A new series of thiazolyl-pyrazoline derivatives (4a–d, 5a–d 6a, b, 7a–d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a–b). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC₅₀ = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC₅₀ = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC₅₀ = 0.024, and 0.005 µM, respectively, whereas their IC₅₀ = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC₅₀ = 0.007 and 0.018 µM). Both compounds 6a and 10a induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates 6a and 10a showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study.

Breast cancer is a disease in which cells in the breast divide continuously without control. There are great limitations in cancer chemotherapy. Hence, it is essential to search for new cancer therapeutics. Herein, a novel series of EGFR/HER2 dual inhibitors has been designed based on the hybridization of thiazole and pyrazoline fragments. The synthesized compounds were screened for their anti-proliferative activity against MCF-7 breast cancer cell line and MCF-10 normal breast cell line. Interestingly, synthesized compounds 6e and 6k showed very potent antiproliferative activity towards MCF-7 with IC₅₀ values of 7.21 and 8.02 µM, respectively. Furthermore, enzymatic assay was performed against EGFR and HER2 to prove the dual inhibitory action. Compounds 6e and 6k showed potent inhibitory activity for EGFR with IC₅₀ of 0.009 and 0.051 µM, respectively, and for HER2 with IC₅₀ of 0.013 and 0.027 µM, respectively. Additionally, compounds 6e and 6k significantly stimulated apoptotic breast cancer cell death. Compound 6e was further explored for its anticancer activity in vivo using a Xenograft model. Moreover, computational modeling studies, ADMET studies and toxicity prediction were performed to investigate their potential drug candidates.

Thiazoles and pyrazolines represent a class of heterocyclic compounds with attractive and considerable interest in medicinal chemistry due to their diverse pharmacological activities. Hybridizing thiazole and pyrazoline moieties has emerged as an innovative approach to drug discovery, enabling the synthesis of novel compounds with enhanced therapeutic potential. The hybridization of thiazole and pyrazoline scaffolds allows for incorporating different functional groups and substitution patterns, which can influence the compound's bioactivity, selectivity, and pharmacokinetic profile. The hybridization of these two heterocyclic moieties has resulted in compounds with diverse pharmacological properties, such as antimicrobial, antitumor, anti-inflammatory, and antioxidant. Furthermore, thiazolyl-pyrazolines' ability to interact with specific molecular targets, such as enzymes, receptors, or signalling pathways, makes them attractive candidates for drug development. This abstract provides an overview of the hybridization strategy and highlights the medicinal chemistry aspects and biological activities of thiazolyl-pyrazolines.

Dysregulation of cyclin-dependent kinases (CDKs) drives uncontrolled cell cycle progression in several malignancies, making CDK4 and CDK6 appealing therapeutic targets. This paper details the rational design, synthesis, and thorough assessment of fifteen new pyrazolo[1,5-a]pyrimidine derivatives (19a–o) as cyclin-dependent kinase inhibitors. Structure–activity relationship research identified compound 19i as the primary candidate, exhibiting enhanced antiproliferative efficacy against HCT-116 colorectal cancer cells with an IC₅₀ of 1.02 μM, slightly higher than that of doxorubicin (IC₅₀, 1.08 μM). Mechanistic investigations demonstrated that 19i generates significant G0/G1 phase cell cycle arrest and substantial apoptotic cell death, with total apoptosis reaching 47.76% of the treated cells. ELISA analysis verified the activation of p53-dependent intrinsic apoptosis, evidenced by a 6.90-fold increase in p53, a 3.03-fold increase in Bax, a 0.39-fold decrease in Bcl-2, and a 9.56-fold increase in caspase-3 activity. Biochemical kinase tests revealed significant suppression of CDK4 (IC₅₀ 0.087 μM) and CDK6 (IC₅₀ 0.114 μM). Molecular docking revealed essential binding interactions, including hydrogen bonds with Lys35 and Val101, aromatic π–π stacking, and a new halogen bond with Glu94. Molecular dynamics simulations validated prolonged protein conformational stability and efficient target engagement. These findings collectively designate the pyrazolo[1,5-a]pyrimidine scaffold as a viable framework for CDK-targeted anticancer therapies.