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...

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Main Authors: Huda S. Al-Salem, Md Arifuzzaman, Iman S. Issa, A. F. M. Motiur Rahman
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
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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
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AT afmmotiurrahman isatinhydrazoneswithmultiplereceptortyrosinekinasesrtksinhibitoryactivityandinsilicobindingmechanism
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