesized a new series of chalcone derivatives bearing 2,4-thiazolidinedione and their analogs (7a-o) and evaluated their potential anti-bacterial activities against both Gram-positive and Gram-negative bacteria. The findings indicate that some of the compounds showed anti-bacterial activity against Gram-positive bacteria, particularly against multidrug-resistant strains of clinically isolated bacteria. Among the compounds tested, 7h was found to have the most potent inhibitory capacity. This suggests that these chalcone derivatives have the potential to be developed as new anti-bacterial agents. The study also suggests that the Chalcone and Thiazolidine ring in these compounds may play a crucial role in their anti-bacterial activity. Further development of these compounds and more studies are needed to investigate the mechanism of action and to optimize the efficacy of these compounds as anti-bacterial agents. These results imply that the new series of chalcone derivatives bearing 2,4-thiazolidinedione and their analogs (7a-o) have the potential to be developed as new anti-bacterial agents, particularly against multidrug-resistant strains of clinically isolated bacteria.
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Received on 21.07.2024 Revised on 06.12.2024 Accepted on 15.02.2025 Published on 02.08.2025 Available online from August 08, 2025 Research J. Pharmacy and Technology. 2025;18(8):3730-3738. DOI: 10.52711/0974-360X.2025.00537 © RJPT All right reserved
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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License. |
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