Letters in Drug Design & Discovery - Volume 15, Issue 7, 2018

Background: Coumarins are secondary plant metabolites typically found in the species of Asteraceae, Rutaceae and Umbeliferae families which demonstrate several pharmacological properties, including antioxidant activity. As antioxidants, coumarins are known to influence the formation and uptake of Reactive Oxygen Species (ROS), to reduce the oxidative damage caused by free radicals and to prevent eicosanoid formation, being of interest for drug design. In this context, we designed the synthesis of 4-chloromethylcoumarins via Pechmann condensation with different substituents at the position 6 of the coumarin ring through Click chemistry reactions, aiming to improve their antioxidant activities. Methods: The synthesis of the envisioned compounds started with Pechmann condensation using hydroquinone and ethyl 4-chloroaceacetate followed by functionalization of the phenolic hydroxyl with propargyl bromide via Williamsom ether synthesis. Subsequently, Click chemistry reactions were performed under microwave irradiation using previously synthesized organic azides, then yielding five 6-substituted-4-chloromethylcoumarin analogues. These compounds had their intrinsic toxicities estimated via cell viability assays using the NIH 3T3 Cell Line (mouse embryonic fibroblasts) by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The antioxidant activities were then assayed using the DCFH-DA (2',7'-diihydrochlorofluorescin diacetate) assay. Result and Conclusion: Five novel coumarins were synthesized with low to moderate yields (11-61%), while four of these compounds displayed some degree of toxicity in the cell viability assay. However, the remaining coumarin, LaSOM 322, was nearly atoxic in all the assayed conditions and displayed the most relevant antioxidant properties, being a promising lead for subsequent optimization.

Background: Schiff bases have a broad spectrum of biological activities including antiviral, antibacterial, antifungal, antimalarial, anti-inflammatory antiproliferative and antipyretic properties. 1,3,4-oxadiazoles have been reported to show spectrum of biological activities including such as antiviral, fungicidal, antineoplastic, antimicrobial anti-HIV, antitubercular, antihypoglycemic, antimalarial, antioxidant, analgesic, anti-inflammatory, anticonvulsant, anticancer and inhibition of tyrosinase, antitumor and antiproliferative. Morpholine is known as a valuable structure for the synthesis of more efficacious antimicrobial agents. Therefore, the study presents the synthesis, antimicrobial and antioxidant evaluation of a series of 1,3,4 substituted oxadiazole derivatives. Methods: Synthesis of compounds 2(a-d): 0.01 mol 4-amino-1-((5-mecapto-1,3,4-oxadiazol-2-yl) methyl)-3-(thiophen-2-ylmethyl)-1H-1,2,4-triazol-5(4H)-one (1) and 0.01 mol aromatic aldehydes were heated in oil bath without solvent for 2-3 h at 160-180 0C. Then on completion of the reaction, followed by TLC examination, allowed to cool to room temperature. The separated solid was filtered and crystallized from a mixture of DMSO and water (1:2). Synthesis of compounds 3(a-d). A mixture of formaldehyde (0.02 mol) and morpholine (0.02 mol) in DMF was added to solution of compound 2 (0.01 mol) in DMF. The resulting mixture was stirred overnight at room temperature. The precipitated solids were filtered, washed with water and recrystallized from DMF/water. Determination of Antioxidant Activity: The FRAP method was used for the determination of total antioxidant capacity, based on the reduction of yellow Fe3+ -TPTZ complex to the blue Fe2+ -TPTZ complex by electron donating substance under acidic condition. Radical scavenging activity of compounds against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical was spectrophometrically at 517 nm. The assay is based on the color change of the DPPH solution from purple to yellow as the radical is deactivated by the antioxidants. Briefly, the stock solutions of each extract were prepared in DMSO and if necessary sequential dilutions were made. Results: All of the compounds synthesized in this study, except 3c, showed antioxidant activity in the free-radical scavenging (DPPH) and ferric reducing (FRAP) tests at different grades (Figs. 1 and 2). The antioxidant activities of the compounds were differentially influenced in the DPPH and FRAP tests from the substituents of Schiff and Mannich bases. It has been determined that the effects of the substituent type of the thiophene ring on the activity were different for Schiff bases (2ad) and Mannich bases (3a-d). High-to-low activity sequencing was H-CN-NO2-Br (in DPPH assay) and NO2-H-CN-Br (FRAP assay) on schiff bases while Br- H- NO2-CN (in DPPH assay) and H-Br- NO2-CN (in FRAP assay) on mannich bases. Similarly, in DPPH and FRAP assay, the Schiff bases (2a-d) were more active when compared with the Mannich bases (3a-d). Conclusion: In the work, new eight Schiff bases bearing thiophene, 1,2,4-triazolone, 1,3,4-oxadiazole, morpholine moieties were synthesized. The new compounds, well characterized by elemental analyses, IR, 1H NMR and 13C NMR were tested for their antioxidant and antimicrobial activities. In DPPH and FRAP assay, the compounds 2(a-d) with Schiff base were more active when compared with the compounds 3(a-d) containing Schiff base and morpholine substituent and 2(a-c) had a respectable antioxidant potential. The lowest MIC value, i.e. the highest antimicrobial activity, were observed in compound 2a against Bacillus cereus RSKK 709 with a MIC value of 31.25 μg/mL.

