Design and synthesis of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as PDE 4B inhibitors endowed with bronchodilator activity

Rehab H Abd El-Aleam; Riham F George; Kevin J Lee; Adam B Keeton; Gary A Piazza; Amr A Kamel; Mahmoud E El-Daly; Ghaneya S Hassan; Hamdy M Abdel-Rahman

doi:10.1002/ardp.201900002

Design and synthesis of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as PDE 4B inhibitors endowed with bronchodilator activity

Arch Pharm (Weinheim). 2019 Aug;352(8):e1900002. doi: 10.1002/ardp.201900002. Epub 2019 Jul 29.

Authors

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University, Beni Suef, Egypt.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
³ USA Mitchell Cancer Institute Drug Discovery Laboratory, University of South Alabama, Mobile, Alabama.
⁴ Pharmacology and Toxicology Department, Faculty of Pharmacy, Minia University, El-Minia, Egypt.
⁵ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University, Badr City, Cairo, Egypt.
⁶ Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt.

PMID: 31353608
DOI: 10.1002/ardp.201900002

Abstract

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM. Eight compounds were screened for their bronchodilator activity, where compounds 7f and 7e elicited promising bronchodilator activity with EC₅₀ values of 18.6 and 57.1 µM, respectively, compared to theophylline (EC₅₀ = 425 µM). Molecular docking at the PDE 4B active site revealed a binding mode and docking scores comparable to those of a reference ligand, consistent with their PDE 4B inhibition activity.

Keywords: 1,2,4-triazolo[1,5-a]pyrimidine; bronchodilator activity; phosphodiesterase 4B.

MeSH terms

Animals
Bronchodilator Agents / chemical synthesis
Bronchodilator Agents / chemistry
Bronchodilator Agents / pharmacology*
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Humans
Male
Molecular Docking Simulation
Molecular Structure
Muscle Contraction / drug effects
Muscle, Smooth / drug effects*
Phosphodiesterase 4 Inhibitors / chemical synthesis
Phosphodiesterase 4 Inhibitors / chemistry
Phosphodiesterase 4 Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Trachea / drug effects*
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*

Substances

1,2,4-triazolo(1,5-a)pyrimidine
1,2,4-triazolo(1,5-c)pyrimidine
Bronchodilator Agents
Phosphodiesterase 4 Inhibitors
Pyrimidines
Triazoles
Cyclic Nucleotide Phosphodiesterases, Type 4