Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs

A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.     

Combined structure-based pharmacophore, virtual screening, and 3D-QSAR studies of structural diverse dehydrosqualene synthase inhibitors

Dehydrosqualene synthase (CrtM) is a key enzyme in the synthesis of presqualene diphosphate in Staphylococcus aureus. In the current study, a combination of structure-based pharmacophore and 3D-QSAR methods are used to clarify the essential quantitative structure–activity relationship (QSAR) of known CrtM inhibitors; the multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of CrtM based on twenty crystal structures of CrtM inhibitor complex. Performances of the MCBP-based virtual screening approach were applied to screen specs chemical databases (202, 408 compounds). Thirty-eight compounds were selected from the final hits and should be shifted to experimental studies. The MCBP model has been successfully used to identify the bioactive conformation and align 24 structurally diverse CrtM inhibitors. The QSAR analyses have been performed on these CrtM inhibitors based on MCBP guided alignment. These results may provide important information for further design and discovery of novel CrtM inhibitors.     

Quantitative structure-activity relationship and complex network approach to monoamine oxidase A and B inhibitors

The work provides a new model for the prediction of the MAO-A and -B inhibitor activity by the use of combined complex networks and QSAR methodologies. On the basis of the obtained model, we prepared and assayed 33 coumarin derivatives, and the theoretical prediction was compared with the experimental activity data. The model correctly predicted 27 compounds, and most of the active derivatives showed IC 50 values in the muM-nM range against both the MAO-A and MAO-B isoforms. Compound 14 shows the same MAO-A inhibitory activity (IC 50 = 7.2 nM), as clorgyline used as a reference inhibitor and has the highest MAO-A specificity (1000-fold higher compared to MAO-B). On the other hand, compounds 24 (IC 50 = 1.2 nM) and 28 (IC 50 = 1.5 nM) show higher activity than selegiline (IC 50 = 19.6 nM) and high MAO-B selectivity with 100-fold and 1600-fold inhibition levels, with respect to the MAO-A isoform.     

Identification of novel HIV-1 integrase inhibitors using shape-based screening, QSAR, and docking approach

The objective of this study is to identify novel HIV‐1 integrase (IN) inhibitors. Here, shape‐based screening and QSAR have been successfully implemented to identify the novel inhibitors for HIV‐1 IN, and in silico validation is performed by docking studies. The 2D QSAR model of benzodithiazine derivatives was built using genetic function approximation (GFA) method with good internal (cross‐validated r² = 0.852) and external prediction (). Best docking pose of highly active molecule of the benzodithiazine derivatives was used as a template for shape‐based screening of ZINC database. Toxicity prediction was also performed using Deductive Estimation of Risk from Existing Knowledge (DEREK) program to filter non‐toxic molecules. Inhibitory activities of screened non‐toxic molecules were predicted using derived QSAR models. Active, non‐toxic screened molecules were also docked into the active site of HIV‐1 IN using Auto Dock and dock program. Some molecules docked similarly as highly active molecule of the benzodithiazine derivatives. These molecules also followed the same docking interactions in both the programs. Finally, four benzodithiazine derivatives were identified as novel HIV‐1 integrase inhibitors based on QSAR predictions and docking interactions. ADME properties of these molecules were also computed using Discovery Studio.     

Synthesis, biological evaluation and 3D-QSAR of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase A inhibitors

The present report provides a extended study of the chemistry, the inhibitory activity against monoamino oxidases (MAO), and molecular modeling including the 3D-QSAR hypothesis of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives. Four series of about eighty novel pyrazoline derivatives were prepared and investigated for their ability to inhibit the activity of the A and B isoforms of MAO selectively. Most of the new synthesized compounds proved more reversible, potent, and selective inhibitors of MAO-A than of MAO-B, and could be taken into account to develop the search further in this field, knowing that reversible and selective MAO-A inhibitors are used as antidepressant and antianxiety drug. The 30 most active compounds show inhibitory activity on MAO-A in the 8.6 x 10(-8) - 9.0 x 10(-9)M range. Moreover, it should be pointed out that for most of them a high IC(50) > or = 10(-9)M value is associated with a high A-selectivity (Selectivity Index MAO-B/MAO-A in the 10,000-16,250 range). Furthermore, due to the presence of a chiral centre at the C5 position of the pyrazole moiety, we performed the semi-preparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation, and from the results of these experiments it has been possible to point out a difference in inhibiting the two isoforms selectively between the racemic mixture and the single enantiomers. The molecular modeling work was carried out combining the Glide docking approach with CoMFA with the aim to rationalize the structure-activity relationships of each pyrazoline inhibitor toward MAO-A and MAO-B isoforms and to derive a suitable selectivity model.     

Novel monoamine oxidase inhibitors, 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, and their differential reversibility

Although possible usefulness of non-selective monoamine oxidase (MAO) inhibitors for Parkinson's disease therapy has been suggested in the literature, MAO inhibitors whose inhibition is reversible and have dual action to both MAO-A and -B subtypes is not available yet. Subtype selectivity and reversibility of a series of novel MAO inhibitors, 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, were studied. Several dual MAO inhibitors, which inhibit both MAO-A and -B, were obtained. When administered to mice, their effects were generally reversible. Among the derivatives, RS-1636 and RS-1653 had much longer duration of brain MAO-B inhibition than that of MAO-A. In vitro, the inhibited MAO-A activity by these compounds was partially recovered by buffer change at 4 degrees C, while little MAO-B activity was recovered. Although it is not fully elucidated yet, the reversibility of these inhibitors is probably determined primarily by this dissociation profile. This unique differential reversibility indicates that optimization of the balance of actions can be achieved by differentiating reversibility to each target molecule.     

