Letters in Drug Design & Discovery - Volume 14, Issue 6, 2017

Background: Halogen-substituted thiourea derivatives exert well-documented antimicrobial, antiviral and anticancer properties. Objective: This work evaluates antimicrobial and cytotoxic activities of newly synthesized fluorinated thiourea compounds. Method: Two series of thioureas were obtained by the condensation reaction of 4-amino-1- benzylpiperidine (1a-14a) or furfurylamine (1b-14b) and fluorinated isothiocyanates. The anti HIV- 1 activity evaluation was based on inhibition of virus-induced cytopathogenicity in exponentially growing MT-4 cell, determined by the MTT method. Antibacterial potency was examined by the disc-diffusion method under standard conditions using Mueller-Hinton II agar medium according to CLSI guidelines. Antifungal effects were assessed using Mueller-Hinton agar and 2% glucose and 0.5μg/mL Methylene Blue Dye Medium. The viability of HaCaT and A549 cells was assessed by determination of MTT salt conversion by mitochondrial dehydrogenase, whereas release of lactate dehydrogenase from the cytosol to culture medium was a marker of the cell death. Results: The X-ray crystallography studies showed the conformations adopted by the molecules 2a, 7a, 2b and 7b. Compounds 1a and 14a proved cytotoxic against MT-4 cells and different other cell lines derived from human haematological tumors (CC50 < 10 μM). They influenced on viability, mortality and the growth rate of healthy HaCaT cells. Derivatives 1a, 6a and 2b exhibited moderate activity against Gram-positive bacteria (MIC values 8-128 μg/ml). Conclusion: The results indicate that new 1,3-disubstituted thioureas exert moderate in vitro antimicrobial and cytotoxic effects.

Background: A set of novel sulfanyl aminonaphthoquinone derivatives (5a-j) were synthesized starting from 2,3-dichloro-1,4-naphthoquinone (1). The amine substituents were introduced via a nucleophilic substitution at reflux temperature. Subsequent reactions of 2-chloro- 3-arylamino-1,4-naphthoquinones (3a-d) with different thiols (4a-c) led to the formation of the desired amino- and thio- substituted products (5a-j). Methods: The purity and identity of the synthesized compounds were verified with IR, 1H and 13C NMR, and MS spectroscopy. In vitro antimicrobial activity was evaluated in a panel of seven bacterial strains (three Gram-positive and four Gram-negative bacteria) and one fungi with an additional study of antibiofilm activities. The anticancer activities of two selected compounds (5e and 5f) were evaluated against 60 human tumor cell lines derived from nine neoplastic diseases by National Cancer Institute (NCI). Results: As a result, compound (5e) was identified as a hit with antibacterial efficiency against human originated pathogens S. aureus with minimal inhibitory concentration (MIC) of 19.53 μg/mL. When considering the antibiofilm activities of antibacterial molecule 5e against the S. aureus biofilms, the minimum biofilm eradication concentration (MBEC) value was 10000 μg/mL. Concerning on anticancer activities, both compounds (5e and 5f) exhibited moderate anticancer activities on some of tumor cells, but no activity against normal peripheral blood mononuclear cells (PBMC). In addition, docking study was used to provide further insights into the experimental observations. Conclusion: Taken together, compound 5e could be considered as a promising starting point for further development.

Background: On the basis that various substituted salicylamides have shown interesting biological properties, we designed and synthesized new salicylamide derivatives with dipeptide moieties. Methods: The synthesis was based on the gradual building of target molecules and provided optically pure compounds. Conclusion: The obtained compounds were tested for their antiproliferative effect against three leukaemia cell lines in vitro and displayed GI50 values in the mid-micromolar range.

Background: In recent years, thiazole derivatives incorporated with hydrazone moiety have attracted a great deal of interest due to their pivotal role in the field of current cancer research. Methods: In the present study, new thiazolyl hydrazone derivatives were synthesized via the reaction of 1-(4-phenylcyclohexylidene)thiosemicarbazide with 2-bromoacetophenone derivatives. MTT assay was performed to assess the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human liver hepatocellular carcinoma and C6 rat glioma cell lines. The selectivity of the compounds was investigated using NIH/3T3 mouse embryonic fibroblast cell line. Results: 4-(4-Methylsulfonylphenyl)-2-(2-(4-phenylcyclohexylidene)hydrazinyl)thiazole (7) was found to be the most promising anticancer agent against HepG2 cell line with an IC50 value of 0.316 mM when compared with cisplatin (IC50=0.091 mM). Compounds 2 and 6 also exhibited cytotoxic effects on HepG2 cell line with IC50 values of 0.81 mM and 0.79 mM, respectively. Besides, compounds 2, 6 and 7 did not show any cytotoxicity against NIH/3T3 cell line. Conclusion: In particular, compound 7 was found to be a potent anticancer agent to go further studies due to its selective antitumor activity against HepG2 cell line.