Background: Ibandronate is a prominent representative of α-hydroxymethylenebisphosphonic acid (dronic acid) derivatives applied in the treatment of bone diseases. Methods: Ibandronate was synthesized from N-methyl-N-pentyl-β-alanine using phosphorus trichloride and phosphorous acid in different ratios, applying sulfolane as the solvent (1.), or under solvent-free conditions (2.), or in ionic liquids as additives (3.). Results: In the first two cases (1. and 2.), using phosphorus trichloride and phosphorous acid in molar ratios of 2:4 and 3:4, pure ibandronate was obtained in yields of 72-83%. In the presence of 10% of [bmim][BF4] as an additive (3.), a better yield of 82/90% was obtained applying ratios of 2:2 and 3:2 of the P-reagents assuming less of the phosphorous acid. Conclusion: The new methods developed mean record outcomes in respect of the valuable drug, ibandronate.

Background: The Wnt signaling is one of the crucial pathways in embryonic development and numerous types of human cancers. Porcupine, as well as the Wnt protein palmitoyltransferase, is essential to the regulation of the Wnt signaling pathway. The aims of this paper are to we use the three-dimensional quantitative structure-activity relationship (3D-QSAR) models to gain indepth comprehension into the structural requirements of PPN inhibitors. Meanwhile, we utilize the 3D-QSAR models to predict the PPN inhibitory activities of new tricyclic derivatives and further design high-efficiency and potential PPN inhibitors. Methods: Using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) approaches implemented in the SYBYL-X 2.0 software packages in the present study. Results: The statistical results obtained from CoMFA and CoMSIA models were full of credibility and remarkable predictive power. Conclusion: In this study, CoMFA and CoMSIA models were developed for a series of tricyclic compounds as Porcupine Inhibitors for Wnt pathway production inhibitory activity. All of these models possessed good internal predictivity. These 3D-QSAR models for tricyclic compounds gain insights into the relationship of various structural attributes for the biological activity. The calculation of the data computed from the present study can be used to predict the PPN inhibitory activities of new tricyclic derivatives and further design high-efficiency and potential PPN inhibitors.

Background: Indole derivatives and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines are important heterocyclic compounds in medicinal chemistry. They have displayed broad spectrum of biological activities such as anticancer, antimicrobial, antioxidant and anti-inflammatory activities. Objective: The objectives of this research were to synthesize 4-amino-5-mercapto-3-[(5-substituted- 2-methyl-1H-indol-3-yl)methyl]-1,2,4-triazoles and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines incorporating an indole skeleton and to evaluate their antibacterial activity. Methods: 4-Amino-5-mercapto-3-[(5-substituted-2-methyl-1H-indol-3-yl)methyl]-1,2,4-triazoles were synthesized from the fusion reaction of 5-substituted-2-methylindole-3-acetic acids with thiocarbohydrazide. The reaction of 4-amino-5-mercapto-3-[(5-substituted-2-methyl-1H-indol-3-yl)methyl]- 1,2,4-triazoles with a series of phenacyl bromides produced the corresponding 1,2,4-triazolo[3,4- b][1,3,4]thiadiazines. The structures of 1,2,4-triazoles and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines were elucidated by IR, NMR and mass spectral data and were evaluated for their antibacterial activity using 96-well microbroth dilution assay. Results: In the current study, two new 4-amino-5-mercapto-3-[(5-substituted-2-methyl-1H-indol-3- yl)methyl]-1,2,4-triazoles (2b-c) and twenty four new 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines incorporating an indole skeleton (3a-h, 4a-h and 5a-h) have been synthesized. Conclusion: Compound 4d bearing chlorinated indole moiety and 4-methylphenyl group at C-6 position of triazolothiadiazine ring showed promising inhibition activity against Bacillus subtilis subsp. spizizenni, Bacillus cereus and Staphylococcus aureus with MIC value 3.91 μg/ml. Compound 4d also exhibited promising activity against MRSA ATCC 29213 at MIC 7.81 μg/ml.

