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Modification of acetazolamide synthesis: new derivatives and investigation of their biological properties

Maryam Falakshahi, Nosrat O. Mahmoodi, Behzad Khalili, and Sarah Poormoradkhan Melal

Department of Organic Chemistry, College of Chemistry, University of Guilan, Rasht, Iran

Received: 14 November 2023 Accepted: 5 June 2024

Abstract:

Acetazolamide 1 is a carbonic anhydrase inhibitor used in the medical treatment of glaucoma, epileptic seizure, idiopathic intracranial hypertension, altitude sickness, etc. The synthesis of acetazolamide from the corresponding thiol derivative 4 requires oxidation and converting it to the sulfonyl chloride intermediate 5. This research aimed to enhance the safety, environmental conditions, and efficiency of the oxidation process by substituting chlorine gas for sodium hypochlorite (commercial bleach). The use of chlorine gas in place of conventional oxidation methods offered significant benefits, including the synthesis of several novel compounds with a high level of purity, specifically designated as 6a-6f. These novel compounds were produced through the reaction of synthesized key sulfonyl chloride 5 with various amines, hydrazones, and bis-amine precursors, leading to the creation of new sulfonamide derivatives. A thorough investigation was conducted to determine the antibacterial activity (ABA) and antioxidant activity (AOA) of the newly synthesized compounds. The results indicated that the ABA impact of the prefabricated bis-products (7a and 7b) was significantly higher than that of the standard mono-product (6a). This suggests that the bis-products possess enhanced antibacterial properties compared to their mono-product counterparts. Moreover, the hydrazine-based products synthesized (8a-8g) demonstrated remarkable efficacy against both Gram-positive and Gram-negative bacteria. These products, particularly compound 9g, showed superior antibacterial effects when compared to commonly used antibiotics such as ciprofloxacin and tetracycline. This highlights the potential of these new compounds as effective antibacterial agents. In terms of antioxidant activity, a comparison with ascorbic acid revealed that compounds 9c, 9a, 9b, 9e, and 8d exhibited superior AOA. This indicates that these compounds have a strong potential to act as antioxidants, which can be beneficial in various applications where oxidative stress is a concern. In summary, the substitution of chlorine gas for sodium hypochlorite in the oxidation process not only improved safety and environmental conditions but also led to the efficient synthesis of highly pure novel compounds. These compounds displayed significant ABA and AOA, suggesting their potential as valuable agents in medical and industrial applications. The enhanced properties of the bis-products and hydrazine-based compounds, in particular, underscore the importance of this research in developing new, effective chemical entities. Future research will focus on further optimizing these compounds for clinical use, evaluating their pharmacokinetics and toxicity profiles, and exploring their applications in other therapeutic areas such as anticancer and antiviral treatments.

Graphical abstract

Keywords: Acetazolamide; Sulfonyl chloride; Sulfonamide; Sodium hypochlorite; Thiadiazol

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03551-x

Chemical Papers 78 (11) 6513–6529 (2024)