Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics

Drug likeness prediction of 5-hydroxy-substituted coumarins with high affinity to 5-HT1A and 5-HT2A receptors

“…The potency of coumarins may be modified by the number of small substituents, such as the hydroxy, alkoxy or carbonyl groups in various positions of coumarin moiety (Abdelhafez et al, 2010;Drzewiecka et al, 2013;Hassan et al, 2016;Paul et al, 2013;Sarkanj et al, 2013;Tsay et al, 2013). One of the latest trends is search for the new anti-psychotic drugs among coumarin derivatives, and their affinities to serotoninergic receptors 5-HT 1A and 5-HT 2A were defined (Chen et al, 2014;Chen et al, 2013). Several studies have shown that activation of 5-HT 1A receptor increases dopamine release in the frontal cortex, which may improve negative symptoms and cognitive deficits in schizophrenia (Lameh et al, 2007).…”

Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics

“…According to the above results, the 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole moiety was selected as a privileged fragment, as our previous studies have proved that compounds bearing this pharmacophore show favorable activities for D 2 , 5-HT 1A and 5-HT 2A receptors [ 14 , 15 , 17 ]. Next the effect of substituents on the 7-hydroxy-2,2-dimethylchroman-4-one group ( Table 2 ) was investigated, such as five-membered rings, six-membered rings, methyl and chlorine groups.…”

“…To verify this multi-receptor affinity strategy, we have previously developed several novel potential antipsychotics, such as compounds 1 and 2 shown in Figure 1 , both of which could significantly alleviate the positive symptoms of schizophrenia, are associated with lower weight gain and lower prolactin levels, and have obvious therapeutic effects. In order to obtain versatile molecules with better therapeutic effects and less side effects, in this paper, a series of new compounds was designed and synthesized by means of a polypharmacological strategy and molecular hybridization method on the basis of our previous research [ 14 , 15 ]. The design concept of new compounds as shown in Figure 1 , where the general structure contains a flavone-like moiety, a heterocyclic or arylpiperazine (piperidine) moiety and a flexible linker.…”

“…The choice of heterocyclic or arylpiperazine (piperidine) originates from the commercial atypical antipsychotics [ 16 ], such as risperidone, brexpiprazole, aripiprazole. The linker flexibility of the new compounds also be evaluated as our previous SAR studies have proved it to play an important role in modulating the receptor function profiles [ 14 , 15 , 17 ].…”

Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HT1A Serotonin Receptor Antagonists

“…Among many groups considered as the bulky moiety connected to N-arylpiperazine coumarin derivatives have gained some attention, particularly after the investigations of Chen et al, who showed that selected N-arylpiperazines connected to coumarins in position 7 via a (CH 2 ) 4 linker have nanomolar Ki values toward 5-HT 1A and 5-HT 2A receptors [17,18]. Inspired by these works we have expanded the family of potential serotonin agonists/antagonists based on the same design principle by introducing different arylpiperazine derivatives of 7-hydroxycoumarin, some of which showed subnanomolar affinities to 5-HT 1A receptor and low nanomolar affinities to 5-HT 2A receptor [19,20].…”