Letters in Drug Design & Discovery - Volume 14, Issue 4, 2017

Background: The healthy appearance of the skin becomes increasingly important worldwide, and among the problems that affect the skin are oxidation and hyperpigmentation. The first causes loss of tissue elasticity, and the second causes dermatitis, melasma, and lentigo. Quinolines are used as treatment of a variety of diseases, as malaria, tumor, hyperpigmentation, and it has also other properties such as antioxidant. Quinolines derivatives are synthetized and evaluate the depigmenting and antioxidant activities and the activity was statistically equal to kojic acid and presented the best percentage of tyrosinase inhibition, indicating that this molecule may have promissory utility in the future. Objectives: In this work, we evaluate the depigmenting and antioxidant activities of some quinoline (AMQ) derivatives hybridized to sulfa, nicotinamide or hydrazine groups. Method: The ability to inhibit the activity of tyrosinase enzyme was evaluated using the enzymatic method described by Macrini et al. with modifications. The antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DDPH) assay. Results: The tyrosinase inhibitory ability screening demonstrated, in the qualitative assay, that the compounds A, B, and C [24] presented IA% lower than 50%, and only the compound D [24] and kojic acid had IA% higher than 50%. Regarding the antioxidant activity, the compounds C and D showed antioxidant effect statistically similar to ascorbic acid (p= 0.676 and p= 1.000, respectively), and each other; the anologs A and B presented antioxidant activity statistically lower than ascorbic acid. Conclusion: According to the data, the best molecular modification was the introduction of a nicotinamide, compound D, in the aminoquinolinic nucleus that gave a tyrosinase inhibitory activity statistically equal to kojic acid. Yet this compound presented the best percentage of tyrosinase inhibition, approximately 84%, indicating that this molecule may have utility in cosmetic industry in the future. However, studies must continue to be done evaluating the in vivo activity.

Background: Oxidative stress caused by reactive oxygen species (ROS) plays a significant role in many human disorder such as cancer, rheumatoid arthritis, atherosclerosis, stroke, neurodegeneration, and diabetes as well as the process of aging. Compounds interfere with the action of ROS might be useful in prevention and treatment of these pathologies. Indole nucleus seems to protect the nervous system against oxidative stress. Methods: Herein, several indole compounds containing 4-substituted piperazine moieties were synthesized. Compounds 1, and 4-15 were obtained by amidification reaction using 1,1’-carbonyldiimidazole (CDI) and compounds 2 and 3 were obtained by the reaction of amine and substituted chloropyridine ring using potassium carbonate. Antioxidant activities of compounds were determined by in vitro lipid peroxidation levels on rat liver, superoxide formation and 2,2-diphenyl-1-picrylhydrazyl (DPPH) stable radical scavenging activities in comparison with vitamine E (α-tocopherol). Results: The results indicated that compounds 6 (75%), 7 (66%), 8 (75%), 11 (88%), and 12 (69%) showed strong inhibiory effects on superoxide radical formation compare to vitamine E (62%). Compound 11 can be considered as the most active one among them. Compound 10 (38%) showed slight activity in lipid peroxidation inhibition assay. Compounds are not good inhibitor of DPPH except compound 10, which has also slight inhibition (20%).

Background: Cancer is the leading cause of death worldwide. Induction of apoptosis in cancer cell is the main strategy for the development of anticancer agents targeting apoptosis pathway. Procaspase-3 is one such target for the induction of apoptosis via activation of caspase 3. Novel molecules are needed as procaspase-3 activators which will induce apoptosis in cancer cell. Objective: The main objective of this work is to design 2-substituted benzimidazole derivatives using 3D QSAR study, and to predict the activity of designed compounds as procaspase-3 activators, and apoptosis inducer. Method: 3D QSAR study was performed on the series of substituted benzothiazole derivatives using Sybyl X software. Distill alignment was used for 3D QSAR analysis. Best CoMFA and CoMSIA models were used for the activity prediction of designed compounds. External validation using MAE-based criteria were performed, and applicability domain of QSAR models were also determined. Osiris property explorer and Med Chem Designer software were used for the prediction of in silico pharmacokinetic properties, and toxicities. Results: CoMFA and CoMSIA models were developed using Distill alignment method, which were statistically very good, and validated using well known procedures. Contour maps generated using 3D QSAR study were used for the design of novel compounds. Designed compound showed better predicted activity, and no toxicity. Conclusion: The present QSAR approach with predicted activity and physicochemical properties helped in the design of benzimidazole derivatives as procaspase-3 activators and apoptosis inducer.

