Medicinal Chemistry - Volume 12, Issue 6, 2016

There are rapidly replicating human data suggesting the therapeutic and neurorestorative role of repetitive transcranial magnetic stimulation (rTMS) in clinical depression. However there are only limited experimental studies in the literature and the neurobiological mechanisms of the technique are still unclear. Studies have suggested that modulating of either excitatory or inhibitory neural circuitry may be responsible for the mechanism of action of rTMS while it is still unclear whether rTMS exerts a neuroprotective effect. In the light of these findings, we aimed to review the neuroprotective effect of rTMS in animal models of depression. We have shown that rTMS may exert significant neuroprotective effect through acting on the oxidative injury, stress hormones, dopamine and serotonin levels, Brain Derived Neurotrophic Factor expression, neuroinflamation and hippocampal cell proliferation.

Background: The ALDH-2 enzyme has been identified as an important therapeutic target for the development of new drugs for the treatment of cocaine addiction. Several studies involving the synthesis, the design and pharmacological evaluation of daidzin (isoflavonoid inhibitor of ALDH-2) analogs were conducted. Methods: In this study, we used two in silico approaches effective to understand the mechanism of inhibition of ALDH-2 enzyme, the molecular docking and constructing a pharmacophore model, and we established a correlation between the inhibitory profiles of daidzin and its analog for ALDH-2 and their interaction profiles to understand the structural basis for their inhibitory activities. Results: Docking is efficient and opportune tool to guide the design of new inhibitors of ALDH-2. From the results of the molecular docking studies performed herein and their relationships with the inhibitory profiles of some daidzin analogs described previously in the literature, pharmacophore groups associated with ALDH-2 enzyme recognition were identified. Summarizing our findings, the presence of a linear alkyl chain with a terminal hydrogen bond acceptor group in position 7 is important for the interaction with the Gln-289 residue. Additionally, the presence of a group that is capable of performing hydrogen bonding interactions as either a donor or acceptor in the 4’ position is important for the interaction with the Glu-268 residue; this group is the primary pharmacophore that should be attached to the scaffold of the aromatic nucleus of an ideal inhibitor of ALDH-2. Conclusion: The structure inhibitory activity relationships among daidzin analogs were established using a molecular docking tool, thus identifying the structural reasons for the inhibition of the ALDH-2 enzyme. We defined the key pharmacophore groups required for enzyme inhibition and the maintenance of interactions with the amino acids Gln-289 and Glu-268, which are related to the potency of the ALDH-2 inhibitors. This study is highly relevant for the design of new ALDH-2 inhibitors using different medicinal chemistry tools to develop novel therapies for controlling cocaine addiction.

Background: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS occurs across mucosal surfaces or by direct inoculation. Objective: The objective of this study was to consider chemically diverse scaffold sets of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) subjected to ideal oriented QSAR with large descriptor space. Method: We generated a four-parameter QSAR model based on 111 data points, which provided an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds. Results: The robustness of the model is demonstrated by its statistical validation (Ntraining = 111, R2 = 0.85, Q2lmo = 0.84) and by the prediction of HIV-1 inhibition activity for experimentally measured compounds. Conclusion: Finally, 5 novel hit compounds were designed in silico by using a virtual screening approach. The new hits met all the pharmacophore constraints and predicted pIC50 values within the binding ability of HIV-1 RT protein targets.

Background: The search for new cholinesterase inhibitors is still a promising approach for management of Alzheimer’s disease. Schiff bases are considered as important class of organic compounds, which have wide range of applications including as enzyme inhibitors. In the present study, a new green ionic liquid mediated strategy was developed for convenient synthesis of two series of Schiff bases 3(a-j) and 5(a-j) as potential cholinesterase inhibitors using aromatic aldehydes and primary amines in [bmim]Br. Methods: The synthesized compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential by modified Ellman’s method. The molecular interactions between the most active compound and the enzyme were analyzed by molecular docking. Results: Among them, 3j displayed higher inhibitory activities than reference drug, galanthamine, with IC50 values of 2.05 and 5.77 μM, for AChE and BChE, respectively. Interestingly, all the compounds except 3b displayed higher BChE inhibitions than galanthamine with IC50 values ranging from 5.77 to 18.52 μM. Molecular docking of compound 3j inside the TcAChE and hBChE completely coincided with the inhibitory activities observed. The compound forms strong hydrogen bonding at the peripheral anionic site of AChE whereas on BChE, it had hydrophobic and mild polar interactions. Conclusion: An efficient and eco-friendly synthetic methodology has been developed to synthesize Schiff bases in a very short reaction time and excellent yields in ionic solvent, whereby the compounds from series 3 showed promising cholinesterase inhibitory activity.

