Letters in Drug Design & Discovery - Volume 13, Issue 4, 2016

Background: Risk factors represented by genetic, environmental or social stress induce severe psychiatric disorders such as depression, schizophrenia or severe neurodegenerative processes. Antipsychotics are required for the pharmacological treatments of these disorders, but their molecular mechanisms and especially those involved in protecting the nervous system, are still unclear. The latest strategies in the neuroscience field consider as very important the discovery of new applications, such as promoting neurite growth by antipsychotics that are already clinically-approved. Objective: We reviewed in silico and in vivo studies that addressed aspects of the molecular mechanisms by which antipsychotics induce a decrease of psychotic symptoms while promoting neurite growth. Method: We presented the biological activities of psychiatric drugs evaluated by QSAR models based on 2D and 3D- dependent and independent molecules alignment. These are correlated with common pharmaceutical descriptors and also with new components of QSAR models such as the contributions of membrane ions to the antagonism of these drugs at membrane receptors. We also presented in vivo studies that by using a chemical genetic approach, piperazine antipsychotics, paliperidone, amisulpride and also aripiprazole as promoters of neurite outgrowth have been identified. Results: 2- trifluoromethyl-phenothiazine dihydrochloride and 2-trifluoromethyl-phenothiazine hydrochloride derivatives exhibited a weak influence on frequency of necrotic effect on lymphocytes in culture in comparison with fluphenazine. Conclusion: Based on the idea that an increasingly attractive strategy in pharmaceutical science is to discover new applications for already clinically approved drugs, we are confident that future studies will predict similarities or differences in neurite outgrowth promotion capabilities of new antipsychotics.

Introduction: Aspartate transcarbamylase (ATCase) is involved in the initial steps of pyrimidine nucleotide biosynthesis and subject to regulation. Objective: Since Phenobarbital is an important drug, the current study focuses on a comparative investigation of the inhibition of bacterial and murine ATCase by some phenobarbital analogues. Methods: Phenobarbital analogues (thymidine, phenobarbital, and thiobarbituric acid) have been subjected for in vitro and in vivo investigation of their effect on ATCase in mice and three strains of Escherichia coli. Results: The half maximal inhibitory concentrations (IC50) of ATCase activity were measured for each compound. According to IC50 values, an in vitro and in vivo inhibition was obtained upon the treatment of mammalian and bacterial ATCases with the three compounds, whereas thiobarbituric acid is the most potent among all. Its obtained IC50 values are 0.2 ± 0.045 and 0.3 ± 0.03 mM for the bacterial and mammalian enzyme, respectively. Furthermore, the in vivo treatment of ATCase with different doses of these compounds showed the same tendency in a dose-dependent manner. Conclusion: These observations suggest that these inhibitors may interfere with the regulation of the enzyme and eventually lead to an additional biological effect of phenobarbital analogues in mammals and bacteria.

Lichen polyketides (1−14), isolated from Roccella montagnei and Parmotrema cooperi,were evaluated for their urease inhibitory potential. Compound 5 (methyl-β-orcinol carboxylate) was found to be the most potent inhibitor among the series with the IC50 = 17.4 ± 3.0 μM, as compared to the standard thiourea (IC50= 21.0±0.1 μM). SAR studies revealed that mononuclear polyketidesare more potent inhibitors as compared to depsides, diphenylethers, and dibenzofurans. Saturation transfer difference (STD) NMR experiments were used to identify the structural features responsible for the inhibition of urease enzyme at the atomic levels. STD-NMR technique revealed that aromatic moiety and methyl protons of the compound 5 are involved in interactions with the receptor protein. Since C-8 and C-10 methyl protons received the maximum saturation from the receptor protein, this indicated their close proximity to the protein. Weak STDNMR signals for lecanoric acid (8) could be attributed to its larger size. Molecular docking studies predicted that carboxylic moieties of these polyketides act as anchors to bind with the bimetallic active site of the urease enzyme.

Protein Tyrosine Phosphatase (PTP)-1B is a cytosolic receptor like PTPase, which plays an important role in treatment of type 2 diabetes mellitus (T2DM) via negative regulation of insulin signaling pathway. It is evident from the literature that biphenyl ring substituted compounds possess significant PTP-1B inhibitory activity due to extended interaction of the additional phenyl ring with the allosteric site of PTP-1B along with sufficient lipophilicity to cross intracellular barrier. Additionally, 2-thioxothiazolidin-4-one scaffold is a bio-isostere of 2, 4-thiazolidinedione with potent antidiabetic potential. Therefore, it was considered of interest to design and study the mode of binding of novel N- 3 substituted biphenyl-2-thioxothiazolidin-4-one derivatives using molecular docking technique by MVD software. The results of our designing study may be useful for the future development of novel PTP-1B inhibitors for the management of T2DM.

