Design, synthesis and molecular docking of new fused 1 H-pyrroles, pyrrolo[3,2- d]pyrimidines and pyrrolo[3,2- e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

Amany Belal; Nagwa M Abdel Gawad; Ahmed B M Mehany; Mohammed A S Abourehab; Hazem Elkady; Ahmed A Al-Karmalawy; Ahmed S Ismael

doi:10.1080/14756366.2022.2096019

Design, synthesis and molecular docking of new fused 1 H-pyrroles, pyrrolo[3,2- d]pyrimidines and pyrrolo[3,2- e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1884-1902. doi: 10.1080/14756366.2022.2096019.

Authors

Amany Belal^{1

2}, Nagwa M Abdel Gawad³, Ahmed B M Mehany⁴, Mohammed A S Abourehab^{5

6}, Hazem Elkady⁷, Ahmed A Al-Karmalawy⁸, Ahmed S Ismael¹

Affiliations

¹ Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
² Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif, Saudi Arabia.
³ Medicinal Chemistry Department, Faculty of Pharmacy, Cairo University, Giza, Egypt.
⁴ Department of Zoology, Faculty of Science, Al-Azhar University, Nasr City, Egypt.
⁵ Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁶ Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Minia University, Minia, Egypt.
⁷ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁸ Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University- Egypt, New Damietta, Egypt.

Abstract

A new series of 1H-pyrrole (6a-c, 8a-c), pyrrolo[3,2-d]pyrimidines (9a-c) and pyrrolo[3,2-e][1, 4]diazepines (11a-c) were designed and synthesised. These compounds were designed to have the essential pharmacophoric features of EGFR Inhibitors, they have shown anticancer activities against HCT116, MCF-7 and Hep3B cancer cells with IC₅₀ values ranging from 0.009 to 2.195 µM. IC₅₀ value of doxorubicin is 0.008 µM, compounds 9a and 9c showed IC₅₀ values of 0.011 and 0.009 µM respectively against HCT-116 cells. Compound 8b exerted broad-spectrum activity against all tested cell lines with an IC₅₀ value less than 0.05 µM. Compound 8b was evaluated against a panel of kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 and GSK3 alpha kinases with 10-23% compared to imatinib (1-10%). It has also arrested the cell cycle of MCF-7 cells at the S phase. Its antiproliferative activity was further augmented by molecular docking into the active sites of EGFR and CDK2 cyclin A1.

Keywords: 1H-pyrrole; 4]diazepine; Anticancer; CDK2 inhibitor; EGFR inhibitor; pyrrolo[3,2-d]pyrimidine; pyrrolo[3,2-e][1.

MeSH terms

Antineoplastic Agents* / chemistry
Azepines / pharmacology
Cell Proliferation
Cyclin A1 / metabolism
Cyclin-Dependent Kinase 2 / metabolism
Drug Screening Assays, Antitumor
ErbB Receptors / metabolism
Glycogen Synthase Kinase 3 / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors
Protein Serine-Threonine Kinases
Protein-Tyrosine Kinases
Pyrimidines* / chemistry
Pyrroles / chemistry
Structure-Activity Relationship

Substances

Antineoplastic Agents
Azepines
Cyclin A1
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
DYRK3 protein, human
EGFR protein, human
ErbB Receptors
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
CDK2 protein, human
Cyclin-Dependent Kinase 2
Glycogen Synthase Kinase 3

Grants and funding

Deanship of scientific research at Umm Al-Qura University supported this work by grant code (22UQU4290565DSR37).