Sulfur-substituted alpha-alkyl phenethylamines as selective and reversible MAO-A inhibitors: biological activities, CoMFA analysis, and active site modeling

A series of phenethylamine derivatives with various ring substituents and with or without N-methyl and/or C-alpha methyl or ethyl groups was synthesized and assayed for their ability reversibly to inhibit monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds showed potent and selective MAO-A inhibitory activity (IC(50) in the submicromolar range) but none showed appreciable activity toward MAO-B. A three-dimensional quantitative structure-activity relationship study for MAO-A inhibition was performed on the series using comparative molecular field analysis (CoMFA). The resulting model gave a cross-validated q(2) of 0.72 and showed that in this series of compounds steric properties of the substituents were more important than electrostatic effects. Molecular modeling based on the recently published crystal structure of inhibitor-bound MAO-A provided detailed evidence for specific interactions of the ligands with the enzyme, supported by previous references and consistent with results from the CoMFA. On the basis of these results, structural determinants for selectivity of substituted amphetamines for MAO-A are discussed.     

Phenylethylamine-induced stereotypies in the rat: a behavioral test system for assessment of MAO-B inhibitors

Stereotyped sniffing behavior together with forepaw padding — defined as the -phenylethylamine (PEA) syndrome — is induced by MAO-B inhibitors in rats injected with 30 mg/kg IP PEA. The comparison of the abilities of the MAO-B inhibitors to induce the syndrome and to inhibit MAO-B in rat brain homogenates indicated that at least 75% of MAO-B activity in rat brain had to be inhibited to induce the PEA syndrome. A good correlation was found between the abilities of MAO-B inhibitors to induce the behavioral syndrome and to increase levels of PEA in rat brain. Specific MAO-A inhibitors potentiated the behavioral effect of the MAO-B inhibitor deprenyl, while they did not induce the syndrome themselves or only at very high doses. Inhibitors of the reuptake of 5-HT or noradrenaline were inactive under the described experimental conditions. This behavioral test system seems to be useful in vivo screening test in rats for detecting compounds with strong MAO-B inhibiting activity.     

Design, synthesis, antimicrobial, anticancer evaluation, and QSAR studies of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones

A series of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones (1–17) was synthesized and tested in vitro for its antimicrobial and anticancer potentials. The biological screening results indicated that compounds having m-chloro substituent on benzaldehyde portion showed antimicrobial potential, whereas compounds having chloro, methoxy, and hydroxyl groups showed anticancer potential. The quantitative structure activity relationship (QSAR) studies indicated the importance of topological parameter, valence first order molecular connectivity index in describing antifungal activity. The developed QSAR models, however, were statistically insignificant with reference to anticancer activity of the synthesized compounds.     

Selective inhibition of MAO-A,not MAO-B,results in antidepressant-like effects on DRL 72-s behavior

The effects of monoamine oxidase inhibitors (MAOIs) that selectively inhibit the MAO-A or MAO-B forms of MAO were studied in rats performing under a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Clorgyline and CGP11305A, irreversible and reversible MAO-A inhibitors, respectively, increased the reinforcement rate, decreased the response rate, and enhanced temporal discrimination. The irreversible MAO-B inhibitor (–)-deprenyl did not produce similar effects. Pargyline did not increase the reinforcement rate at low doses that selectively inhibit MAO-B, but did increase the reinforcement rate at doses that inhibit MAO-A by more than 90%. The present results are in accord with clinical data demonstrating that MAO-A inhibitors are effective therapeutic agents in treating depression while MAO-B inhibitors are of questionable antidepressant efficacy. The present findings provide further evidence that the DRL 72-s schedule may be useful both as a screen for identifying new antidepressants and for investigating the neurochemical effects of antidepressant drugs that are responsible for their therapeutic effects.     

Elaborate ligand-based modeling reveals new human neutrophil elastase inhibitors

Human neutrophil elastase inhibitors (HNE-Is) have been recently implicated in inflammatory diseases. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory HNE leads via combining pharmacophore modeling, quantitative structure–activity relationship (QSAR) analysis, and in silico screening. We employed the pharmacophoric models and associated QSAR equation to screen the National Cancer Institute (NCI) list of compounds. Virtual screening identified 14 novel leads from NCI compounds. The most potent hit 126 exhibited 93 % inhibition at 10 μM.     

Combined Molecular Docking, 3D‐QSAR,and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine‐binding Site

Interference with dynamic equilibrium of microtubule–tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure–activity relationship (SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine‐site inhibitors (CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D‐QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A‐132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs.     

QSAR studies on pyrrolidine amides derivatives as DPP-IV inhibitors for type 2 diabetes

A large series of pyrrolidine amides derivatives as DPP-IV inhibitors was subjected to quantitative structure–activity relationship (QSAR) analysis. These 248 geometrical structures were constructed and optimized at the HF/6-31G* level of theory by the Gaussian program. The 2D–QSAR model was developed from a training set consisting of 186 compounds by the minimum redundancy maximum relevance–sequential floating back–support vector regression method with a good determination coefficient: the squared correlation coefficient (R _train ²  = 0.867) and the tenfold cross-validation squared correlation coefficient (q _train-CV ²  = 0.669). The QSAR model was then tested using an external test set consisting of 62 compounds and provided a satisfactory external predictive ability (R _test ²  = 0.666). 2D–QSAR model is robust and reliable when compared with 3D–QSAR techniques for the analogous compounds. According to the QSAR analysis, the electronic effect plays an important role for the substituents of the pyrrolidine and carbon rings. The study would serve as a guideline in designing more potent and selective drugs against type 2 diabetes.