Current Bioactive Compounds - Volume 13, Issue 4, 2017

Background: Neoflavonoids comprise a group of compounds that have a C6-C3-C6 carbon skeleton and that naturally occur in higher plants from families Clusiaceae, Leguminosae, Rubiaceae, Passifloraceae, Asteraceae and Rutaceae. Objective: Neoflavonoids have drawn great interest lately due to their pharmacological and biochemical properties found in vitro and in vivo studies, which is attributed to the pattern of substitutions found in their basic chemical structure. Methods: This review was prepared by analyzing articles selected from Science Direct, Scopus, Pub Med, Web of Science and SciFinder. Results: Among other pharmacological activities, in vitro and in vivo studies have highlighted these compounds as promising bioactive molecules in the treatment of some parasitic neglected tropical infections (NTIs) such as malaria, leishmaniasis and American trypanosomiasis (Chagas Disease). Neoflavonoids have also showed activity against HIV-1 (human immunodeficiency virus type 1), and have been used to develop new molecules for the treatment of HIV/AIDS. Conclusion: Therefore, a more intensive research of neoflavonoids can provide inputs to discover and develop alternative therapies from new bioactive molecules. Thus, this review summarizes the results of studies involving neoflavonoids and their derivatives with therapeutic implications in the treatment of NTIs and HIV.

Background: Despite being known for their antibacterial activity, the oxazolidines are molecules with wide pharmacological action and may act as anticonvulsants, anti-inflammatory and antineoplasic agents. However, such activities have been poorly explored and only two oxazolidinic derivatives hit the market until now. Therefore, this review covers the main biological activities of oxazolidines, indicating which of the classes and substituents have the best biological results as well as the synthesis methodology used to obtain them. Methods: The search for bibliographic data was made using a question focused on the oxazolidine structure and their respective activities, besides using inclusion/exclusion criteria clearly defined. The selected papers were subjected to qualitative content analysis methodology to be used in this review. Results: The oxazolidines remain excellent candidates for antibacterial, presenting three compounds in clinical testing phase (Radezolide, Cadezolide and Sutezolide), besides being a good candidate as antitubercular agents. Other less explored activities have niches with a great therapeutic potential such as the oxazolidines acting on 5-HT receptors (anticonvulsant) and Zolmitriptan (anti-migraine), and also mefloquine-oxazolidine derivatives which may act as antineoplasic and antitubercular agents. Conclusion: This review summarizes the versatility and great therapeutic potential that oxazolidines can offer, reinforcing the need for further studies and investments for this class of molecules.

Background: Dermaseptin-01 (DRS-01) is an antimicrobial peptide isolated from the skin secretions of frogs from Phyllomedusa genus with potential antileishmania properties. Considering that the innate immunological mechanisms underlying the production of reactive oxygen and nitrogen species is essential in controlling infection by microorganisms, the effects of DRS-01 on the immune response still remain unknown. Methods: The effects of DRS-01 (1.0 - 256 µg mL-1) against promastigote forms of Leishmania amazonensis were evaluated, and then the IC50 value was obtained. The cytotoxicity assessment of DRS-01 by MTT assay, as well as the possible role of immunomodulatory mechanisms (phagocytic capability, and production of nitrite and hydrogen peroxide) were investigated on BALB/c peritoneal macrophages. Results: DRS-01 induced a concentration-dependent leishmanicidal effect at all times of incubation (24, 48 or 72 h). Besides, the 50% of cell viability was decreased at 32 to 128 µg mL-1 in macrophages incubated during 24 h in the MTT assay. The evaluation of immunomodulatory mechanisms demonstrates that DRS-01 (1.0 - 16 µg mL-1) increased the phagocytic capacity and the production of hydrogen peroxide, besides the decrease in the production of nitrite (8 or 16 µg mL-1). Conclusion: DRS-01 is a leishmanicidal compound acting as a modulator of the innate immunity of macrophages from BALB/c mice, reinforcing further studies concerning its potential biomedical applications in the treatment of leishmaniasis.

