Current Bioactive Compounds - Volume 13, Issue 3, 2017

Background: Plants and their products have been used to treat human diseases since time immemorial. Ursolic acid (UA), a pentacyclic triterpenoid found in a wide range of plants, possesses a plethora of biological traits, such as anti-inflammatory, anti-oxidative, and anti-cancer properties. Extensive research has been undertaken to elucidate the biological, pharmacological, and clinical roles of UA in the treatment of human diseases. However, the mechanism and molecular targets by which UA acts has not yet been clearly elucidated. Methods: This review summarizes the studies, findings, and data related to UA with reference to diseases of the liver, heart, brain, and muscles, fertility, and cancer. Results: Among 89 papers included in this review, 18 papers defined the anticancer property of UA against numerous cancers and indicated the molecular pathways and strategies involved in the therapeutic action. Eleven papers showed protective role of UA in liver diseases including its capacity to enhance liver regeneration. Ten papers included facts related to beneficial effect on cardiovascular diseases and body homeostasis, and showed UA as a remedy for heart diseases. Nine papers demonstrated the medicinal value of UA against brain and neurological disorders. UA showed healing effects in skeletal muscle diseases such as muscle atrophy in 6 papers. Seven papers defined anti-diabetic and anti-nephropathy characteristics of UA. Antimicrobial properties of UA were presented in 10 papers. Six papers showed the ability of UA to cure obesity and hyperlipidemia. In addition, 4 papers revealed negative effects of UA that inhibits sperm motility during spermatogenesis. This review identifies the multifarious therapeutic activities of UA in numerous health disorders including cancer. Conclusion: Summarizing and correlating the published data on UA facilitates better understanding of UA on its potential as a therapeutic agent.

Background: Quinoxaline is versatile ring systems which possesses a wide range of physicochemical and biological activities. This heterocyclic nucleus is becoming an attractive target for extensive research due to its inherent diverse properties. Various efficient, mild and eco-friendly methods have been developed for the preparation of quinoxaline derivatives in high yields. Here, we have highlighted some convenient methods for quinoxaline synthesis along with their novel biological properties. Methods: Various novel, mild, eco-friendly and efficient methods have been developed for the preparation of quinoxaline derivatives in high yields. Recent development in synthesizing quinoxaline derivatives includes the application of principles of green chemistry as it is pollutant free and environmental friendly. The present review highlights some convenient methods of synthesis based on both organic and green approach and also its wide varieties of biological activities which would be very much promising in the field of medicinal chemistry. Results: More than eighty papers have been included in the manuscript. The clear synthesis and biological profiles have been highlighted in this manuscript. I believe all these results must be useful for the current development in quinoxaline chemistry. Conclusion: Quinoxaline derivatives have been emerging as important chemical moieties for last twenty years. Recent development in synthesizing quinoxaline derivatives includes the application in principles of green chemistry as it is pollutant free and environmental friendly. Here, in this review, we described the pathways which were based on both conventional and green approach. The literature survey also reveals that quinoxaline and its derivatives show a wide variety of biological activities such as anticancer, antiviral, antimicrobial, anticonvulsant and antichagasic, which would be very much promising in the field of medicinal chemistry.

Background: Analysis of different types of cancer such as breast, prostate and ovarian carcinomas have shown that protein kinase B is overexpressed, making this an important target in drug design studies. We use various models of structure-based drug design to investigate the PKB target screening half a million compound databases. Genetic algorithms and grid generation are the bases used in the docking procedures in order to select the best hits that exhibit chemical, electronic and structural characteristics that promote the appropriate interactions with the desired target. Toxicity is predicted using databases implemented in software that create models based on chemical structures taking into consideration the toxicophoric groups. A wide variety of pharmaceutical relevant properties is determined in order to make decisions about molecular suitability. The molecular dynamics simulations indicate that the inhibitor is stable in the docking site. After screening and analysis, we are able to suggest the most promising lead compound. Methods: The Structure-based virtual screening focuses on the three-dimensional information of the therapeutic target. Docking procedures with the crystal structure of PKB inhibitor (PDB code 2X3D) in pH = 7.0 using GOLD 5.1 (www.ccdc.cam.ac.uk) and GLIDE 2014-3 (www.schrodinger.com) select the compounds that have the best interaction with the target to find new potential compounds, which are able to inhibit PKB. The study works with different databases, such as Maybridge, Zinc and Chembridge. Simulations of molecular dynamics with Discovery Studio (www.accelrys.com), ADME predictions with QikProp (www.schrodinger.com) and toxicity prediction with Derek (www.lhasalimited.com) were the next and final steps. Results: From a chemical universe of half a million compounds from several databases it was possible to select 4 top chemical structures with good inhibiting profile for PKB, with suitable ADME/Tox properties, using a low cost strategy made possible by structure-based virtual screening techniques Conclusion: Virtual screening strategies, such as docking have shown to be an important tool in the search for new promising drugs in cancer. ADME/Tox analysis allows discarding problematic inhibitors at an early stage of the Drug Discovery process. From a chemical universe of half a million compounds from several databases it was possible to select 4 top chemical structures with good inhibiting profile for PKB, with suitable ADME/Tox properties, using a low cost strategy made possible by structurebased virtual screening techniques.

