Current Bioactive Compounds - Volume 14, Issue 4, 2018

Background: The phophatidylinositol 3-kinase (PI3K) pathway is critical in regulating diverse cellular functions and its deregulation is associated to one third of human cancers. Therefore, several PI3K inhibitors have been developed with many of these entering preclinical and early clinical assessments. Structure based design has led to the development of broad array of agents including dual inhibitors of PI3K and mTOR, pan-PI3K inhibitors and isoform specific inhibitors for cancer therapy. However, as we move towards deeper clinical assessment, there are challenges with regards to therapeutic index, toxicity profile, overcoming feedback loops and the like. This review explores these classes of PI3K inhibitors, their strategies and progress in clinical assessment. Method: A structured search of bibliographic databases was undertaken for peer-reviewed literature using a focused review query. The quality of retrieved articles was assessed using standard tools. The contents of the screened articles were ananlyzed to deduce interventions and findings extracting the quintessence in a conceptual framework. Results: A total of 104 papers have been referenced in the review that includes research papers, review articles, conferences/meetings proceedings and theses. The papers were studied and assessed according to our objective and classified for the refinement of the data to be extracted from them. This review identifies classes of PI3K inhibitors and the status of these inhibitors in terms of its clinical value. Conclusion: This review precisely talks about the finding and strategies of PI3K inhibitors in clinical development. Though the future of PI3K inhibitors against cancer might seem beaming, there are challenges to face regarding strategic development, clinical regimen, tolerability and limited monotherapy activity.

Background: Chitosan is a natural polymer which has limited solubility. Chitosan is capable of being modified using multiple alternatives for chitosan chemical modifications that provide different desirable properties. Method: N-methyl chitosan was successfully prepared and characterized. N-methyl chitosan was characterized by the FTIR, XRD, SEM, TEM, solubility, water content, and specific surface area. Antifungal activity against Candida albicans of N-methyl chitosan and gauze coated N-methyl Chitosan were also determined in this study. The antifungal activity tests were performed using agar diffusion and broth microdilution methods. Gauze coating with N-methyl chitosan was performed with a pad-dry-cure method. The SEM photograph of N-methyl chitosan clearly showed the rugged nature of particles. The TEM image shows that N-methyl chitosan produced from synthesis possessed round shape, with an average diameter of 50 nm. Results: The results of solubility in water, water content, and specific surface of N-methyl chitosan were 2.04 mg/mL, 18.12%, and 0.995 m2/g, respectively. Conclusion: N-methyl chitosan exhibited antifungal activity against C. albicans with MIC and MFC 0.75% and 1%, respectively. The maximum clear zone produced by gauze coated N-methyl chitosan occurred at 1% concentration of N-methyl chitosan, 60 seconds of dipping time, and 10 times of dipping frequency.

Background: The combretastatin-A4(1) is a phenolic cis-stilbene, natural product, and was isolated from the stem wood of the South African tree Combretum caffrum in the 1980. Combretastatin A-4 (CA - 4) has received special attention in the last few years. It showed strong antitumor activity by inhibiting tubulin polymerization and interacting with the colchicine binding site on tubulin. CA-4 also acts as Vascular Disrupting Agent (VDAs), and preferentially cut off the blood supply of immature tumors leading to their death. So we designed, synthesized and screened the anticancer activities of pyrazole amides fused combretastatin derivatives. Method: The anticancer activity of the compounds was determined using MTT (3-(4, 5-dimethylthiazol- 2-yl)-2, 5-diphenyl tetrazolium bromide) reduction assay. Results: The compounds 11b, 11c and 11d exhibited potent anticancer activities than the standard drug doxorubicin against three cancer cell lines A375, MCF-7 and Colon-205 with IC50 values ranging from 0.18 μM to 3.78 μM. The compounds 11g, 11h, 11i and 11j also showed potent anticancer activities than the positive control doxorubicin against A375 with IC50 values of 1.78 μM, 0.34 μM, 2.67 μM and 1.67 μM, respectively. Conclusion: From these results, the compound 11d was identified as a promising drug lead which showed promising anticancer activity with IC50 value of 0.18 μM towards A375 breast cancer cell line as compared to the standard drug doxorubicin (IC50 value 5.51 μM).