Background: In continuation of our research on sonochemistry and due to the importance and application of hydrazones and N-acylhydrazones in drug discovery, in this work we report a new general and efficient synthesis of these classes with different aromatic and heteroaromatic nucleus assisted by ultrasound and their respective anti-tuberculosis and anti-cancer activities. Method: Derivatives 7-chloroquinoline 10 and 12 were the most promising compounds against cancer and TB, respectively. Conclusion: Unfortunately all new hydrazones and N-acylhydrazones evaluated displayed no activity anti cancer and TB.

Background: Tetrandrine has good pharmacological effects, especially in the treatment of pulmonary hypertension. It has the potential to be valuable for clinical applications, however the poor solubility and the high variability of oral bioavailability greatly limited its development. Our research group prepared a new type of tetrandrine microspheres by using chitosan. However, it was lack of pharmacodynamic evaluation and difficult to evaluate if the application of this dosage form can really meet the target to improve curative effect. Methods: In this study, we established animal model of rats with hypoxic pulmonary hypertension, and evaluated acute therapeutic effect by prepared tetrandrine microspheres. Results: In vivo pharmacodynamic showed that tetrandrine lung targeting microspheres had stronger and longer effect to reduce pulmonary arterial pressure (mPAP) than aqueous solvent. After apply tetrandrine lung targeting microspheres on hypoxia rats, no matter the level of dose, mSBP all had no obvious change. Conclusion: Thus it indicated that tetrandrine lung targeting microspheres were mainly effective inside lung, with certain selectivity.

Background: A series of new class of twenty four 1, 4-benzodizepines were designed and by using molecular docking study with GABAA receptor, high scoring fourteen molecules were synthesized from this library. Binding affinity of ligands towards GABAA was evaluated on the basis of dock score and bonding interactions like hydrogen bonds, hydrophobic bonds and pi-stacking. Methods: All compounds were found to possess a good dock score, but varied in the formation of bonding interactions. Methoxy group substituted ligands showed particularly very important role in these interactions. All the synthesized molecules were characterized by IR, 1H-NMR and Mass spectrometric data and investigated for their antianxiety and antiepileptic actions. Conclusion: Compound 3-(3-ethoxy-4-hydroxybenzylidene)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin- 2-one was found to possess very effective in both the activities. All results, docking as well as pharmacological evaluations were compared to diazepam.

Background: A new series of pyrazole containing 1,4-dihydropyridine derivatives 5a-i and 6a-i were synthesized from substituted acetylated aryls and substituted phenylhydrazine by the multistep reaction. Method: The target compounds 1,4-dihydropyridine derivatives were obtained from green synthesis of 1,3-disubstituted phenyl-1H-pyrazole-4-carbaldehydes 4a-i with ethyl acetoacetate and methyl acetoacetate at higher temperatures in the presence of ammonium acetate and the catalytic amount of ammonium metavanadate (NH4VO3). The role of ammonium metavanadate was increases rate of the reaction and obtained high yields. Result: Structures of newly synthesized 1,4-dihydropyridine moiety containing pyrazole derivatives were confirmed by FT-IR, NMR and Mass spectral studies. The structure of compound 5b was confirmed by S-XRD study. Further, these compounds were tested for in-vitro antitubercular and antimicrobial studies. Compounds 5a, 5b, 5i, 6a, 6b, 6g, 6h, and 6i were found to be active against all the bacterial microorganisms. Conclusion: The above mentioned compounds have shown lowest MIC ranging between 3.12-12.5 μg/ml against Mycobacterium tuberculosis and MIC values ranging between 7.8- 15.6 μg/ml for Mycobacterium smegmatis, Staphylococcus aureus and Pseudomonas aeruginosa. For the control of life threatening diseases such as tuberculosis, these eight compounds may be strongly promising synthetic compounds.

Background: This work reports synthesis and in vitro cholinesterase inhibitory activity of novel indole-isoxazole hybrids. Method: The synthetic procedure was started from different ethyl 5-arylisoxazole-3-carboxylate derivatives. Hydrolysis and reaction of the later compound with tryptamine afforded the desired products in good yields. Conclusion: Among the synthesized compounds, N-(2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl) isoxazole-3-carboxamide (4b) showed the best anti-cholinesterase activity.