Background: Quantitative analysis of enzyme reactivity is a basic requirement for the development of precise diagnostic methods and drug discovery processes, and reduces the number of animal tests. Designed engineering proteins are preferred for developing effective synthesis methods for industrial uses. The specific affinity for an enzyme reaction can be analyzed in silico, but it is difficult to develop a general rule for the selectivity of the enzyme reaction because of a lack of sufficient data. The oxidation reactivity of pig and sheep D-amino acid oxidase (DAO) was quantitatively analyzed in silico. Methods: The unknown stereo structure of sheep DAO was constructed based on its sequence datum and the stereo structure of pig DAO. Stereo structures of new DAO and amino acid complex as well as an amino acid and inhibitor complex were optimized using the MM2 program. The reactivity was analyzed by further calculation of the atomic partial charge (apc) using MOPAC-PM5. Results: Conformation analysis of DAO and an inhibitor complex was achieved but not described the reactivity as the calculated energy level and the difference in enzyme-ligand interactions. The stereo structures indicated that the electron transfer (oxidation reaction) center of DAO is α-carbon. The calculated atomic partial charge of the targeted atoms using the PM5 program was found to be related to the relative oxidation reactivity (r2 = 0.84, n = 7). The inhibition of kojic acid was also quantitatively analyzed. The atomic partial charge was related to the inhibition ratio (r2 = 0.95, n = 4). Conclusion: Qantitative in silico analysis of the enzyme reaction of DAO was achieved with high precision. Inhibition of kojic acid was also quantitatively analyzed. However, the selective inhibition of pmercuric benzoic acid (HgBA) for glycine was not quantitatively described. Inhibition of pig DAO was clear, but that of sheep DAO was uncertain. The small size of glycine may enable its entrance into the reaction chamber of the sheep DAO structure whereas HgBA did not tightly contact the flavin ring of coenzyme FAD.

Background: Coumarins, possesing antimicrobial activity are often used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Molecular hybridization concept was used to design coumarin hybrid molecules. Synthesized molecules were evaluated for their invitro antibacterial activities. We designed Coumarin derivatives of diphenyl ether and oxadiazole. Most of the compounds showed antimicrobial activity against gram-positive as well as gram-negative bacteria. Methods: ADME properties of the molecules calculated by Qikprop program. It predicts both physically appropriate descriptors and drug like properties. Oxadiazole and diphenyl ether hydrazone derivatives of coumarin were designed by molecular hybridization concept. Designed molecules were synthesized and confirmed by spectral data; further synthesized molecules were screened for antimicrobial activity by using the REMA plate method. Results: We analyzed drug like properties with 44 physically relevant descriptors of coumarin derivatives by Qikprop, out of 28 ligands 14 all coumarin-oxadiazole derivatives structures exhibited allowed values for the properties analyzed and exhibited drug-like characteristics derived from Lipinski's rule of 5. Biological screening of coumarin-oxadiazole derivative of nitrophenyl 8g was active against both gram positive and negative bacteria. It was seen that electron withdrawing substituent such as nitro group was important for activity. For coumarin -diphenyl hydrazone derivatives, halogens chloro substituent also exhibited significant activity as compare to fluoro substituted compounds. The most active hydrazone derivatives were 6c and 6g with chloro and trifluoromethoxy substitution on benzene ring. In part B, fluoro substitution at aromatic ring had no effect on improvement of antibacterial activity. However it showed that electron withdrawing group were more active and exhibited significant improvement in the antibacterial activity. Conclusion: The efficient and instructive SAR study will provide deeper insight into further optimization of coumarin-oxadiazole and coumarin-diphenyl ether derivatives representing to promising leads for further exploration as antibacterial agents.

