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.

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).

Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer's disease.

During the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease ß-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC50 = 3.4 and 3.6 µM respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 µM), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant ß-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 µM) and 25 (35% inhibition, 10 µM). These results suggest that indolylpropyl benzamidopiperazines based compounds constitute promising leads for a multitargeted approach for Alzheimer's disease.

Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4ß2, Dopamine and Serotonin Transporters.

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4ß2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4ß2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4ß2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4ß2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/ß2 subunit interfaces of α4ß2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.

Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives.

A combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2LOO ) of .75 and .73 as well as conventional correlation coefficients (R2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.

Synthesis, binding assays, cytotoxic activity and docking studies of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor.

Herein we report the design, synthesis, bioinformatic and biological studies of benzimidazole and benzothiophene derivatives as new cannabinoid receptor ligands. To test the hypothesis that the lack of a hydrogen bond interaction between benzimidazole and benzothiophene derivatives with Lys192 reduces their affinity for CB1 receptors (as we previously reported) and leads to CB2 selectivity, most of the tested compounds do not exhibit hydrogen bond acceptors. All compounds displayed mostly CB2 selectivity, although this was more pronounced in the benzimidazoles derivatives. Furthermore, docking assays revealed a ∏-cation interaction with Lys109 which could play a key role for the CB2 selectivity index. The series displayed low toxicity on five different cell lines. Derivative 8f presented the best binding profile (Ki = 0.08 µM), high selectivity index (KiCB1/KiCB2) and a low citoxicity. Interestingly, in cell viability experiments, using HL-60 cells (expressing exclusively CB2 receptors), all synthesised compounds were shown to be cytotoxic, suggesting that a CB2 agonist response may be involved.

3D-QSAR/CoMFA-based structure-affinity/selectivity relationships of aminoalkylindoles in the cannabinoid CB1 and CB2 receptors.

A 3D-QSAR (CoMFA) study was performed in an extensive series of aminoalkylindoles derivatives with affinity for the cannabinoid receptors CB1 and CB2. The aim of the present work was to obtain structure-activity relationships of the aminoalkylindole family in order to explain the affinity and selectivity of the molecules for these receptors. Major differences in both, steric and electrostatic fields were found in the CB1 and CB2 CoMFA models. The steric field accounts for the principal contribution to biological activity. These results provide a foundation for the future development of new heterocyclic compounds with high affinity and selectivity for the cannabinoid receptors with applications in several pathological conditions such as pain treatment, cancer, obesity and immune disorders, among others.