Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands

Abstract

A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a–o) and (2-{4-[3-(1H-3-indolyl)-propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a–l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure–activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).

Design Strategies, Chemistry and Therapeutic Insights of Multi-target Directed Ligands as Antidepressant Agents

“…Further, docking studies were performed against human SERT and the findings highlighted that compounds 10a , 10b , 10c and 11a exhibited pi-pi interaction between the indole ring and pi-donor aromatic residue Tyr176 residue. Protonated piperazine displayed coulombic interaction with Asp98 and pi-cation interaction with Try95 [ 108 ]. The designing scheme and SAR studies of the current series are demonstrated below in Fig.…”

Chimeric Structures in Mental Illnesses—“Magic” Molecules Specified for Complex Disorders

“…Another example of potent bivalent antidepressants is a group of compounds provided by Cerda-Cavieres et al [ 109 ]. According to the recent knowledge, they synthesized potent SERT ligands: indolyl propyl-piperazine derivatives, which were further merged either with MAOI modulators being morpholine- or D2 receptor modulator-benzoxazinone units, respectively (e.g., compound 7n) [ 109 ].…”

“…Another example of potent bivalent antidepressants is a group of compounds provided by Cerda-Cavieres et al [ 109 ]. According to the recent knowledge, they synthesized potent SERT ligands: indolyl propyl-piperazine derivatives, which were further merged either with MAOI modulators being morpholine- or D2 receptor modulator-benzoxazinone units, respectively (e.g., compound 7n) [ 109 ]. Similarly, Accenta Pharmaceuticals has utilized a hybrid approach to combine the key pharmacophoric moieties of Nocaine (DAT/NET selective) and Modafinil (DAT preferred) to develop the TRI JZ-IV-10, which was characterized by improvements in both the potency and affinity for all the three transporters [ 110 ].…”