With the aim of finding new chemical entities based on coumarin and chalcone scaffolds, new hybrid compounds 2-5 were designed and synthesized. The trypanocidal activity of these compounds was tested against the epimastigote, trypomastigote and amastigote stages of the Trypanosoma cruzi parasite. Cytotoxicity assays were also performed in RAW 264.7 and VERO cells. Compound 5 presented the highest trypanocidal activity of the series, with trypanocidal values higher than nifurtimox for the trypomastigote and epimastigote stages., but presenting cytotoxic effects in the mammalian cells. A SAR study suggested that methoxy substitution at positions 2 and 5 in the designed scaffold seemed to be a key feature for the trypanocidal activity. Therefore, the coumarin-chalcone scaffold can be taken into account for further lead optimization and design new and more effective trypanocidal compounds.

Background: The frequent use of antibacterial agents and the exposure of the patients to lifesaving intervention processes are consistently associated with the increased chance of nosocomial infections and the emergence of multidrug resistant microorganisms in the hospital environment. Thus, new antimicrobial agents are of unmet need to treat the severe nosocomial infections caused by these putative pathogens resistant to currently available agents. Method: Design, synthesis, and biological evaluation of analogues of nitazoxanide (NTZ), an FDA approved thiazolide antiparasitic, as new antimicrobial agents against nosocomial pathogens were described. The NTZ analogues were rationally explored on the basis of either increasing the electronic resonance effects at the nitrothiazolide moiety or improving the anionic form of the whole NTZ structure. Results: The MICs and MBCs values of these NTZ analogues against prevalent nosocomial pathogens were measured. The benzologous analogues 3a and 4a and p-chlorobenzenesulfonamides 8d and 9d exhibited tremendous antimicrobial activities, which were 100- to 2000-fold more potent than NTZ and ciprofloxacin. Conclusion: The results demonstrated that delicate manipulation of the NTZ core structure could lead to promising antimicrobial agents against the nosocomial pathogens.

Background: Synthesis, characterization and investigation of antibacterial activity of ten novel Schiff base derivatives of 4-formylbenzoic acid is presented. Their structures were determined using 1H and 13C NMR, EI(+)-MS and elemental analyses. Additionally, DFT calculations of interaction energies in complexes of the novel drugs and DNA bases are carried out. Objective: Design and synthesis of thiazole derivatives with benzoic acid scaffold to obtain compounds with an improved antibacterial activity. Method: The examined compounds were screened in vitro for antibacterial activity using the broth microdilution method. Geometrical parameters of the investigated complexes were optimized within the Density Functional Theory (DFT) approximation using the B3LYP functional and the 6-311G** basis set. The docking simulations were performed using the FlexX docking module. Results: Among the derivatives, compound 4b showed very strong bacterial activity against staphylococci, MIC 1.95-3.91 μg/ml, micrococci, MIC 0.98 μg/ml, and Bacillus spp., MIC 7.81-15.62 μg/ml. The compounds 4c, 4d, 4e and 4j also showed high bioactivity against staphylococci, MIC 3.91-31.25 μg/ml, and micrococci, MIC 0.98-15.62 μg/ml. Interaction energy values for investigated guanine complexes are about 2 kcal/mol lower than for the corresponding cytosine complexes. Molecular docking studies of all compounds on the active sites of bacterial enzymes indicated gyrase B as possible target. Conclusion: To conclude, an efficient and economic method for the synthesis of thiazoles containing benzoic acid moiety has been developed. The results of antibacterial screenings reveal that some obtained compounds show high to very strong antibacterial activity. The DFT calculations showed that interaction of the obtained drugs with guanine is stronger than with cytosine. Molecular docking studies of all compounds on the active sites of bacterial enzymes indicated gyrase B as possible target.

Background: The emergence of drug-resistant bacteria in clinical practice has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We previously described a set of imidazopyridine antibacterial leads that contain a core composed of benzimidazole and a central phthalic acid linker. These compounds showed potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. In this respect, we conducted a systematic exploration of new disubstituted imidazole functionalities on quinoline 4-position as the central linker, to determine the factors that direct the potent antibacterial activity. We found that some of the newly synthesized compounds possessed more potent activity compared to currently available medications. The newly synthesized compounds were screened against several clinical isolates and Staphylococcus aureus, including the methicillinresistant (MRSA) and the methicillin-sensitive (MSAA). Methods: The goal of this work is to undertake rigorous testing of new hybrid scaffolds of quinoline flanked by diaryl imidazoles and their structure-activity against a range of bacterial strains. Described herein is the account of the modification of the central linker region, the imidazole functionality, and substituents at the 4-position of the quinoline, and their effect on the antibacterial potency of the resulting derivatives. Our efforts here have been driven by previous reports on the applications of Pfitzinger cyclization protocol. This complexity-generating reaction transforms a relatively simple substrate, into a more complex products with the potential for diversification via functionalization of the resultant acid. Results: We identified compounds that possess potent and broad-spectrum antibacterial activities against clinical isolates and drug resistant strains. Structure-Activity relationships of these compounds were further explored to determine the crucial structural features needed to enhance their antibacterial activity. In this respect, it was found that, hydrophobic and electron-withdrawing moieties, such as halogens, were required on each end of the isoquinoline-based bisaryl imidazole hybrid motifs to produce broad-spectrum activity against the tested strains. Thus, molecules containing halophenyl or pyridyl arms were found more potent than molecules containing thiophene and/or electron-releasing groups on the phenyl arms, which showed much less antibacterial activity against the tested strains. Conclusion: In summary, 4-(4,5-diphenyl-1H-imidazol-2-yl)-2-phenylquinoline systems can be assembled efficiently through the Pfitzinger ring expansion- condensation strategy. This approach appears to hold considerable synthetic utility. The particular value of such a synthetic route resides on the conciseness and efficiency through which imidazo-quinoline construction can be synthesized from structurally simple and accessible acetophenone precursors.

