2-Thiopyrimidine/chalcone hybrids: design, synthesis, ADMET prediction, and anticancer evaluation as STAT3/STAT5a inhibitors

Abstract

A novel 2-thiopyrimidine/chalcone hybrid was designed, synthesised, and evaluated for their cytotoxic activities against three different cell lines, K-562, MCF-7, and HT-29. The most active cytotoxic derivatives were 9d, 9f, 9n, and 9p (IC 50 ¼0.77-1.74 mM, against K-562 cell line), 9a and 9r (IC 50 ¼1.37-3.56 mM against MCF-7 cell line), and 9a, 9l, and 9n (IC 50 ¼2.10 and 2.37 mM against HT-29 cell line). Compounds 9a, 9d, 9f, 9n, and 9r were further evaluated for their cytotoxicity against normal fibroblast cell line WI38. Moreover, STAT3 and STAT5a inhibitory activities were determined for the most active derivatives 9a, 9d, 9f, 9n, and 9r. Dual inhibitory activity was observed in compound 9n (IC 50 ¼113.31 and 50.75 mM, against STAT3 and STAT5a, respectively). Prediction of physicochemical properties, drug likeness score, pharmacokinetic and toxic properties was detected.

One‐potandtwo‐potmethods for chalcone derived pyrimidines synthesis and applications

“…[184] A series of protected thiopyrimidine (28) was synthesized from the chalcone derived 2-thiopyrimidine derivatives, which were initially prepared from chalcone (26) with thiourea in ethanolic and KOH. The sulfur in thiourea is an active group to further react with acetyl chloride (A) in the presence of catalyst TEA to achieve (28) in 43%-82% yield [185] (Scheme 7). Interestingly, thiopyrimidine derivatives 28a, 28b, 28f, 28k showed cytotoxic activities and the most potent due to the substituent's nature and the positions of EDG.…”

“…Interestingly, thiopyrimidine derivatives 28a, 28b, 28f, 28k showed cytotoxic activities and the most potent due to the substituent's nature and the positions of EDG. [185] Furthermore, homocyclic thiopyrimidines have been prepared from homochalcones (29) with thiourea in ethanolic sodium hydroxide via microwave irradiation (MW) at 60 C for 3-4 h to obtain (31) in 50%-88% yield. MW synthesis offers higher yield and faster reaction times.…”

Novel chalcone/aryl carboximidamide hybrids as potent anti-inflammatory via inhibition of prostaglandin E2 and inducible NO synthase activities: design, synthesis, molecular docking studies and ADMET prediction

“…Prediction of the physicochemical characters, pharmacokinetics and toxicity is an important tool in drug discovery of biologically active agents 10 , 62 . Thus, the most active derivatives 4c , 4d , 6c and 6d were analysed for prediction of Lipinski’s Rule of Five 63 and Veber’s standard 64 .…”

Discovery of orally active chalcones as histone lysine specific demethylase 1 inhibitors for the treatment of leukaemia

“…Chalcones as 1,3-diaryl-2-propene-1-ones with the enone system between two aromatic rings possess a wide range of biological activities such as antibacterial, antioxidative, anticancer, antileishmanial, antiulcer, antiangiogenic, antiviral, immunosuppressive and anti-inflammatory activities [9][10][11] . More particularly, a number of synthetic and natural chalcones exhibited the potent anticancer activity against many cancer cell lines 12,13 . Chalcone 1 (Figure 2), a natural product isolated from the root of Glycyrrhiza inflata, could inhibit the drug transport function of ABCG2 and reverse ABCG2-mediated multidrug resistance in human multidrug-resistant cancer cell lines 14 .…”

“…Hz, 3H) 13. C NMR (100 MHz, CDCl 3 ) d 195.44, 188.67, 167.31, 143.09, 142.27, 133.67, 130.34, 130.25, 129.84, 121.57, 121.55, 119.17, 116.20, 115.98, 52.04, 51.78, 40.33, 11.94.…”