Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities

Published on Dec 1, 2021in Journal of Enzyme Inhibition and Medicinal Chemistry4.673
· DOI :10.1080/14756366.2020.1837124
Ahmed M. Shawky9
Estimated H-index: 9
(UQU: Umm al-Qura University),
Nashwa A. Ibrahim5
Estimated H-index: 5
(UQU: Umm al-Qura University)
+ 2 AuthorsAhmed M. Gouda11
Estimated H-index: 11
(UQU: Umm al-Qura University)
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Abstract
In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxic...
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References59
Newest
#1Ashraf N. Abdalla (UQU: Umm al-Qura University)H-Index: 12
#2Usama Shaheen (UQU: Umm al-Qura University)H-Index: 6
Last. Ammar Bader (UQU: Umm al-Qura University)H-Index: 21
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Among the hundreds of reported Achillea species, A. membranacea (Labill.) DC. is one of the six that grow in Jordan. Many species of this genus are used in folk medicine to treat a variety of ailments and several biological and pharmacological activities have been ascribed to their essential oil (EO). For this study, the EO obtained from a specimen of A. membranacea grown in Jordan was analyzed by GC–MS. Ninety-six compounds were detected, of which oxygenated monoterpenes was the predominant cla...
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#1Chunhui Cheng (Huada: Beijing University of Chemical Technology)H-Index: 5
#2Fan Yun (Huada: Beijing University of Chemical Technology)H-Index: 5
Last. Qipeng Yuan (Huada: Beijing University of Chemical Technology)H-Index: 56
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Abstract In the current study, we reported a series of novel 1-H-pyrazole-3-carboxamide-based inhibitors targeting histone deacetylase (HDAC) and cyclin-dependent kinase (CDK). The representative compounds N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (7c) and N-(4-(2-((2-aminophenyl)amino)-2-oxoethyl)phenyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (14a) with potent antiproliferative activities towards five solid cancer cell lines, showed ...
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ABSTRACT Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is currently the subject of many drug discovery programs in the pharmaceutical industry. The US FDA approved four small molecule protein kinase antagonists in 2019; these include entrectinib, erdafitinib, pexidartinib, and fedratinib. Entrectinib binds to TRKA/B/C and ROS1 and is prescribed for the tr...
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#1Jing-wei Liang (PRC: China Medical University (PRC))H-Index: 6
#2Ming-Yang Wang (PRC: China Medical University (PRC))H-Index: 5
Last. Fan-hao Meng (PRC: China Medical University (PRC))H-Index: 8
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AbstractCyclin-dependent kinase 2 (CDK2) is the family of Ser/Thr protein kinases that has emerged as a highly selective with low toxic cancer therapy target. A multistage virtual screening method ...
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#1Khalid M. Attalah (UQU: Umm al-Qura University)H-Index: 1
#2Ashraf N. Abdalla (UQU: Umm al-Qura University)H-Index: 12
Last. Ahmed M. Gouda (Beni-Suef University)H-Index: 11
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Abstract Two new series of ethyl benzoate bearing pyrrolizine and indolizine moieties 8-11 were synthesized and evaluated for their anti-inflammatory and anticancer activities. Among these derivatives, compounds 9a, 10b and 11b displayed in vivo anti-inflammatory and analgesic activity comparable to ibuprofen. The acute ulcerogenicity and histopathological studies revealed better GIT safety profile than ibuprofen. Mechanistic study of these compounds revealed inhibitory activity against COX-1/2 ...
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#1Ahmed M. Shawky (UQU: Umm al-Qura University)H-Index: 9
#2Mohammed A.S. Abourehab (Minia University)H-Index: 10
Last. Ahmed M. Gouda (Beni-Suef University)H-Index: 11
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Abstract Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC50 = 0.10–22.96 μM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1–258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13–44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of...
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#1Taj Mohammad (Jamia Millia Islamia)H-Index: 18
#2Sagar Batra (Amity Institute of Biotechnology)H-Index: 3
Last. Imtaiyaz Hassan (Jamia Millia Islamia)H-Index: 19
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Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based mole...