Background: Triazole based drugs are widely used in cancer patients for the treatment of lifethreatening invasive fungal infections. A recent report on the usefulness of 1,2, 3- triazole scaffold for the inhibition of tyrosine kinases stimulated our curiosity to design new molecules based on this moiety. Methods: A series of new heterocyclic compounds containing 1,2,3 triazole moiety tethered to substituted vanillin or isovanillin were synthesized and analysed for their anticancer activity. The cyclopentyl/ cyclohexyl ethers derived from vanillin and isovanillin were subsequently treated with MeMgI to give the carbinols. Reaction of these carbinols with TMSN3 and ZrCl4 as Lewis acid gave the desired azides. Click chemistry on azides with diverse acetylenes furnished the triazoles. The new triazole hybribs were screened o against 60 human cancer cell lines at a 10μM dose for their potential anticancer activity. Results: The two active compounds (8a, 10a) showed strong inhibitory effect against different cell lines, with highest inhibition against breast cancer panel. To elucidate the underlying molecular mechanisms, these compounds were examined for their clonogenic potential and anchorage-independent growth of estrogen receptor positive (MCF7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDAMB- 468) breast cancer cells and investigated for induction apoptotic pathways. Conclusion: The outcomes from the current study will add much to the existing knowledge of the breast cancer research. This provides a rewarding conclusion and opens the way for future researchers to design and synthesize the novel active compounds against breast cancer.

Background: Since the introduction of Gleevec in 2001, protein kinases have been explored as therapeutic targets for the treatment of several cancers. Specifically, anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase belonging to the insulin receptor superfamily, plays an important role in anaplastic large-cell lymphomas (ALCLs) and non-small cell lung carcinomas (NSCLCs). The first inhibitor of ALK, Crizotinib, was launched in 2011 but, due to the rapid emergence of resistance, the development of new inhibitors is still necessary. Herein we describe the use of in silico methods to identify potential ALK inhibitors, with putative low toxicity and favorable pharmacokinetic profiles. Method: We used the 3-D structures of seven inhibitors of ALK to generate a pharmacophore model, which was screened against a database of commercial substances. The resulting 75,000 compounds were then analyzed by shape-fitting rigid body docking and the top 10% scored compounds were rescored via flexible ligand-docking. The ten best-ranked ligands had their most probable binding modes predicted with the aid of the analyses of the molecular interaction fields. Predicted toxicities and pharmacokinetic properties were then studied in order to identify the most promising candidates for ALK inhibitor therapy. Results: From the ten best-ranked compounds, six were predicted to perform H-bonds with the amino acids bearing the binding site of ALK: compounds 8, 10, 12, 13, 15 and 17. Favorable druglikeness scores were observed for three of these compounds, 10, 12 and 15, and for other three compounds: 11, 14, and 16. Alerts for toxicity were observed for 11 (tumorigenicity), 14 and 15 (severe and moderate teratogenicity, respectively). Conclusion: From the ten best-ranked ligands, two compounds (10 and 12) seem to be particularly attractive due to the good predicted binding affinities, adequate pharmacokinetic profiles and low toxicity. Also, they may be subjected to pharmacophoric and bioiosteric replacements to produce analogues with reduced structural complexity/better synthetic accessibility, two central issues in lead optimization and scale up synthesis.