Background: Prostate cancer represents the second most frequently diagnosed malignancy in men, and is considered as the fifth leading cause of death from cancer in men. The aims of this paper are shown the development of new, rapid, and clean synthetic routes toward focused libraries of such compounds is therefore of great importance to both medicinal and synthetic chemists. Methods: The preparation of benzochromene and benzoquinoline derivatives using the Michael addition between benzylidenemalononitrile derivatives and the 1-tetralones respective, in presence of catalytic amount of piperidine, or in presence of ammonium acetate, and catalytic amount of acetic acid respectively is reported, together a studies of their activity against human prostate cancer cells PC-3 and LNCaP in vitro. Results: From a total of 56 compounds, 12 were cytotoxic, inhibiting PC-3 cell viability, and the three most active compounds were also cytotoxic to LNCaP and MatLyLu cells. An important remark is that the three compounds were significantly more toxic to cancer cells compared to non-cancer cells (HK-2 and BPH-1). Conclusion: Three compounds proved to be most active, showed cytotoxic effects in different human and non-human prostate cancer cell line. The mechanism of the antitumor activity of this structure seems to be related by inhibition of MMP-9.

Method: This work reports on the Surflex docking and 3D-QSAR studies viz., CoMFA, CoMSIA and Topomer CoMFA on a set of 64 compounds that are inhibitors of enoyl ACP reductase enzyme. Diversity method was used to validate the generated test and training set. Results and Discussion: These sets were then used to generate, steric, electrostatic, hydrophobic, H-bond donor and acceptor contour maps. The results showed the best predictions for CoMFA model (q2 = 0.567, r2 pred = 0.902), CoMSIA (q2 = 0.586, r2 pred = 0.894), and Topomer CoMFA model (q2 = 0.652, r2 pred = 0.785). By comparing the results of both the studies we observed that amine, carbonyl, and pyrazoline rings are important for binding to receptor. Conclusion: These findings would help researcher to design new chemical entities by targeting enoyl ACP reductase enzyme.

Background: A series of pyrimidothiadiazinones 5a-n were prepared from aminomethylation of pyrimidinethione 1 with different primary amines and formaldehyde through Mannich reaction. The spectral data of the formed products confirmed the suggested structures. Method: Most of the newly synthesized compounds were tested for their antimicrobial and anticancer activities. Depending on the obtained results, the newly synthesized compounds possess good to moderate activities. Compound 5e exhibited the highest antibacterial activity measured in 22.1, 18.6, 17.2 and 16.8 mm against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Pseudomonas aeruginosa, respectively. Compound 5e exhibited highest potency with MIC values of 125, 250, 250, and 500 μg/mL against E. coli, S. aureus, B. subtilis, and P. aureginosa, respectively. Results: Compound 5j exhibited the highest inhibitory effect against breast carcinoma (MCF-7) and hepatocellular carcinoma (HepG2) cell lines. Also, molecular docking against E. Coli Enoyl Reductase; PDB ID (1LXC) and Human Dihydrofolate Reductase; PDB ID (1DLS) revealed high free binding energy and good binding mode. The structure activity relationship (SAR) of tested compounds was also studied.