Background: In vitro-in vivo correlation (IVIVC) is a quantitative and reliable relationship between in vitro drug release and in vivo absorption, which is desirable for rational development and optimization of sustained release formulations. The present work demonstrates development and application of IVIVC for 150 mg sustained release tablets of bupropion hydrochloride. Methods: Two sustained release prototype tablets of bupropion were formulated and optimal dissolution method was developed with USP type 2 (paddle type, with sinker) apparatus operated at 100 rpm, using 900 ml of phosphate buffer (pH 6.8). Prototypes were evaluated to obtain in vitro data for IVIVC model development. Primary in vivo dataset for development of IVIVC model was the individual plasma concentration data from two arms of a three-way crossover study in 15 healthy volunteers post administration of the prototypes. The third arm was a reference formulation for external validation. Mean plasma concentration data of immediate release formulation from literature was used to compute the in vivo weighting function. Results: A deconvolution based approach was employed to generate in vivo input function (fraction drug absorbed). A linear correlation model was developed between fraction absorbed and fraction dissolved and was validated (internal and external) based on prediction error of pharmacokinetic parameters. The prediction errors were less than 10% for both internal and external validations, demonstrating the validity of developed model. Conclusion: A ‘level A’ IVIVC was developed and validated for bupropion hydrochloride and the model was successfully applied to select a prototype for pivotal bioequivalence study.

Background: Anthocyanins are water-soluble photo-protective compounds which rapidly degrade in aqueous environments. Stability as well as skin permeation and UV protection are of concern in the development of sunscreen products from anthocyanins. An anthocyanin complex (AC) was developed and tested for its feasible applications as a sunscreen in in vitro. Methods: Two sources of anthocyanins used as the main components of AC were aqueous extracts of Clitoria ternatea (CT) and Rosa damascena (RD). Total anthocyanins in solutions of AC, CT and RD, randomly sampled after storage at various pH and temperatures, were quantified by pH differential method. Cell viabilities of human keratinocyte (HaCaT) and human forehead fibroblast (HFF) exposed to AC were determined by MTT (3-(4,5-dimethylthiazol-2-yl-2-yl)-2,5-diphenyltetrazolium). In in vitro permeation tests, total phenolic contents permeated from AC, CT and RD through porcine skin were analyzed by Folin-Ciocalteu assay, and, the porcine skin was cross-sectioned for fluorescent stereomicroscopic photographing. The effects of UVA radiation on the skin were compared between pretreatment with AC and blank and subjected to ATR-FTIR spectroscopy (between 800 to 4,000 cm-1). Results: Total anthocyanins of AC in aqueous solutions were not affected by pH between 2-9 nor storage temperatures between 4-50ºC for 7 days, whereas those of CT and RD were decreased in pH- and temperature-dependent manners. AC was not cytotoxic to human keratinocytes and human fibroblasts up to 1 mg/ml. In vitro skin permeation of total reducing contents was AC < CT < RD, through porcine skin, of which fluorescent stereo-microphotographs revealed that AC accumulated in the uppermost layer, while CT and RD diffused in the deeper layers. ATR FTIR revealed that biochemical changes around the regions of hydroxyl groups, lipids and proteins in excised porcine skin exposed to UVA for 4 h were retarded by AC pretreatment. Conclusion: The potential of AC as a topical sunscreen has been demonstrated due to its noncytotoxicity to the skin cells, improved stability of total anthocyanins, and localization at the skin surface where it exerts UVA protection.

Objective: This study was accomplished to evaluate the in vitro antioxidant activity, in vivo antipyretic and the anti-inflammatory activities of the n-butanol extract of roots and aerial parts of Algerian Eryngium campestre L. Materials and Methods: The antioxidant properties were tested using DPPH radical scavenging and β- Carotene linoleic acid of various extracts from roots and aerial parts of E. campestre L., total phenolic and flavonoid contents were also determined. Furthermore, the anti-inflammatory and antipyretic activities of the n-butanol extracts were investigated on female wistar rats at the dose levels of 250 and 500 mg/kg body weight, using the egg albumin induced oedema and brewer's yeast induced pyrexia method respectively. Results: n-butanol extract of aerial parts had considerably higher antiradical activity with IC50 value of 16.140 µg/ml, and a good anti-inflammatory activity comparable to the standard drug diclofenac. Also, the n-butanol extract of roots possessed a better antipyretic effect (at both dose 250 mg/kg and 500 mg/kg) compared to the n-butanol extract of aerial parts. Conclusion: These results suggested that Eryngium campestre L. could be used to treat various inflammatory diseases.