Background: The present discussion reports the synthesis of a series of novel derivatives 2, 4-disubstituted -1, 5 -diphenyl substituted -1-H-imidazole derivatives and their molecular modeling studies as antitubercular agents. Methods: Various substituted aromatic aldehydes (0.01 mol) and anilines (0.01mol) reacted in the presence of methanol and glacial acetic acid into Schiff bases. Schiff bases were treated with TOSMIC (0.01 mol), dioxane, methanol and K2CO3 to give various key intermediates such as 1, 5- diphenyl substituted -1 -H- imidazole derivatives. 1, 5- diphenyl substituted -1 -H- imidazole derivatives which are utilized to develop further derivatives. Results: The synthesized derivatives were characterized using IR, 1HNMR and Mass spectra. Compounds A-IVn,B-IVe,B-IVf, B-IVg, B-IVj, B-IVk, B-IVm, B-IVn, C-IVa, C-IVc, exhibited the potent antitubercular activity at (1.6 μg/ml to 100 μg/ml) concentration. The results indicated that compounds containing diphenyl substitution with 2–Fluro, 3-Nitro, 2-Chloro, 4-Bromo, 3-Hydroxy,4- Methoxy,4-Nitro, 3-Chloro, 4-dimethylamino and 2,4-dinitro showed potent anti-tubercular activity. QSAR analysis revealed the importance of electronic and steric parameters in anti-tubercular potential of imidazole derivatives. Conclusion: Developed Imidazole derivatives showed promising anti-tubercular activity, further development of imidazole derivatives using QSAR and pharmacophore modelling will result in the development of potent anti-tubercular derivatives in the future.

Background: Emergence and reemergence of infectious diseases are major problems in public health and global economics. Due to selective pressure and widespread use of antifungal drugs, there have been increasing reports of antifungal resistance. Thus, new therapeutic drugs and/or approaches are needed to improve the management of these diseases and to overcome these problems. Our Bacillus and Brevibacillus sp. possess non - peptide group of compounds that may be good candidates for use as antifungal agents. Methods: 7 strains of Bacillus and Brevibacillus sp. were isolated from different habitats of Jabalpur, central India and identified by 16S rRNA sequencing. These strains were tested for antifungal activity against the test pathogens, viz. Alternaria solani (MTCC 2101), Aspergillus niger (MTCC 404), Candida albicans (MTCC 1637), Curvularia lunata (MTCC 2030) and Fusarium solani (MTCC 3004). Aqueous extracts of each antifungal strain, showing antifungal activity, were tested for the presence of non - peptide compounds by GC-MS. Results: The 7 antifungal strains were identified as Bacillus anthracis B48, Bacillus cereus B46, Bacillus tequilensis B37 and B47, and Brevibacillus brevis B63, B86 and B87. Br. brevis B87 exhibited the maximum activity against all the pathogens and B. tequilensis B37 recorded the minimum. GC-MS profile of the extract of all the strains revealed a diverse array of non-peptide (prosthetic groups) compounds, but ketones and pyrroles were present in the highest concentrations. The non-peptide groups 3,6-Diisobutyl- 2,5-piperazinedione and Hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, present in higher concentration in Br. brevis B87, might be responsible for its maximum antifungal activity as compared to the other isolates. Conclusion: The ketones and pyrroles from our strains may have great antifungal potential and need to be exploited further in the management of fungal pathogens and diseases of humans, plants and animals.

Background: Dodonaea angustifolia is used in Ethiopian traditional medicine to treat malaria. The objective of this work was to conduct bioassay guided fractionation of the leaves of D. angustifolia using Plasmodium berghei infected mice. Method: The antiplasmodial activity of the extracts and pure compounds was evaluated using the standard Peter's four-day suppressive method. The structures of isolated compounds were elucidated using chemical and spectroscopic methods. Results: In this study, the ethyl acetate soluble portion of the 80% aqueous MeOH extract of the leaves significantly suppressed parasitaemia in Plasmodium berghei infected mice (80.28% at 150 mg/kg). Three active compounds which exhibited significant percent suppression of parasitaemia by 81% at 40 mg/kg, 80% at 50 mg/kg and 70% at 40 mg/kg, respectively were identified. These are the flavanone pinocembrin (1), the flavanol santin (2) and the clerodane diterpene 2-hydroxy-15,16-epoxyceloda- 3,13(16),14-trien-18-oic acid (3). Under similar conditions, chloroquine suppressed parasitaemia by 100% at 25 mg/kg. Chemical study of the ethanol extract of the leaves yielded 5,7,4'-trihydroxy-3,6- dimethoxyflavone (4), ent-16-hydroxy-labdan-3α,8β-dihydroxy,13(14)-en-15,16-olide (5) and 5,6,7- trihydroxy-3,4'-dimethoxyflavone (6). Compound 6 has not been reported before as a natural product. Conclusion: From the leaves of D. angustifolia, three compounds with significant antiplasmodial activities were isolated and characterized, with pinocembrin as the most active compound.