Background: The amine 2 obtained via two steps starting from thiomorpholine was converted into the corresponding 1,3-thiazole (4), arylmethileneamino (5a-d) and hydrazide (7) derivatives using conventional and also microwave techniques. The synthesis of 1,3,4-oxadiazole (8), arylidenenhydrazide (9a-c) and carbothioamides (10a,b) was performed with the treatment of 7 with CS2, suitable amines and suitable isothiocyanates, respectively. Method: Moreover, the treatment of compounds 10a,b with ethylbromoacetate, 2-bromo-1-(4-chlorophenyl) ethanone, conc. H2SO4 and NaOH yielded the corresponding, 1,3-thiazolidinone (11a,b), 1,3-thiazole (12), 1,3,4-thiadiazole (13a,b) and 1,2,4-triazole (14) derivatives, respectively, by either conventional or microwave mediated conditions. The one-pot three component synthesis of fluoroquinolone derivatives (15a,b and 16) was performed by condensation between compounds 8 and 14 with norfloxacine and ciprofloxacine under conventional or microwave irradiation conditions. Results: The effects of different catalysts, solvents and microwave powers on conventional and microwave-prompted reactions was also examined. The synthesized compounds were screened for their antimicrobial, enzyme inhibition and antioxidant activities. Molecular docking of some of the synthesized compounds into the active sites of lipase, α-glucosidase and urease was also carried out in order to predict the binding affinity and non-covalent interactions between them.

Background: Considering that inflammation is involved in many degenerative conditions, some derivatives of tolfenamic acid, naproxen and indomethacin were synthesised and evaluated biologically. They were found to possess increased anti-inflammatory activity, being more potent than the parent drugs. Method: Thus, compound 4, the ester of naproxen with di-tert-butyl-4-(hydroxymethyl)phenol, caused about 80% reduction of carrageenan-induced rat paw oedema, much higher than that of the starting drug. The antioxidant structure containing compounds 1-4 could inhibit soybean lipoxygenase, as well as rat microsomal membrane lipid peroxidation, both effects attributed to the presence of SH or phenolic groups. The effect of compound 1, the amide of tolfenamic acid with L-cysteine ethyl ester, on paracetamol-induced oxidative liver injury and on brain oxidative stress caused by ischemia– reperfusion was examined. Results: It was found that 1 could protect rat liver from glutathione depletion, being comparable to Nacetylcysteine, the classical antidote against paracetamol overdose, and restore hepatic function, as judged by the levels of hepatic enzymes in plasma and the microscopic examination of multiple liver slices. After cerebral ischemia, 1 reduced caspase-3 by 60% and significantly decreased the number of apoptotic cells, especially in hippocampus and cerebellum.

Background: Melatonin, a hormone synthesised by the pineal gland, has a significant role in the regulation of the circadian biological clock. Objective: The present study aims at investigating how matrix tablets comprised of common hydrogels influence the release profile of melatonin at both physiological pH’s. Moreover, we designed and developed liposomes incorporating this hormone in order to compare its release profile. Methods: Preparation of matrix tablets and liposomal formulations. Drug release studies. Results: Hydrogel based matrix tablets of the chronobiotic hormone melatonin were developed aiming at effecting its sustained release at pH 1.2 and 7.4. The matrix tablets used were comprised of hydroxypropyl methylcellulose (HPMC) and dextran. Moreover, melatonin was encapsulated into conventional liposomes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and dipalmitoyl-phosphatidyl glycerol (DPPG), in an attempt to compare the hormone’s release profile from liposomal formulations with its respective release from matrix tablets. Conclusion: Both liposomal and solid pharmaceutical formulations, albeit their different mechanistic drug-leaching mode of action, are suitable for treating sleep onset problems and/or sleep maintenance discomforts.

