Design, synthesis, cytotoxicity, and molecular docking studies of novel thiazolyl–hydrazone derivatives as histone lysine acetyl‐transferase inhibitors and apoptosis inducers

Abstract

Compounds containing both thiazole and arylsulfone moieties are recognized for their high biological activity and ability to fight a variety of ailments. Thus, in this context, new derivatives of (thiazol‐2‐yl)hydrazone with an arylsulfone moiety were synthesized as CPTH2 analogs with potent anti‐histone lysine acetyl‐transferase activity. Compounds 3, 4, 10b, and 11b showed an excellent inhibitory effect on P300 (E1A‐associated protein p300), compared to CPTH2. Among all the tested derivatives, compound 10b revealed the highest activity against both P300 and pCAF. In addition, the new hits were tested for anticancer efficacy against two leukemia cell lines. Most of them showed a moderate to potent antitumor effect on the k562 and CCRF‐CEM cell lines. Interestingly, the activity of compound 10b against the k562 cell line was found to be higher than that of CPTH2. Furthermore, it showed a good safety profile, better than CPTH2 on normal cells. Molecular docking analysis was carried out to reveal the crucial binding contacts in the inhibition of the P300 and pCAF enzymes.

Quinoline‐based thiazolyl‐hydrazones target cancer cells through autophagy inhibition

“…The focused library of the investigated QTHs composed of three sets Apoptosis as the mechanism of cancer cell death caused by applying various thiazolyl-hydrazones is well documented. [67][68][69][70][71] On the other hand, only two publications report that thiazolyl-hydrazones may induce cell death by autophagy. Results reported by Wang et al revealed that bromophenol-based thiazolyl-hydrazones kill cancer cells by autophagy induction.…”

An insight into therapeutic efficacy of heterocycles as histone‐modifying enzyme inhibitors that targets cancer epigenetic pathways

“…One of the histone‐modifying enzymes, histone acetyltransferases involve in the acetylation of specific amino acid residues; plays a vital role in pathogenesis (Parthun, 2012., Poziello et al, 2021). Literature reports suggest preclinical studies on the inhibition of histone acetyltransferases like p300/CBP and PCAF (Abbas et al, 2022; He, Wei, et al, 2021; Kopytko et al, 2021; Manzo et al, 2009). Based on mechanism‐based cellular activity, many HAT inhibitors reported are heterocycles (Baell & Miao, 2016; He, Wei, et al, 2021).…”