Background: Pyrazolines have played a pivotal role in antimicrobial and anticancer drug discovery. Moreover, thiazoles have attracted a great deal of interest due to their crucial roles in the lead identification and optimization. Objectives: The purpose of the current work was to design and synthesize new antimicrobial and anticancer agents. Methods: New thiazolyl-pyrazoline derivatives (2a-d) were synthesized via the ring closure reaction of 3-(2-thienyl)-5-(2,6-dichlorophenyl)-1-thiocarbamoyl-2-pyrazoline (1) with phenacyl bromides. The compounds were evaluated for their in vitro antimicrobial effects on pathogenic bacteria and Candida species using Microdilution assay, BacTiter-GloTM microbial cell viability assay and Fluorescence microscopy. The possible binding interactions of compound 1 in the active site of CYP51 were confirmed by molecular docking studies, whereas its genotoxicity was investigated using Ames MPF test. Furthermore, MTT assay was performed to determine the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, C6 rat glioma, and NIH/3T3 mouse embryonic fibroblast cell lines. A computational study for the prediction of ADME properties of all compounds was also performed. Results: Compound 1 was found to be the most potent anticandidal agent against Candida species. MTT and Ames MPF assays indicated that compound 1 was neither cytotoxic nor genotoxic at the concentrations tested. Docking studies showed that compound 1 interacted with Heme group in the active site of CYP51. This compound also exhibited selective anticancer activity against HepG2 and C6 cell lines. According to in silico studies, this compound did not violate Lipinski's rule, making it a potential orally bioavailable chemotherapeutic agent. Conclusion: Compound 1 was identified as a promising candidate for further mechanistic studies.

Background: A new series of quinazoline linked chalcone conjugates were synthesized and evaluated for their in vitro cytotoxicity. Methods: The quinazoline-chalcone derivatives (13a-r) have been prepared by the Claisen-Schmidt condensation of various substituted benzaldehydes (12a-r) with substituted l-(4-(3,4- dihydroquinazolin-4-ylamino)phenyl)ethanone (11a-b) in the presence of aqueous NaOH. Three potential compounds 13f, 13g and 13h exhibited cytotoxicity against leukemia (GI50 value of 1.07, 0.26 and 0.24 μM), Non-small lung (GI50 values of 2.05,1.32 and 0.23 μM), colon (GI50 values of 0.54, 0.34 and 0.34 μM) and breast (GI50 values of 2.17, 1.84 and 0.22 μM) cell line, respectively. Results and Conclusion: Based on these biological results, it is evident that compound 13h has the potential to be considered for further detailed studies either alone or in combination with existing therapies as potential anticancer agents.

Objective: In this paper, the synthesis, plasma and microsomal stability, and in vitro and in vivo pharmacological profile of urea derivatives (6a-d) designed by molecular simplification on prototype LASSBio-998 are described. Methodology: Compounds were synthesiized exploring condensation of amine derivatives with cyclohexylisocyanate. Plasma and microsomal stabilities were analyzed by HPLC. Chemical stability was investigated at pH 1.2 and 7.4. Aqueous solubility was determined using UV-spectroscopy. The in vivo activity was determined using hypernociception induced by carrageenan and capsaicininduced nociception models. Results: Among the synthesized compounds, LASSBio-1495(6b) stood out displaying antihipernociceptive and antinociceptive activities by oral administration; it inhibited pp38 expression in PMA - differentiated THP-1 cells and TNFα production induced by LPS; inhibited p38α activity, albeit in low potency (IC50 = 60 ± 4.5 μM); and showed better solubility and metabolic stability than the original prototype LASSBio-998. Conclusion: The simplified urea derivatives 6a-d showed improvement in their solubility and stability profile, displayed potent anti-TNFα activity through mechanism that is probably independent of p38α inhibition, and exhibited antihypernociceptive and antinociceptive effects by oral administration.