Background: Obesity alters endocrine and metabolic function of the adipose tissue leading to an increased release of fatty acids, adipokynes and pro-inflammatory molecules which in turn lead to complications related to the onset of metabolic syndrome. Methods: To this regard, natural antioxidants have been found to have anti-inflammatory and protective action in cardiovascular diseases, diabetes mellitus and obesity. Caffeic acid phenethyl ester (CAPE) is synthesized in a variety of plants and is one of the main components of propolis. CAPE inhibits oxidative stress and showed beneficial effects under various experimental conditions. Aims: The aim of the study was to evaluate the effect of CAPE on adipocyte function after an inflammatory stimulus with lipopolysaccharide (LPS) (1 ng/ml for 6h). Results: Our data showed that LPS caused an increased expression of proinflammatory interleukin IL-6 and a lipolytic effect on the adipocytes. CAPE treatment inhibited LPS effects through a significant decrease of IL-6 and a concomitant increase of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/Enhancer Binding Protein alpha (CEBPα), fatty acid synthase (FAS), fatty acid binding protein 4 (FABP4), diacylglycerol O-acyltransferase 1 (DGAT1) and transcription factor sterol regulatory element binding protein-1c (SREBP-1c). Moreover, the increased levels of adiponectin, heme oxygenase-1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), peroxisome proliferator- activated receptor alpha (PPARα) and Sirtuin-1 suggest that CAPE administration restores adipocyte function following inflammation. Conclusion: In conclusion, the use of this metabolite such as a food supplement may represent a possible strategy for the treatment of conditions related to metabolic syndrome.

Introduction: Chronic inflammation of organs has been linked with various steps involved in carcinogenesis. Delta-opioid receptors (DOR) and farnesyl transferase (FT) inhibitors have the capability to obstruct various intracellular pathways affecting inflammation and cell proliferation. They become an effective targets for the treatment of inflammation and cancer. Objectives: The work presented here reports the in-silico studies of anti-inflammatory and anti-cancerous properties of Callistemon viminalis derived natural compounds. Methods: This study includes quantitative structure activity relationship (QSAR) and quantitative structure toxicity relationship (QSTR). Biological activity and pharmacophore modeling of selected phyto-ligands against δ -opioid receptor (PDB ID: 4EJ4) and farnesyl transferase (PDB ID: 1S63) were evaluated. Results: Among 12 molecules investigated selectively 4 compounds exhibited excellent drug–likeness properties. Further, pharmacokinetic study revealed that these compounds were having minimal side effects. These compounds also showed a nicely bounded into the active site of DOR and FT with minimum binding energy through molecular docking. Pharmacophore model generated for these compounds showed potential anti-inflammatory and anti-cancer properties by showing appreciable interaction with DOR and FT. Conclusion: Hence, finally concluded compounds α-Terpineol, catechin, methyl gallate and ellagic acid have showed excellent binding energy and inhibitory constant for DOR and FT and it may be considered as a good inhibitor of the DOR and FT.

Background: Sequential therapy is one of the most common regimens for H. pylori eradication. The progressive ageing may lead to several problems in the management of H. pylori. Objective: We aimed to assess the effectiveness/safety of sequential therapy in elderly patients and evaluate possible predictive factors of failure. Methods: We retrospecively enrolled 76 patients >65 years old (elderly group) and 69 controls diagnosed of H. pylori by upper endoscopy/histology and a non-invasive test. Patients received 10-day sequential therapy (esomeprazole 40 mg and amoxicillin 1 g for the first 5 days followed by clarithromycin 500 mg plus tinidazole 500 mg, all b.i.d). Comparison between groups was carried out by t-test or χ2 test where appropriate. Binomial logistic regression was used to determine factors influencing treatment failure. Results: Eradication was achieved, at Intention-To-Treat analysis, in the 78.9% and 75.4% in the elderly and control group, respectively, and, at Per-Protocol analysis, in the elderly patients in the 81.1% and in controls in the 76.5%, not statistically different. Both groups experienced a similar rate of side effects (27% vs 26.5% p = 1). At univariate analysis, treatment failure in the elderly group positively correlated with female sex (OR=22.5), side effects (OR=5.3), intestinal metaplasia (OR=6.7) and gastric atrophy (OR=6.8), while negatively with antritis (OR=0.15). However, at multivariate analysis, none of the cited variables was found statistically significant. Conclusion: Sequential therapy is safe in old patients and has satisfactory effectiveness, but an “a priori” model predicting the outcome based only on clinical data is not reliable.