Background: A lead quinuclidine-based nicotinic ligand (EQA) served as the basis for the design of novel compounds. A new series of 3-substituted quinuclidines was designed, synthesized and evaluated as nicotinic ligands. Methods: The goal was to improve affinity for nicotinic receptors in the CNS. Interatomic distance calculations were performed on the proposed compounds as well as, known nicotinic ligands. The proposed compounds were then synthesized, characterized and evaluated in in vitro assays as nicotinic receptor ligands. Results: Compounds 9a and 9b were found to inhibit the specific binding of 3H-(S)-Nicotine with Ki values of 48 nM and 42 nM respectively, indicating high affinity interactions with the α4β2 subtype. Data suggest that several compounds act as partial agonists at CNS receptors with an efficacy between 28 and 40% and are potent partial activators of human muscle type receptors (α1β1γδ; Emax= 80% that of 100 μM nicotine). Conclusions: Together these results indicate a partial agonism at muscle type receptors (ca. 40%) with no significant activation of rat ganglion-type receptors (α3β4*: asterisk indicates potential additional subunit that could partner to form the ganglionic receptor). The partial agonism inducing dopamine release from striatal synaptosomes (α4β2α6α4β2β3, and/or α6β2β3) suggest that these compounds may in addition be acting at the α4β2 and/or the α6β3* receptors. The partial agonists reported herein are interesting nicotinic ligands worthy of further investigation.

Background: Non steroidal anti-inflammatory drugs are the most widely prescribed drugs to manage pain and inflammatory conditions, but their long term use is associated with gastrointestinal toxicity. Objectives: The study aimed to synthesize an ester-based prodrug of a non steroidal anti-inflammatory agent, mefenamic acid in order to improve the therapeutic index vis a vis to overcome the side effects such as gastrointestinal irritation and bleeding associated with the use of mefenamic acid. Methods: The ester prodrug (MA-NH) was prepared by condensing mefenamic acid with N-hydroxymethylsuccinimide in the presence of Phosphorus oxychloride. The pharmacokinetic profile, including stability and release of mefenamic acid and N-hydroxymethylsuccinimide from the ester prodrug (MA-NH) was studied by RP- HPLC in acidic medium (pH 1.2), basic medium (pH 7.4), 80 % v/v human plasma, 10 % w/v rat intestinal homogenate and 10 % w/v rat liver homogenate (pH 7.4). Results: The chemical structure of the title compound was characterized by using modern spectroscopic techniques. The prodrug was found to be stable in acid medium, but it hydrolyzed and released sufficient quantities of the drug in alkaline medium. The prodrug produced lesser number of ulcers and showed improved analgesic and anti-inflammatory activity as compared to the parent drug. Conclusion: The results indicate that the synthesized prodrug (MA-NH) is better in terms of analgesic and antiinflammatory activities and with less GI toxicity than the parent drug.

Background: The QSRRs and QSARs are relatively new approaches to relate internal chemical structure and particular biological activity. This methodology is based on theory that mechanisms which took place into chromatography column are similar to those that occur in a living organism at the molecular level, for example when compounds penetrate into cells. Objective: In this paper, we aim to describe different cytostatic activities of selected anticancer drugs as QSRR and QSAR models, and prove usefulness of connected QSRR and QSAR methodology in different types of studies. Method: Chromatographic experiments using gradient RP-HPLC method and different C18 stationary phases were performed. As a result we obtained retention parameter log kw. Moreover, to calculate descriptors, which characterize lipophilicity of analyzed antitumor drugs, DryLab program was utilized. Molecular modeling studies were performed by using HyperChem program. Dragon software was used to calculate structural descriptors, and then selected descriptors were used to build QSRR and QSAR models. Obtained data were analyzed by multiple regression analysis (MLR). Results: Experimental log kw and predicted log kw from QSRR models developed, were further used in QSAR analysis. The goodness of fit was in the range of R2= 0.75 - 0.95, and the predictive performance of the models was Q2 = 0.6 - 0.81. Conclusion: Both QSRR and QSAR strategies presented in this paper, allowed predicting HPLC retention parameters and cytotoxic activities of anticancer medicines without the necessity to carry out time-consuming and expensive experimental tests.