Synthesis and cytotoxic activity evaluation of some new 1, 3, 4-oxadiazole, 1, 3, 4-thiadiazole and 1, 2, 4- triazole derivatives attached to phthalimide

Abstract

Background and purpose: In the last few decades, nitrogen-rich heterocyclic compounds such as 1, 3, 4-thiadiazoles, 1, 2, 4-triazoles and 1, 3, 4-oxadiazoles have received considerable attention because of their notable biological properties, especially cytotoxic effects. The small molecules of mentioned azole derivatives revealed very intensive antitumor activity. In addition, phthalimide-thiadiazole and naphthalimide-triazole hybrid derivatives have shown remarkable cytotoxic effects. According to these observations, some of the hybrid derivatives containing the phthalimide-five-membered azoles were prepared in three steps in this research. Experimental approach: The thiol group of azoles was treated with ethyl chloroacetate which was followed by a reaction with hydrazine hydrate to provide acid hydrazide derivatives. Subsequently, the corresponding acid hydrazides were utilized to prepare the final derivatives through the reaction with phthalic anhydride. Cytotoxic activity of final compounds was evaluated against MCF-7 and HeLa cell lines using MTT assay. Findings/Results: Compound 3d containing two phthalimide moieties in its structure showed a significant improvement in cytotoxic activity with an IC 50 value of 29 μM against HeLa cell line. Compounds 3a-3c showed less cytotoxic effects against both cell lines. Conclusion and implications: The combination of the thiadiazole nucleus with two phthalimide structures increased the cytotoxic activity against the HeLa cell line. This increase in cytotoxic activity is probably due to its being more lipophilic characteristic and interaction of this derivative with the biological targets of two directions.

Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities

“…Moreover, the analogs exhibited low CC 50 values (89.34-206.5 µg/mL) in normal rhesus monkey kidney epithelial cell lines (Abdellattif et al, 2021). Similarly, and Hassanzadeh, Jafari et al (2021) synthesized and characterized four new derivatives (178-181) (Figure 14) that were evaluated for their inhibition of MCF-7 and HeLa cells, with IC 50 values ranging from 67.0 to 92.0 µM in MCF-7 cells and 29.0 to 77.0 µM in HeLa cells Hassanzadeh, Jafari, et al, 2021). scavenging activity of 79.62% as evaluated by the 2,2-diphenyl-1picrylhydrazyl assay (Tumosienė et al 2020).…”

“…The main strategy for AD treatment involves the use of acetylcholinesterase inhibitors (Kumar et al, 2019). Hassanzadeh, Hassanzadeh et al (2021) and Hassanzadeh, Jafari et al (2021) reported the synthesis and evaluation of a series of isoindoline‐1,3‐dione‐containing phthalimide derivatives (Figure 7) as acetylcholinesterase(AChE) inhibitors. The most potent analogs, including 58 , 60 , 62–63 , and 65 , exhibited AChE inhibition with IC 50 values of 2.1–2.9 µM, while compounds 59 , 61 , 64 , and 66 showed IC 50 values ranging from 4.8 to 7.4 µM (Hassanzadeh, Hassanzadeh, et al, 2021; Hassanzadeh, Jafari, et al, 2021).…”

“…Hassanzadeh, Hassanzadeh et al (2021) and Hassanzadeh, Jafari et al (2021) reported the synthesis and evaluation of a series of isoindoline‐1,3‐dione‐containing phthalimide derivatives (Figure 7) as acetylcholinesterase(AChE) inhibitors. The most potent analogs, including 58 , 60 , 62–63 , and 65 , exhibited AChE inhibition with IC 50 values of 2.1–2.9 µM, while compounds 59 , 61 , 64 , and 66 showed IC 50 values ranging from 4.8 to 7.4 µM (Hassanzadeh, Hassanzadeh, et al, 2021; Hassanzadeh, Jafari, et al, 2021). In another study, Panek et al (2017) synthesized and evaluated a series of phthalimide derivatives containing piperazine, hexahydropyrimidine, 3‐aminopyrrotidine, and 3‐aminopiperidine moieties (Figure 7) as AChE inhibitors (Panek et al, 2017).…”

Synthesis, Reactions, and Antimicrobial Evaluation of 2-(1,3-dioxoisoindolin-2-yl)acetohydrazide derivatives

“…Furthermore, hybrid of thiadiazole-phthalimide and triazole-phthalimide moieties have afforded remarkable cytotoxic effects. [14][15][16] Heterocyclic compounds that have five and six membered ring are considered as a pivotal scaffold of targeted drugs in pharmaceutical and medicinal chemistry, this is a results of their resemblance with many biologically efficient compounds in our body. Also, they provide many medicinal and biological applications such as antimicrobial, anticonvulsant, antibacterial, anticancer, anti-inflammatory and antifungal effects.…”