Background: Using Multi-Walled Carbon Nanotubes (MWCNTs) as a drug delivery system, can avoid the need for solvents and preventing drug precipitation in aqueous solution. Soyasapogenol B (SSB) acts as an important therapeutic agent owing to its numerous reported biological activities. Hence, this work deals with preparation and characterization of SBB loaded onto functionalized MWCNTs with tetraethyl orthosilicate (TEOS) and/or chitosan. Method: SSB was immobilized onto functionalized MWCNTs using miniemulsion technique. Moreover, niosomes were utilized to encapsulate the prepared systems. The formulations were analyzed by Fourier Transform Infrared Spectroscopy (FTIR), Transmission Electron Microscope (TEM) and particle size distribution analysis. In vitro release profiles of loaded SSB particles were carried out and kinetics of release were also studied. In vitro cytotoxicity of the prepared materials was examined and evaluated by SRB assay using different human cell lines such as normal melanocytes (HFB4), and carcinoma breast and liver (MCF7 and HepG2, respectively) in comparison with the standard doxorubicin. Results: SSB loaded materials exhibited successful encapsulation in niosomes, resulting in sustainable in drug release. Study of kinetics of release revealed presence of several complex factors affecting SSB release. Mathematical processing of the in vitro release data showed that the release of SSB from niosomal formulations obeyed more than one model. The second order and Higuchi's models were the most fitting models in case of presence of chitosan or TEOS, respectively. While, all formulations exhibited low cytotoxic properties on all tested cell lines. Conclusion: FTIR, particle size and TEM analysis confirmed that SSB was successfully loaded onto functionalized MWCNTs. Moreover, the different niosome formulations based on functionalized MWCNTs were prepared with sustainable SSB release in. The cytotoxicity could be minimized in case of chitosan and TEOS functionalization.

Background: The identification and quantification of quercetin in tropical fruits could be an incentive to consume these fruits as health promoters. The purpose of this study was to identify and quantify the levels of quercetin in tropical fruits extracts, and then select the extract with the highest levels of quercetin, in order to synthesize nanoparticles using cashew gum as core material. Method: The detection and quantification of quercetin of pulps and by-products of tropical fruits were performed using HPLC. The extraction of cashew gum (core material) was performed in order to synthesize the particles, using the extract that presented higher content of quercetin. The nanoparticles were submitted to characterization (particle size, X-ray diffraction, infrared spectroscopy, color, phenolic compounds, rheological behavior, antioxidant and antimicrobial activity). Results: The Surinam cherry and mango by-products in addition to the mombim, acerola and Surinam cherry pulps were found to have the highest levels of quercetin. The Surinam cherry by-product was selected to synthesize the cashew gum nanoparticles. Nanoparticles (Surinam cherry and standard quercetin) have similar particle size, between 4.34 and 6.01nm. The Surinam cherry nanoparticle had higher levels of phenolic compounds and similarly high antioxidant activity compared to control nanoparticles. The samples showed a pseudoplastic behavior. The Surinam cherry nanoparticle synthesized with cashew gum had lower minimum inhibitory concentration than pure fruit extract for Salmonella enterica. Conclusion: The nanoparticles with Surinam cherry by-product extract can be included in food products for higher level of bioactive compounds and as natural preservative.

Background: Interest in novel sources of edible and vegetable oils have been growing due to the growing population and its accompanying energy needs. The present study investigates the physicochemical characteristics, the antioxidant property and antibacterial activity of the vegetable oil extracted from Alocasia fornicata collected from Mizoram, India. This vegetable oil could potentially serve as a highly valuable and cost-effective supplement. Method: The fixed oil was extracted by using Soxhlet extractor and it was subjected to various preliminary phytochemical and physicochemical tests including specific gravity, viscosity, iodine number, acid value, saponification number and peroxide value. The antibacterial effects were estimated against different pathogenic strains such as Klebsiella pneumonia, Pseudomonas aeruginosa, Bacillus subtillis and Escherichia coli following disc diffusion method. Antioxidant activity of the fixed oil was evaluated by DPPH scavenging activity and compared against a standard ascorbic acid. Results: The yield of the fixed oil was found to be 8.39%. Results from various tests showed that the fixed oil exhibit a positive test for sterols and terpenoids, and also possess certain antibacterial and antioxidant properties. The scavenging property was also increased in a dose dependent manner. The IC50 value for the DPPH scavenging activity of the oil was also found to be 174.26 μg/mL. Conclusion: Crude vegetable oil was extracted from the spadix of Alocasia fornicata and its property was reported for the first time. The oil was found to exhibit properties that are typical of vegetable oils. The oil also possesses antioxidant and antimicrobial property which indicates its applicability in food and other industries.

Background: Rhizosphere is rich in microbial flora. Actinomycetes are a diverse group of organisms which are reported to produce antibiotics, vitamins, enzymes and plant growth promoting substances. Aim: The main objective of this study was to screen actinomycetes from the soil samples for the production of various enzymes that could be used for industrial applications. Method: Rhizosphere soils samples were collected from five different agricultural fields located in the Kolathur village, Tamil nadu, India. Thirty isolates were isolated and designated as VITMS1-VITMS30. The maximum number of isolates (43.3 %) was obtained from the rhizosphere soil samples of brinjal field and maximum number of isolates was isolated on starch casein agar (90%). The isolates were characterized morphologically in ISP media 1-7, Starch casein agar, Bennet agar and AIA, respectively. Results: The isolates were screened for eight different enzymes – α-amylase, protease, gelatinase, chitinase, lipase, DNase, cellulase and urease. From the results observed, all the thirty isolates showed positive α-amylase, lipase and gelatinase activity. All the isolates exhibited cellulase activity but in very low levels. Out of 30 isolates, 19 isolates exhibited protease activity; 24 isolates were positive for DNase activity; 10 isolates showed chitinase activity and 20 isolates showed urease activity. Conclusion: The soil samples from the kolathur village harbor diverse actinomycetes which exhibited good enzymatic activity.

