Synthesis and evaluation of a novel class of ethacrynic acid derivatives containing triazoles as potent anticancer agents

Therapeutic potential of 1,2,3‐triazole hybrids for leukemia treatment

“…50.1-700 nM and 20.2-650 vs. 2.1-120 nM) against A549, MCF-7, PC3, U87-MG, SKOV3, and HCT-116 cancer cell lines [108] ; the 1,2,3-triazole-curcumin hybrids 49a,b (IC 50 : 3.13 and 3.95 μM, MTT assay) were around three times more active than curcumin (IC 50 : 10.51 μM) against CCRF-CEM leukemia cells, and hybrid 49a decreased mitochondrial transmembrane potential, arrested SubG0 phase and induced apoptosis [109] ; benzotriazolehydrazone hybrid 50 (IC 50 : 25 nM, SRB assay) was 18-fold more potent than doxorubicin (IC 50 : 450 nM) against HL-60 leukemia cells, and this hybrid accumulated cells in pre-G1 phase, arrested cell cycle at G2/M phase and induced apoptosis [110] showed promising activity against HL-60 and its multidrugresistant counterpart HL60R cells, demonstrating its potential to overcome drug resistance. [111] 9 | CONCLUSION…”

“…Besides the above-mentioned hybrids, 1,2,3-triazoleartemisinins, [97,98] 1,2,3-triazole-aziridines, [99,100] 1,2,3-triazoledithiocarbamates, [101] 1,2,3-triazole-indoles, [102] 1,2,3-triazolemollugin, [103] 1,2,3-triazole-D-(+)-pinitols, [104] 1,2,3-triazole-nerols, [105] 1,2,3-triazole-retinoids, [106] 1,2,3-triazole-salinomycin, [107] 1,2,3-triazoleethacrynic acids, [108] 1,2,3-triazole-curcumins, [109] benzotriazolehydrazones, [110] and 1,2,3-triazole-10,11-dihydro-9H-9,10- [3,4] epipyrroloanthracene-12,14(13H,15H)-diones [111] also possessed certain antileukemic activity. Amongst them, the 1,2,3-triazole-salinomycin hybrid 47 (Figure 8; IC 50 : 250 nM, MTT assay) was 2.3-and 136.8-fold more potent than salinomycin (IC 50 : 580 nM) and cisplatin (IC 50 :…”

“…Besides the above‐mentioned hybrids, 1,2,3‐triazole‐artemisinins, [ 97,98 ] 1,2,3‐triazole‐aziridines, [ 99,100 ] 1,2,3‐triazole‐dithiocarbamates, [ 101 ] 1,2,3‐triazole‐indoles, [ 102 ] 1,2,3‐triazole‐mollugin, [ 103 ] 1,2,3‐triazole‐ d ‐(+)‐pinitols, [ 104 ] 1,2,3‐triazole‐nerols, [ 105 ] 1,2,3‐triazole‐retinoids, [ 106 ] 1,2,3‐triazole‐salinomycin, [ 107 ] 1,2,3‐triazole‐ethacrynic acids, [ 108 ] 1,2,3‐triazole‐curcumins, [ 109 ] benzotriazole‐hydrazones, [ 110 ] and 1,2,3‐triazole‐10,11‐dihydro‐9 H ‐9,10‐[3,4]epipyrroloanthracene‐12,14(13 H ,15 H )‐diones [ 111 ] also possessed certain antileukemic activity. Amongst them, the 1,2,3‐triazole‐salinomycin hybrid 47 (Figure 8; IC 50 : 250 nM, MTT assay) was 2.3‐ and 136.8‐fold more potent than salinomycin (IC 50 : 580 nM) and cisplatin (IC 50 : 3.42 μM) against HL‐60 leukemia cells, but the SAR revealed that 1,2,3‐triazole moiety was not essential for the high activity [ 107 ] ; the 1,2,3‐triazole‐ethacrynic acid hybrids 48a,b (IC 50 : 310 and 290 nM, MTT assay) not only were highly active against HL‐60 leukemia cells, but also were comparable to doxorubicin (IC 50 : 50.1–700 nM and 20.2–650 vs. 2.1–120 nM) against A549, MCF‐7, PC3, U87‐MG, SKOV3, and HCT‐116 cancer cell lines [ 108 ] ; the 1,2,3‐triazole‐curcumin hybrids 49a,b (IC 50 : 3.13 and 3.95 μM, MTT assay) were around three times more active than curcumin (IC 50 : 10.51 μM) against CCRF‐CEM leukemia cells, and hybrid 49a decreased mitochondrial transmembrane potential, arrested SubG0 phase and induced apoptosis [ 109 ] ; benzotriazole‐hydrazone hybrid 50 (IC 50 : 25 nM, SRB assay) was 18‐fold more potent than doxorubicin (IC 50 : 450 nM) against HL‐60 leukemia cells, and this hybrid accumulated cells in pre‐G1 phase, arrested cell cycle at G2/M phase and induced apoptosis [ 110 ] ; 1,2,3‐triazole‐10,11‐dihydro‐9 H ‐9,10‐[3,4]epipyrroloanthracene‐12,14(13 H ,15 H )‐dione hybrid 51 (IC 50 : 4.8 and 1.0 μM, MTT assay) showed promising activity against HL‐60 and its multidrug‐resistant counterpart HL60R cells, demonstrating its potential to overcome drug resistance. [ 111 ]…”

Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities

“…EA analogs, alone or as adjuvants, are known to increase the activity of chemotherapeutic agents [ 20 , 21 , 22 , 23 ]. Based on this observation, we have considered improving the reactivity of the Michael acceptor group of EA to increase the inhibitory activity of GSTP1-1, on the one hand, and on the other hand to increase the antiproliferative activity via the apoptosis process through the activation of the caspase protease as we have demonstrated in our previous work [ 24 , 25 ].…”

Novel quinazolinone-isoxazoline hybrids: synthesis, structural elucidation and theoretical DFT mechanistic study

“…Over the last century, heterocyclic compounds have been widely invested as preferred structures in the investigation of new drug candidates capable of remedying various diseases [5][6][7]. Oxygen and nitrogen containing heterocyclic compounds have gained considerable importance due to their applications in various elds [1,[8][9][10]. Quinazolin-4(3H)-one derivatives, in particular, have occupied a primordial place in medicinal chemistry thanks to their wide range of biological activity, namely antifungal [11,12], antibacterial [11,13], antioxidant [14], antitubercular [11], anticonvulsant [15], antimalarial [16], and as potential inhibitors of MERS-CoV and SARS-CoV-2 [2], ...etc.…”