Exploration of Pd-catalysed four-component tandem reaction for one-pot assembly of pyrazolo[1,5-c]quinazolines as potential EGFR inhibitors

Arshad J Ansari; Gaurav Joshi; Umesh Prasad Yadav; Antim K Maurya; Vijai K Agnihotri; Sourav Kalra; Raj Kumar; Sandeep Singh; Devesh M Sawant

doi:10.1016/j.bioorg.2019.103314

Exploration of Pd-catalysed four-component tandem reaction for one-pot assembly of pyrazolo[1,5-c]quinazolines as potential EGFR inhibitors

Bioorg Chem. 2019 Dec:93:103314. doi: 10.1016/j.bioorg.2019.103314. Epub 2019 Sep 26.

Authors

Arshad J Ansari¹, Gaurav Joshi², Umesh Prasad Yadav³, Antim K Maurya⁴, Vijai K Agnihotri⁴, Sourav Kalra³, Raj Kumar⁵, Sandeep Singh⁶, Devesh M Sawant⁷

Affiliations

¹ School of Chemical Sciences and Pharmacy, Central University of Rajasthan NH-8, Bandarsindri, Ajmer 305817, Raj, India.
² Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda 151001, Punjab, India.
³ Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151001, Punjab, India.
⁴ Natural Product Chemistry and Process Development Division, CSIR-IHBT, Palampur, Himachal Pradesh 176061, India.
⁵ Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda 151001, Punjab, India. Electronic address: raj.khunger@gmail.com.
⁶ Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151001, Punjab, India. Electronic address: sandeepsingh82@gmail.com.
⁷ School of Chemical Sciences and Pharmacy, Central University of Rajasthan NH-8, Bandarsindri, Ajmer 305817, Raj, India. Electronic address: dms@curaj.ac.in.

PMID: 31590041
DOI: 10.1016/j.bioorg.2019.103314

Abstract

A series of pyrazolo[1,5-c]quinazolines as EGFR inhibitors was designed and synthesized by highly efficient and novel multicomponent route involving Pd-catalyzed tandem one-pot four-component reaction. The reaction proceeds with good functional group tolerance under a simple condition with excellent regioselectivity and high efficiency. Target compounds were screened against cancer cell lines MDA-MB-231, A549 and H1299. Of these, 9b and 10b exhibited superior anticancer activity (IC₅₀ < 2.5 μM) to erlotinib and gefitinib. Synthetics were able to inhibit EGFR mediated kinase activity, induced ROS in cancer cells promoting mitochondrial mediated apoptosis via halting cell cycle progression at G1 phase.

Keywords: Anticancer; Catalysis; Drug discovery; EGFR; Molecular modelling; Pyrazolo[1,5-c]quinazolines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Binding Sites
Catalysis
Catalytic Domain
Cell Line, Tumor
Drug Design
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Erlotinib Hydrochloride / chemistry
Erlotinib Hydrochloride / metabolism
Erlotinib Hydrochloride / pharmacology
G1 Phase Cell Cycle Checkpoints / drug effects
Humans
Membrane Potential, Mitochondrial / drug effects
Molecular Docking Simulation
Palladium / chemistry*
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Pyrazoles / chemistry*
Pyrazoles / metabolism
Pyrazoles / pharmacology
Quinazolines / chemistry*
Quinazolines / metabolism
Quinazolines / pharmacology
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrazoles
Quinazolines
Reactive Oxygen Species
pyrazolo(1,5-c)quinazoline
Palladium
Erlotinib Hydrochloride
ErbB Receptors