Background: Matrix metalloproteinase-9 (MMP-9) expression is elevated in neurological diseases, and its up-regulation may exert to the pathogenesis of many neurological disorders. Therefore, inhibition of MMP-9 can be of neuroprotective approach. Objective: The present in silico study carried out to explore the possible neuroprotective potential of Withania somnifera phytochemicals through inhibition of MMP-9. Method: Twenty-seven Withania somnifera phytochemicals were selected for this study based on their BBB penetration ability and suitability for Lipinski's rule of five. Further, molecular docking was performed to know whether these phytochemicals inhibit the MMP-9 or not. Results: The results suggest that 17 phytochemicals have the higher affinity for S1'-specificity pocket of the MMP-9 catalytic domain than two inhibitors reverse hydroxamate and quercetin. Because of they directly bound to the active site with lower binding energy and established some hydrogen bonds and hydrophobic interactions with residues critical in mediating inhibition. Conclusion: These phytochemicals have potential as an intrinsically useful oral drug to combat neurological disorders mediated by MMP-9.

Background: Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that plays crucial roles in energy metabolism, DNA repair and cell death. Due to the high proliferation rate and the high energy necessity in cancer cells, NAD biosynthesis and salvage is required. Owing to the NAD importance in cancer cells, NAD salvage/recycling enzymes are targets for drug discovery. Methods: Herein we focused on NMNAT is a housekeeping enzyme in all organisms catalyzing coupling of ATP and NMN or NaMN yielding NAD or NaAD, respectively. In mammals, three NMNAT isoforms, nuclear NMNAT1, cytoplasmic NMNAT2 and mitochondrial NMNAT3 have been identified. Results: As there is no crystal structure for hNMNAT2, 3D structure models were built based on hNMNAT1 (42% identity) and hNMNAT3 (41.5% identity). To date, only a few hNMNAT inhibitors have been reported so far in the literature: Gallotannin, some NAD analogues and aminophenylsulfonamide derivatives. With the aim of investigating the differences in isoenzyme structures and catalytic properties in molecular level, molecular docking studies of compounds 1-5 were performed. Conclusion: Finally, this study might be helpful for the development of inhibitors potentially useful as new chemotherapeutics targeting NMNATs.

Background: Depression is highly prevalent in uremic patients undergoing hemodialysis (HD). We previously found that low free-carnitine levels are associated with depression severity in male patients undergoing HD. However, whether L-carnitine supplementation improves the depression state in male patients undergoing HD remains unclear. Methods: Sixteen male patients undergoing HD were orally administered 900 mg L-carnitine daily or intravenously administered 1000 mg L-carnitine immediately after undergoing HD for 3 months. The depression state and various types of carnitine levels were evaluated using the self-rating depression scale (SDS) and tandem mass spectrometry, respectively, at baseline and 3 months after treatment. Results: L-carnitine supplementation significantly increased serum levels of free and other acylcarnitine types, associated with improved SDS scores in male patients undergoing HD. Univariate analysis revealed that low baseline butyryl- and isovaleryl-/2-methylbutyryl-carnitine levels were significantly correlated with SDS scores after treatment. Multiple regression analysis revealed that butyrylcarnitine levels were a sole independent predictor of SDS scores after treatment (r2 = 0.533). Conclusion: L-carnitine supplementation for 3 months improved the depression state in uremic male patients undergoing HD. Thus, low butyryl-carnitine levels may predict the clinical response to L-carnitine supplementation in male patients undergoing HD and who have mild depression.

Background: Alzheimer’s disease is progressive neurodegenerative disease incidence of which has been steadily growing for past decades. Etiology of Alzheimer’s disease consists of multiple micro and macroscopic changes and to this day is not satisfactorily understood. Conventional therapy is based on inhibition of acetylcholinesterase of Alzheimer’s disease is connected with considerable worldwide expenses. Objective: Six clinically used cholinesterase inhibitors (donepezil, physostigmine, galanthamine, huperzine A, rivastigmine and tacrine) and memantine were compared according to their cholinesterase inhibitory properties. Additionally, the ability of tested compounds to directly inhibit protein aggregation as well as the capability to promote the protein amyloid fibrils depolymerization was determined. Method: Adopted colorimetric assay according to Ellman was used to evaluate the inhibition aktivity against cholinesterases. The ability of compounds to influence agregation inhibition and depolymerization activity was measured by means of thioflavin fluorescence assay. Results: Huperzine A was found to be the most potent, highly selective acetylcholinesterase inhibitor. Tacrine and physostigmine were the most potent butyrylcholinesterase inhibitors. Several inhibitors showed some weak potency to affect protein fibrils aggregation or depolymerization. Namely rivastigmine and galanthamine showed some effect on protein polymerization and depolymerization. Conclusion: Data provided by experiments suggest that clinically used and standard cholinesterase inhibitors influence the protein superstructures however the effect is weak. The need for novel structures of cholinesterase inhibitors with sufficient protein aggregation inhibition and/or depolymerization is evident.