Development of novel oxazolo[5,4-d]pyrimidines as competitive CB2 neutral antagonists based on scaffold hopping

Abstract

A series of novel oxazolo[5,4-d]pyrimidines was designed via a scaffold hopping strategy and synthesized through a newly developed approach. All these compounds were evaluated for their biological activity toward CB/CB cannabinoid receptors, their metabolic stability in mice liver microsomes and their cytotoxicity against several cell lines. Eight compounds have been identified as CB ligands with K values less than 1 μM. It is noteworthy that 2-(2-chlorophenyl)-5-methyl-7-(4-methylpiperazin-1-yl) oxazolo[5,4-d]pyrimidine 47 and 2-(2-chlorophenyl)-7-(4-ethylpiperazin-1-yl)- 5-methyloxazolo[5,4-d]pyrimidine 48 showed CB binding affinity in the nanomolar range and significant selectivity over CB receptors. Interestingly, functionality studies imply that they behave as competitive neutral antagonists. Moreover, all tested compounds are devoid of cytotoxicity toward several cell lines, including Chinese hamster ovary cells (CHO) and human colorectal adenocarcinoma cells HT29.

Synthesis, in silico and in vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents

“…The isomeric oxazolo [5,4-d]pyrimidin-7-one 13 was synthesized using the route improved by Dounchis (Scheme 4). [31] The reaction of benzoyl bromide 11 with silver cyanide led to 7H- [1,3] The reaction of compound 13 with trichlorophosphate in the presence of N,N-dimethylaniline gave 7chloro-2,5-diphenyl [1,3]oxazolo [5,4-d]pyrimidine (14). 7-Aryl-substituted oxazolo [5,4-…”

“…Compound 3b was obtained as light grey solid. Yield General Procedure for the Synthesis of 2-Phenyl [1,3]oxazolo [4,5-d]…”

“…Spectral and elemental analysis data are identical to literature reports. [27 -30] [1,3]oxazolo [4,5-d]…”

“…The oxazolopyrimidine architecture represents an universal scaffold used in the design of bioactive ligands against enzymes or receptors such as adenosine kinase (AK) inhibitors, [1,2] cannabinoid receptor 2 (CB2) neutral antagonists, [3] fatty acid amide hydrolase (FAAH) inhibitors, [4] endothelial differentiation gene receptor 1 (EDG-1) agonist [5] and purinergic G proteincoupled (P2Y1) receptor antagonist. [6] Thus, among the numerous heterocyclic moieties of biological and pharmacological interest, this pharmacophore represents an important structural motif in oncology and infectious disease treatments.…”

“…[15,16] Therefore, synthesis and modification of drugs based on the oxazolopyrimidine scaffold as well as other organic and metal compounds with anticancer properties is currently a pressing issue. [17] We have recently reported in vitro studies of 7piperazine-and 7-diazepan substituted [1,3]oxazolo [4,5-d]pyrimidines against a panel of different cancer cell lines, which have exhibited growth inhibitory, cytostatic and cytotoxic effects at submicromolar and micromolar concentrations. [18,19] To further explore the structure-biological activity relationship of this scaffold, oxazolo [4,5-d]pyrimidines and oxazolo [5,4-d]pyrimidines with phenyl group at C(2), aryl or biaryl substituents at C(5) and electron donating (piperazine) or withdrawing groups (aryl residues) at C(7) were developed as potential VEGFR2 inhibitors.…”