Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism
Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (<b>1</b>) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (<b>2</b>) having potent cytotoxicity, showing cyclin-dependent kinases (C...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-04-01
|
Series: | Applied Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/2076-3417/11/9/3746 |
id |
doaj-1a69cfd4dfd84c8088c51e4e88c6cdf8 |
---|---|
record_format |
Article |
spelling |
doaj-1a69cfd4dfd84c8088c51e4e88c6cdf82021-04-21T23:05:33ZengMDPI AGApplied Sciences2076-34172021-04-01113746374610.3390/app11093746Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding MechanismHuda S. Al-Salem0Md Arifuzzaman1Iman S. Issa2A. F. M. Motiur Rahman3Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaCollege of Pharmacy, Yeungnam University, Gyeongsan 38541, KoreaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaRecently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (<b>1</b>) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (<b>2</b>) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (<b>1</b> and <b>2</b>) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone <b>1</b> and <b>2</b> were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound <b>1</b> exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC<sub>50</sub> = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC<sub>50</sub> = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC<sub>50</sub> = 1.535 µM) tyrosine kinases. On the other hand, Compound <b>2</b> also exhibited excellent inhibitory activity against EGFR (IC<sub>50</sub> = 0.369 µM), VEGFR-2 (IC<sub>50</sub> = 0.266 µM) and FLT-3 (IC<sub>50</sub> = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3.https://www.mdpi.com/2076-3417/11/9/3746isatin-hydrazonesEGFR inhibitorVEGFR-2 inhibitorFLT-3 inhibitor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Huda S. Al-Salem Md Arifuzzaman Iman S. Issa A. F. M. Motiur Rahman |
spellingShingle |
Huda S. Al-Salem Md Arifuzzaman Iman S. Issa A. F. M. Motiur Rahman Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism Applied Sciences isatin-hydrazones EGFR inhibitor VEGFR-2 inhibitor FLT-3 inhibitor |
author_facet |
Huda S. Al-Salem Md Arifuzzaman Iman S. Issa A. F. M. Motiur Rahman |
author_sort |
Huda S. Al-Salem |
title |
Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism |
title_short |
Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism |
title_full |
Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism |
title_fullStr |
Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism |
title_full_unstemmed |
Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism |
title_sort |
isatin-hydrazones with multiple receptor tyrosine kinases (rtks) inhibitory activity and in-silico binding mechanism |
publisher |
MDPI AG |
series |
Applied Sciences |
issn |
2076-3417 |
publishDate |
2021-04-01 |
description |
Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (<b>1</b>) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (<b>2</b>) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (<b>1</b> and <b>2</b>) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone <b>1</b> and <b>2</b> were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound <b>1</b> exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC<sub>50</sub> = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC<sub>50</sub> = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC<sub>50</sub> = 1.535 µM) tyrosine kinases. On the other hand, Compound <b>2</b> also exhibited excellent inhibitory activity against EGFR (IC<sub>50</sub> = 0.369 µM), VEGFR-2 (IC<sub>50</sub> = 0.266 µM) and FLT-3 (IC<sub>50</sub> = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3. |
topic |
isatin-hydrazones EGFR inhibitor VEGFR-2 inhibitor FLT-3 inhibitor |
url |
https://www.mdpi.com/2076-3417/11/9/3746 |
work_keys_str_mv |
AT hudasalsalem isatinhydrazoneswithmultiplereceptortyrosinekinasesrtksinhibitoryactivityandinsilicobindingmechanism AT mdarifuzzaman isatinhydrazoneswithmultiplereceptortyrosinekinasesrtksinhibitoryactivityandinsilicobindingmechanism AT imansissa isatinhydrazoneswithmultiplereceptortyrosinekinasesrtksinhibitoryactivityandinsilicobindingmechanism AT afmmotiurrahman isatinhydrazoneswithmultiplereceptortyrosinekinasesrtksinhibitoryactivityandinsilicobindingmechanism |
_version_ |
1721515322058473472 |