Background: The antibacterial, antifungal and antiparasitic activities of some novel benzosultams and benzosultones in vitro systems are tested. The antibacterial activity has been tested against gram negative bacterium Escherichia coli (E. coli) and gram positive Bacillus subtilis (B. subtilis). The antifungal activity has been tested against an opportunistic pathogenic fungal strain namely Pichia guilliermondii SNP3S. The antiparasitic activity has been tested against filarial parasite Setaria cervi. The active compound 4,7-dimethyl-3,4,7,8-tetrahydro-3λ6-[1,2]thiazino[4,3-f]quinoline-3,3,8-trione was found to exert no toxicity when tested on rat peritoneal macrophage culture. The compounds show moderate to excellent biological activities. The molecular modeling has also been done to compare their inhibitory affinity on human matrix metalloproteinase 9 (MMP-9). Methods: The compounds were initially dissolved in DMSO (Merck, Germany) for making stock thereafter diluted in RPMI dissolved in Milli-Q water to yield desired concentrations (20-100 µg/ml) and used in the study. The commercially available antibacterial and antifungal antibiotics namely Ciprofloxacin and Fluconazole were dissolved in Milli-Q water whereas standard filaricide Ivermectin was prepared in DMSO. Before applying to the biological system, the solution of each compound was filtered through 0.22 µm membrane filters (Millipore, USA). Results: Among the tested ones, compound 8l was found highly active (inhibition zone: 20.5 mm for E. coli and 19 mm for B. subtilis) against the two different types of bacteria tested. In other side, compound 8a-d, 8h and 8i were found to exert some degree of antibacterial effect termed as moderately active. However, compound 8e, 8f and 8k were found to exert no effect on any of the microbes. Conclusion: In this study, we have tested the bioactivity of twelve synthesized compounds at a low dose (50 µg/ml) whereas cytotoxicity was tested at much higher dose (200 µg/ml). The main focus behind the bioactivity and cytotoxicity study was to screen a compound that serve as highly bioactive with low toxicity. Sultam 8l was found to exert minute cytotoxicity in rat peritoneal macrophage culture up to 200 µg/ml which is four times higher than its minimum inhibitory concentration (MIC) for antiparasitic (50 µg/ml) and twenty times than antimicrobial activity (10 µg/ml). Therefore, the active compound 8l may be considered as a possible therapeutic. The molecular modeling of these compounds reveals that they have significant and comparable inhibition affinity towards MMP-9 due to their negative electrostatic potential.

Background: Chromene, benzochromene and their derivatives have been studied extensively due to their biological and pharmacological activities. Benzochromene nucleus has been emerged as a promising and attractive scaffold in the development of potent antitumor agents. Objectives: Design a series of new 2-amino-4H-benzo[h]chromene derivatives and evaluated their antiproliferative activity against three human tumor cell MCF-7, HepG-2, and HCT-116. Materials and Methods: The 2-amino-4H-benzo[h]chromene-3-carbonitrile derivatives 3a-i were synthesized by reaction of 4-methoxy-1-naphthol 1 with α-cyano-4-substitutedcinnamonitriles 2a-i in ethanolic piperidine under reflux for 1 hr. Reaction of 1 with ethyl α-cyano-4-substitutedcinnamates 4a-g afforded ethyl 4H-benzo[h]chromene-3-carboxylates derivatives 5a-d,f,g and 6-methoxy-2-oxo-4-(4- methylphenyl)-2H-benzo[h]chromene-3-carbonitrile 6. The assignment structures 3, 5 and 6 were established on the basis of spectral data. Results: In this study, the anti-proliferative activity of the synthesized compounds 3a-i, 5a-d,f,g and 6 was examined in three human cancer cell lines, MCF-7, HCT-116 and HepG-2, using MTT colorimetric assay. Vinblastine and Colchicine were included in the experiments as a reference cytotoxic compound for the three cell lines.