Design and Synthesis of 2-(1-Alkylaminoalkyl)pyrazolo[1,5-a]pyrimidines as New Respiratory Syncytial Virus Fusion Protein Inhibitors

Abstract

Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections and a significant pathogen for both adults and children. Although two drugs have been approved for the treatment of RSV infections, the low therapeutic index of these drugs have led pharmaceutical companies to develop safe and effective small-molecule anti-RSV drugs. The pyrazolo[1,5-a]pyrimidine series of compounds containing a piperidine ring at the 2-position of the pyrazolo[1,5-a]pyrimidine scaffold are known as candidate RSV fusion (F) protein inhibitor drugs, such as presatovir and P3. The piperidine ring has been revealed to facilitate the formation of an appropriate dihedral angle between the pyrazolo[1,5-a]pyrimidine scaffold and the plane of the amide bond for exertion of anti-RSV activity. A molecular-dynamic study on newly designed compounds with an acyclic chain instead of the piperidine ring proposed and demonstrated a new series of pyrazolo[1,5-a]pyrimidine derivatives, such as 9c with a 1-methyaminopropyl moiety, showing similar dihedral angle distributions to those in presatovir. Compound 9c exhibited potent anti-RSV activity with an EC 50 value of below 1 nM, which was similar to that of presatovir. A subsequent optimization study on the benzene ring of 9c led to the potent RSV F protein inhibitor 14f with an EC 50 value of 0.15 nM. The possibility of improving the biological properties of anti-RSV agents by modification at the 7-position of pyrazolo[1,5-a]pyrimidine is also discussed.

Discovery of 2-Amino-7-sulfonyl-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Potent Reversible FGFR Inhibitors with Gatekeeper Mutation Tolerance: Design, Synthesis, and Biological Evaluation

“…Compound 13 (IC 50 = 197.9 nM) incorporated the imine nitrogen and the cyano group in a pyrrole ring based on the scaffold hopping strategy and exhibited a twofold potency increase. The torsion patterns of the rotatable bonds are closely related to the compound inhibition potency. , The rotatable bonds of different linkers in compounds 10 , 11 , and 13 were analyzed by molecular dynamics (MD) simulations (Figure ). A large SD of the rotatable bond represented a wide distribution of the torsion angle.…”

Non-nucleoside structured compounds with antiviral activity—past 10 years (2010–2020)

“…Its mechanism of action is based on the inhibition of respiratory syncytial virus (RSV, Paramyxoviridae family) fusion with host cell membranes. The piperidine ring has been revealed to facilitate the formation of an appropriate dihedral angle between the pyrazolo [1,5-a]pyrimidine scaffold and the plane of the amide bond for exertion of anti-RSV activity [ 106 ]. Presatovir showed potent antiviral activity in vitro against 75 RSV clinical isolates [ 42 ] and dose-dependent antiviral efficacy in vivo in the Sprague-Dawley rat model of RSV infection.…”

Oxidative Aromatization of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines: Synthetic Possibilities and Limitations, Mechanism of Destruction, and the Theoretical and Experimental Substantiation

“…Azolo[1,5-a]pyrimidines are a very diversified group of heterocycles [ 1 , 2 , 3 ]. Among them, many compounds find application due to their beneficial features, for example, photophysical properties [ 4 , 5 , 6 , 7 ], metal complexes [ 8 , 9 , 10 ], and as medicinal drugs for diabetes mellitus [ 11 , 12 , 13 ], viruses [ 14 , 15 , 16 ], bacteria [ 17 , 18 ], neurological diseases [ 19 , 20 ], tumor diseases [ 21 , 22 , 23 , 24 , 25 , 26 ], Alzheimer’s disease [ 27 , 28 , 29 ], etc.…”