Activation of Notch signalling pathway is triggered by binding of NICD to transcription factor CSL and transcriptional co-activator MAML, which involves in various biological functions as well as progression of diseases. Recent prediction shows suppression of cancer causing genes of this pathway through inhibition of NICD-MAML interaction. Through virtual screening against “NCI Diversity 3” of Zinc database, we identified a potential inhibitor “ZINC01690699” (1-N,4-N-bis[3-(1Hbenzimidazol- 2-yl)phenyl]benzene-1,4-dicarboxamide; 1-N,4-dicarboxamide) possessing highest binding affinity to block the two distinct Binding Sites of NICD to inhibit NICD-MAML interaction and also found the most imperative and essential Binding Site (Site I). Inhibition of this interaction caused by binding of ZINC01690699 is validated by protein-protein docking and the prolonged binding as well as stability of NICD-Inhibitor complex is supported by molecular dynamics simulation. The study not only identifies the best inhibitor but also proposes a potential drug for the treatment of cancers.

Blocking epidermal growth factor receptor (EGFR) has been the hotspot in the field of cancer therapy. Based on the fact that salicylanilides possess well inhibitory activity against EGFR tyrosine kinase, a series of salicylamide analogs bearing 4’-substitution were designed to explore new candidates exhibiting improved efficacy against EGFR. Many of the synthesized compounds inhibited EGFR in the micromolar range, especially compounds 15a and 15b (IC50 = 0.27 μM and 1.1μM, respectively). We report our findings as a basis for further development in salicylamide analogues as EGFR inhibitors.

A series of novel hydrazone derivatives containing pyridine moiety were designed and synthesized from 2,3-dichloro-5-(trifluoromethyl)pyridine as starting materials under microwave irradiation, and their structures were characterized by 1H NMR, MS and elemental analysis. The biological activity of title compounds was determined. The results indicated that some of title compounds exhibited good antifungal activity.

A series of substituted pyrimidinyl (thio)semicarbazide derivatives were designed and synthesized. The antitumor results showed that the activity of thiosemicarbazide compounds (series II) was generally higher than that of the corresponding semicarbazide derivatives (series I). Among them, IIk displayed higher cytotoxicity against HL-60, BGC-823 and Bel-7402 than that of adriamycin and exhibited broad in vitro cytotoxicity against 13 human tumor cell lines. Meanwhile, the cytotoxic selectivity and anti-multidrug resistance were evaluated, and IIk exhibited selective cytotoxicity against cancer cells in comparison to human normal cells and had significant anti-multidrug resistance capability. The bioassay results showed that IIk showed great promise as a potent lead compound for further antitumor discovery.

A series of novel C3-linked β -carboline pyridine (BCP) derivatives have been synthesized via modified Khronke reaction and studied for their DNA-binding affinities. Among all the derivatives, compound 12f has shown significant enhancement in the DNA-binding affinity (ΔTm: 6.3 °C and 6.5 °C at 0 h and 18 h incubation) in comparison to the standard Doxorubicin (ΔTm: 2.4 °C and 2.6 °C at 0 h and 18 h incubation). This result suggested a strong intercalation with DNA double helix. Moreover, molecular modeling studies also showed that the planar β-carboline ring establishes π–π interactions with DNA base pairs and these interactions are further extended due to the presence of pyridine ring. The DNA intercalation has also been investigated for these compounds by molecular docking and the results are in agreement with thermal denaturation data.

A series of novel acetylated piperazine-containing N-glucosides and bis(Nglucoside) 8a-i were synthesized by the nucleophilic addition of acetylated glucopyranosyl isothiocyanate with various substituted piperazines in THF with high yields. Their novel deacetylated products 9a-i were also synthesized after Me- ONa/MeOH treatment. The preliminary bioassays for 18 novel title compounds showed that several compounds have significant fungicidal activity against Fusarium omysporum, Cercospora arachidicola and Phytophthora capsici at 50 μg/mL.