Triazolopyrimidine Nuclei: Privileged Scaffolds for Developing Antiviral Agents with a Proper Pharmacokinetic Profile

Abstract

Viruses are a continuing threat to global health. The lack or limited therapeutic armamentarium against some viral infections and increasing drug resistance issues make the search for new antiviral agents urgent. In recent years, a growing literature highlighted the use of triazolopyrimidine (TZP) heterocycles in the development of antiviral agents, with numerous compounds that showed potent antiviral activities against different RNA and DNA viruses. TZP core represents a privileged scaffold for achieving biologically active molecules, thanks to: i) the synthetic feasibility that allows to variously functionalize TZPs in the different positions of the nucleus, ii) the ability of TZP core to establish multiple interactions with the molecular target, and iii) its favorable pharmacokinetic properties. In the present review, after mentioning selected examples of TZP-based compounds with varied biological activities, we will focus on those antivirals that appeared in the literature in the last 10 years. Approaches used for their identification, the hit-to-lead studies, and the emerged structure-activity relationship will be described. A mention of the synthetic methodologies to prepare TZP nuclei will also be given. In addition, their mechanism of action, the binding mode within the biological target, and pharmacokinetic properties will be analyzed, highlighting the strengths and weaknesses of compounds based on the TZP scaffold, which is increasingly used in medicinal chemistry.

Switching the three-component Biginelli-like reaction conditions for the regioselective synthesis of new 2-amino[1,2,4]triazolo[1,5-a]pyrimidines

“…in EtOH at reflux in the presence of citric acid (2.5 equiv.) (Scheme 3c) following a similar procedure previously reported for the synthesis of 1,4dihydro-benzo [4,5]imidazo[1,2-a]pyrimidine analogues. 25 After 5 h, the reaction furnished a mixture containing 10 only in traces, while, surprisingly, the main product (albeit obtained after purification in 16% yield) was isomer 11, as confirmed by 2D NMR (NOESY experiment), along with traces of another unknown compound (later characterized as the oxidized TZP analogue 9).…”

“…Although the procedure for the synthesis of 9 showed a moderate yield, it was more efficient than the two-step procedure entailing the cyclocondensation reaction (83% yield) and the successive oxidation reaction (26% yield), showing a 22% overall yield. To the best of our knowledge, these two procedures are the first Biginelli-like MCRs in which the reaction of an aminotriazole, an aldehyde, and a β-ketoester leads to the formation of ethyl 2-amino-7-methyl-5-phenyl- [1,2,4]triazolo [1,5-a]pyrimidine-6carboxylate compounds.…”

“…Focusing our attention on the synthesis of ethyl 2-amino-5methyl-7-phenyl- [1,2,4]triazolo [1,5-a]pyrimidine-6-carboxylate (8) and searching for a procedure entailing a single step and without the use of oxidative agents, we evaluated some minor changes in the reaction conditions reported by Chernyshev and co-workers in Scheme 3a. Thus, DMF was first replaced with N-methyl-2-pyrrolidone (NMP) or pyridine, but only a complex mixture after 24 h was observed (data not shown).…”

“…Through this one-step procedure, compound 8 was regioselectively obtained in 40% yield. Even though compound 8 was obtained in a moderate yield, this procedure is the first example of the Biginelli MCR in which the reaction between an aminotriazole, an aldehyde and a β-ketoester leads to the formation of an ethyl 2-amino-5methyl-7-phenyl- [1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate compound. Notably, this one-step MCR procedure having a 40% yield represents to date the best method to obtain oxidized 8, being more convenient in terms of yield, time, use of a mild oxidizing agent, and a green solvent, with respect to the two-step procedure (formation of 10 and subsequent oxidation, Scheme 3a) exhibiting a 34% overall yield.…”

“…Triazolopyrimidine represents a privileged structure in agrochemical and medicinal chemistry, with numerous derivatives that have found applications in several biological and medical fields. [1][2][3] Among the eight different triazolopyrimidine isomers existing in nature, [1,2,4]triazolo [1,5-a]pyrimidine (hereafter abbreviated TZP for convenience) has been the most studied and used isomer in medicinal chemistry, especially to design and synthesize novel anti-infective agents. [3][4][5] However, recent articles and reviews show the potential of this nucleus to develop compounds endowed with several biological activities, also taking advantage of its favourable pharmacokinetic properties.…”