No abstract

A one‐step procedure for the synthesis of new fused Benzo[d]thiazolo‐1,2,3‐triazoles (3 a–3 h and 4 a–4 h) in good yields using sulfonylazides (2) and iodoalkyne (1) through from the 5‐iodo 1,2,3‐triazole generated in situ was developed. Among all, compounds 5‐chloro‐3‐(((1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)benzo[4,5]isothiazolo[2,3‐c] [1,2,3]triazole 8,8‐dioxide (3 e), 3‐(((1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)‐5‐fluorobenzo[4,5]isothiazolo [2,3‐c][1,2,3]triazole 8,8‐dioxide (3 f), 5‐bromo‐3‐(((5‐bromo‐1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)benzo [4,5]isothiazolo[2,3‐c][1,2,3]triazole 8,8‐dioxide (4 d), 3‐(((5‐bromo‐1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)‐5‐chlorobenzo [4,5]isothiazolo[2,3‐c][1,2,3]triazole 8,8‐dioxide (4 e) and 3‐(((5‐bromo‐1,1‐dioxidobenzo[d]thiazol‐2‐yl)sulfonyl)methyl)‐5‐fluorobenzo [4,5] isothiazolo[2,3‐c][1,2,3]triazole 8,8‐dioxide (4 f) showed superior activity against A‐549 and good activity against the MCF‐7. Later, in vitro EGFR results revealed that compounds 4 e and 4 f indicated promising potency with IC50 values of 0.316±0.07 and 0.211±0.09 μM respectively. In silico studies of five potent compounds were also carried out to identify interactions against EGFR receptors and found that the energy calculations were consistent with the IC50 values obtained. In silico pharmacokinetic profile was predicted for potent compounds 3 e, 3 f, 4 d, 4 e, and 4 f using SWISS/ADME and pkCSM, where, all the compounds followed the Lipinski rule without any deviation.

The CuI promoted one‐pot multi‐component synthesis of new fused [1,2,3]triazolo[5,1‐a]isoquinoline derivatives (4 a–4 h, 8 a–8 f & 9 a–9 f) without isolating unsafe azides and their in vitro cytotoxic activity against MCF‐7 & MDA‐MB‐231 (breast cancer cells) and A‐549 (alveolar carcinoma) was reported herein. Out of all, compounds 9‐chloro‐1‐(morpholinomethyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (8 d), 9‐fluoro‐1‐(morpholinomethyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (8 e), 9‐chloro‐1‐((1,1‐dioxidothiomorpholino)methyl)‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (9 d), and 1‐((1,1‐dioxidothiomorpholino)methyl)‐9‐fluoro‐[1,2,3]triazolo[5,1‐a]isoquinolin‐6(5H)‐one (9 e) showed superior potency against all the cell lines than the standard drug erlotinib with IC50 values ranging from 2.45 to 7.19 μM. The most active compounds 8 d, 8 e, 9 d, and 9 e were also screened for their efficacy in inhibiting tyrosine kinase EGFR and results revealed that compound 9 d showed comparable activity with standard drug erlotinib, whereas, compounds 8 d, 8 e, and 9 e showed superior activity than the erlotinib. Molecular modeling studies for active compounds on EGFR (PDB‐ID‐4HJO) were also conducted and the obtained free energies were observed to be in agreement with the in vitro activity data. Finally, compounds 8 d, 8 e, 9 d, and 9 e didn't show AMES toxicity and followed the rules of Egan, Ghose, Veber, Lipinski, and Muegge rules without any deviation.

Herein we described the synthesis of some new quinolinemorpholine coupled 1,2,3-triazole hybrids (6 a-n) from 5chloroquinolin-8-ol using well known reactions like Mannich reaction, O-propargylation, and finally copper (I) catalyzed azide-alkyne cycloaddition (CuAAC). The structures of all newly synthesized hybrids were confirmed by 1 H-NMR, 13 C-NMR, and Mass spectra. All of them were screened for their in vitro cytotoxicity towards three human cancer cell lines including MCF-7, A549 and HepG2 by MTT assay where four compounds (6 c, 6 j, 6 m and 6 n) exhibited more potency than the reference erlotinib against all the three cell lines. In vitro tyrosine kinase EGFR inhibition assay for the same four compounds revealed that 6 m has triple inhibiting power with IC 50 value of 0.14 μM and 6 j has nearly double inhibiting power with IC 50 value of 0.22 μM compared to erlotinib. Molecular docking studies with EGFR have shown that all the above four compounds have more binding energies (À 9.09 kcal/mol to À 9.96 kcal/mol) than that of erlotinib (-7.69 kcal/mol). Finally, in silico pharmacokinetic profile was achieved using SWISS/ADME and pkCSM, where all the four compounds followed Lipinski rule, Veber rule, Egan rule and Muegge rule and the lipophilicity (ClogP) was found to be ranging from 2.98 to 3.69.

The synthesis of some new quinoxaline derivatives ( IVa – n ) and their structure determination using 1 H NMR, 13 C NMR and mass spectral analysis was described herein. The in vitro anti-cancer activity of the these compounds ( IVa–n ) revealed that the compound1-((1-(4-bromophenyl)-1 H -1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5- a ]quinoxalin-4-yl)pyrazolidine-3,5-dione ( IVd ) has shown promising activity, whereas, compounds 1-((1-phenyl-1 H -1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5- a ]quinoxalin-4-yl)pyrazolidine-3,5-dione ( IVa ), 1-(tetrazolo[1,5- a ]quinoxalin-4-yl)-2-((1-( m -tolyl)-1 H -1,2,3-triazol-4-yl)methyl)pyrazolidine-3,5-dione ( IVb ), 1-((1-(3,5-dimethoxyphenyl)-1 H -1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5- a ]quinoxalin-4-yl)pyrazolidine-3,5-dione ( IVh ) and 1-((1-(4-nitrophenyl)-1 H -1,2,3-triazol-4-yl)methyl)-2-(tetrazolo[1,5- a ]quinoxalin-4-yl)pyrazolidine-3,5-dione ( IVi ) exhibited good to moderate activity against four human cancer cell lines such as HeLa, MCF-7, HEK 293T, and A549 as compared to the doxorubicin. Predominantly, the compound displayed excellent activity over HeLa, MCF-7, HEK 293T, and A549 with IC 50 values of 3.20 ± 1.32, 4.19 ± 1.87, 3.59 ± 1.34, and 5.29 ± 1.34 μM, respectively. Moreover, molecular docking studies of derivatives ( IVa – n ) on EGFR receptor suggested that the most potent compound strongly binds to protein EGFR (pdbid:4HJO) and the energy calculations of in silico studies were also in good agreement with the obtained IC 50 values. Supplementary Information The online version contains supplementary material available at 10.1134/S1068162022030220.