Objectives: The main goal of this paper was to conduct the synthesis to determine cytotoxic activity and to carry out docking studies on new LASSBio-1586 isosteres. LASSBio-1586 is a new combretastatin A4 (CA4) analogue previously identified as a simple antitumor drug candidate, able to inhibit microtubule polymerization with broad in vitro and in vivo cytotoxic activity. Methods: The new isosteres (7b-7h, 8a and 9a) were evaluated against HL-60, OVCAR-8, HCT8 and LUCENA tumor cell lines, using cytotoxic test of MTT. The tubulin polymerization assay was performed using a tubulin polymerization assay kit from cytoskeleton® and by CEREP employing a single concentration of 10 μM. Binding mode at β-tubulin colchicine binding site was stablished by blind molecular docking studies. Results: LASSBio-1920 (7h) was identified as the most potent cytotoxic compound with IC50 values ranging from 0.75 nM to 11.5 nM, although it was inactive against MDR tumor cell line LUCENA (IC50 = 80 μM). This compound presented remarkable cytotoxic selective index in comparison with CA4 and LASSBio-1586. Its ability to modulate microtubule polymerization was confirmed and its mode of interaction with colchicine binding site in β-tubulin was demonstrated. Conclusion: Compound 7h is a new isostere of LASSBio-1586 that displayed potent cytotoxic activity and better cytotoxic selectivity index and has been shown to interact with DAMA-colchicine in its co-crystal with β-tubulin.

Background: Nano-drug delivery systems as mesoporous silica nanoparticles (MSNs) with unique properties have the potential to improve drug efficacy. The purpose of the present study was to design of CLM loaded MSNs-NH2 to improve the physicochemical properties and antibacterial activity with enhancement delivery to infected tissues. Methods: A large pore amine functionalized MSN (MSNs-NH2) is described here to facilitate delivery of clarithromycin (CLM) as an antibacterial drug and enhance the efficacy against Gram positive and Gram negative bacterial samples. Prepared particles were characterized by Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), nitrogen adsorption/ desorption isotherms, Fourier Transform Infrared (FT-IR) spectroscopy and X-ray Diffraction (XRD) spectroscopy. The antimicrobial activity was evaluated by agar well diffusion and broth dilution methods. Therefore, the biodistribution of FITC-MSNs was investigated by measure the NIR intensity fluorescent of fluorescent images from whole animal and dissected organs of NMRI mice. Results: The results showed that the CLM loaded MSNs-NH2 (CLM/MSNs-NH2) were successfully prepared having good payload and pH-sensitive drug release kinetics. The antimicrobial investigation against Staphylococcus aureus and Escherichia coli was showed better performance of antimicrobial activity of these nanoparticles. In vivo and ex vivo fluorescent imaging investigation on NMRI mice were shown that FITC-MSNs-NH2 accumulated in the liver and kidney and notably in lung tissue. Conclusion: The CLM/MSNs-NH2 exhibited higher antimicrobial activity and enhanced the possibility of microbial infection therapy especially at respiratory infections.

Background: Aldose reductase is the key enzyme in the polyol pathway, it is implicated in the development of complications associated with diabetes. Objective: The aim of this review is to classify the medicinal plants and their phytoconstituents used in the inhibition of aldose reductase. Methods: We reviewed 83 papers published between 1997 and 2015 (PubMed and Sciencedirect). All the molecules structures were provided in ChemDraw software. Results and Conclusion: In this work we have listed the experiments that have showed therapeutic effect of aldose reductase inhibitors against complications associated with diabetes. We concluded that aldose reductase inhibitors have common components that are responsible for their inhibitory activity. Quercetin, Luteolin 6-C-(6´´-transcaffeoylglucoside), 1,5-di-O-caffeoylquinic acid, Quercetrin, 3,5-Di-O-caffoeylquinic acid, chlorogenic acid, 3,4,5-tri-O-caffeoylquinic acid, kuraridin, Methyl-3,5-di-O-caffeoylquinate, 3, 5-di-Ocaffeoylquinic acid, isoquercitrin, kaempferol-3-O-[2", 6"-di-O-(E)-p-coumaroyl]-β-D-glucopyranoside, desmethylanhydroicaritin, kaempferol-3-O-[2", 6"-di-O-(E)-p-coumaroyl]-β-D-galactopyranoside, casuariin, casuarinin, Luteolin, Methyl-3,5-di-Ocaffeoylquinate, Lavandulylkaempferol, 3,5-di-O caffeoylquinic acid methyl ester, kushenol C, and Desmethylanhydroicaritin showed significant inhibitory potential of aldose reductase.