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#1Hamad M. Alkahtani (KSU: King Saud University)H-Index: 10
#2Mohammed M. Alanazi (KSU: King Saud University)H-Index: 14
Last. Alaa A.-M. Abdel-Aziz (KSU: King Saud University)H-Index: 32
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Abstract A new series of 5,5-diphenylhydantoin derivatives containing benzylidene or isatin (4–19) was synthesized. Their anticancer activity against HeLa, a cervical cancer cell line, A549, a lung cancer cell line, and MDA-MB-231, a breast cancer cell line, was evaluated. Compounds 13, 16, 17 and 18 exhibited potent anticancer activity with average IC50 values against the tested cell lines of 109, 59, 81 and 113 μM, respectively. Compound 16 showed potent EGFR and VEGFR2 inhibitory activity wit...
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#1Solomon Tadesse (UniSA: University of South Australia)H-Index: 9
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Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug ...
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#1Ahmed M. Gouda (Beni-Suef University)H-Index: 11
#2Faisal A. Almalki (UQU: Umm al-Qura University)H-Index: 8
Development of selective COX-1 and COX-2 was successfully used to overcome GIT side effects of the classical NSAIDs. Currently, virtual screening and docking study were extensively used to design of new potent and safe drug candidates. In this study, four series of carprofen derivatives were designed by isosteric replacement of the –NH– with –O–, –S– and –CH2– groups. More than 90 derivatives bearing different alkyl substituents were designed in this study. AutoDock software was used to explore ...
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#2Alaa Alqahtani (UQU: Umm al-Qura University)H-Index: 2
Last. Asmaa G. Safi El-Din (Beni-Suef University)H-Index: 2
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ABSTRACT null null In the current study, we report the synthesis and cytotoxic evaluation of a new series of S-benzo[4,5]thiazolo[2,3-c][1,2,4]triazole-based derivatives 8-12. Cytotoxicity of the new compounds was investigated in A549, MCF-7, and Hep3B cancer cell lines. Among these derivatives, compound 12 bearing an isatin moiety was the most active derivative (IC50 = 2.40-3.53 µM). A mechanistic study of compound 12 was performed using the kinase profiling test to explore its inhibitory activ...
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#1Faisal A. Almalki (UQU: Umm al-Qura University)H-Index: 8
#2Ashraf N. Abdalla (UQU: Umm al-Qura University)H-Index: 12
Last. Ahmed M. Gouda (UQU: Umm al-Qura University)H-Index: 11
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In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and stru...
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#1Ahmed M. Shawky (UQU: Umm al-Qura University)H-Index: 9
#2Nashwa A. Ibrahim (UQU: Umm al-Qura University)H-Index: 5
Last. Ahmed M. Gouda (UQU: Umm al-Qura University)H-Index: 11
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In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a-e showed higher cytotoxicity than their corresponding Schiff bases 15a-e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC50 in the range of 0.52-6.26 μM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC50=0.155-17.08 μM). Mechanistic studies reveale...
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#1Ahmed M. Shawky (Minia University)H-Index: 9
#2Ashraf N. Abdalla (UQU: Umm al-Qura University)H-Index: 12
Last. Ahmed M. Gouda (Beni-Suef University)H-Index: 11
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Abstract Targeting P-glycoprotein (P-gp, ABCB1 transporter), which plays an essential role in multi-drug resistance (MDR) in cancers, with new cytotoxic agents is a promising strategy in cancer chemotherapy. In the current study, we report the synthesis of thirteen novel pyrimidopyrrolizine, pyrimidoindolizine, and diazepinopyrrolizine derivatives. The new compounds exhibited cytotoxic activities against MCF7, A2780 and HT29 cancer cell lines (IC50 = 0.02–19.58 μM) and MRC5 (IC50 = 0.17–20.57 μM...
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#1Qi Liang (Northwest University (China))H-Index: 1
#2Xue ZhaoH-Index: 1
Last. Xinfeng Zhao (Northwest University (China))H-Index: 11
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The rapid growth of demands for drug discovery has necessitated the ongoing pursuit of new methods for specific ligands screening and identification. This work combined receptor-affinity chromatography (RAC) with high-throughput sequencing techniques to rapidly screen and identify the specific ligands. By this method, immobilized angiotensin II type I receptor (AT1R) and endothelin receptor A (ETAR) based on RAC were utilized for lead screening from a DNA-encoded library. The specific ligands of...
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