Background: The use of antimicrobial agents affecting several biological targets at a time is one of the promising ways to fight multidrug-resistant bacterial strains, and hence it may serve to increase the efficiency of chemotherapy. Among the potential antimicrobial agents acting in this manner are redox-active complexes of transition metals with sterically hindered diphenols. Method: We synthesized the redox-active complexes of cycloaminomethyl derivatives of sterically hindered diphenols with Zn(II) ions and estimated the level of their antimicrobial activity against Gramnegative bacteria (Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens, Salmonella typhimurium), Gram-positive bacteria (Bacillus subtilis, Sarcina lutea, Staphylococcus spp., Mycobacterium smegmatis), moulds (Aspergillus niger, Fusarium spp., Mucor spp., Penicillium lividum, Alternaria alternata) and yeasts (Candida spp.) as compared to some standard antimicrobials. The compounds were characterized by means of physico-chemical and pharmacological screening methods. Results: The coordination core of these complexes is a tetrahedral chromophore [ZnO2N2], the phenolic ligands being coordinated in monoanionic form (phenolate). The MIC value (0.010-0.027 μmol·ml–1) comparable to those of standard antibiotics (tetracycline, streptomycin, chloramphenicol) was achieved by structural modification of the ligands and complexation with zinc ions. The derivatives of orthodiphenols and their Zn(II) complexes were found to be able to reduce cytochrome c - one of the key components of the respiratory chain of microorganisms (υ=0.3-1.8 nmol.min–1). The investigation of SOD-like activity provided a means to reveal potential SOD mimics (IC50=1.1-20.5 μmol.l–1) among the ortho-diphenols and their Zn(II) complexes synthesized, because IC50 for the native Cu, Zn-SOD is 0.1 μmol·l-1. Conclusion: The correlation between the antimicrobial activity of these compounds and their reducing ability deserves particular attention since they possess both antioxidant and antimicrobial activities.

Background: The present manuscript describes the synthesis of 3,3-diphenyl propionic acid derivatives. The key intermediate 3,3-diphenylpropionyl chloride was synthesized by the reaction of 3,3-diphenyl propionic acid and thionyl chloride. The 3,3-diphenylpropionyl chloride was further subjected to reaction with various aromatic secondary amines in the presence of potassium carbonate in acetone. Method: After synthesis of compounds, the synthesized compounds were characterized by their IR, 1HNMR, Mass spectral data and elemental analysis. These derivatives were screened for their analgesic activity (Hot plate and tail flick method) and anti-inflammatory activity (Carrageen induced rat paw edema and Egg albumin induced rat hind paw oedema method) by using Diclofenac sodium and Indomethacin as standard drugs, respectively. Results: The compounds AK-5 and AK-3 exhibited significantly potent anti-inflammatory and analgesic activity (two to three times) when comparison was made with control group. The response of promising compound (AK-5) for analgesic and anti-inflammatory action was highest among all the test compound and was almost similar to the standard compounds (Indomethacin and Diclofenac Sodium). Conclusion: The findings of this work verify the potent action of AK-5 compounds as analgesic and anti-inflammatory activity in experimental animals.

Background: Salvia verbenaca is a Mediterranean plant currently belonging to the Lamiaceae family. The plant is widely distributed in Morocco and is widely used in Moroccan traditional folk medicine as a cholagogue, antiseptic, diuretic and astringent. The crushed or chopped fresh leaves are also applied in poultices on wounds and emptied abscesses to facilitate their healing. The aim of this study was to assess the effect of three Salvia verbenaca extracts (hexane, ethyl acetate, n-butanol) on healing of burns and to compare the obtained results with that of silver sulfadiazine (SSD) in rats. Method: A deep second degree burn injury was thus induced by a hot metal cylinder on each rat under standard burning procedure. The burns were daily treated with a cream containing the cream base (group I) constituting the negative control, one of the three explored extracts (groups II, III and IV) and SSD (group V) constituting the positive control. The effects of the treatment were assessed through the burns surface determination until day 18. Histological parameters were assessed after skin histopathology at the end of the experiment. Result: The obtained results showed an accelerated healing process for rats treated with Salvia verbenaca extracts. Thus on day 9 of the experimental study, the observed healed areas were 29.17% (base), 44.34% (hexane), 47.55% (ethyl acetate), 49.16% (n-butanol) and 41.09% (SSD). These results showed that the explored extracts were as efficient as SSD which is the most widely used topical treatment against injury. Moreover, the Salvia verbenaca n-butanol extract was more efficient than SSD. At the end of the experimental study, the best observed result was obtained with the n-butanol extract which remains more efficient than SSD. The histological investigation conducted at the end of the experimental study showed that the studied three Salvia verbenaca extracts significantly increased re-epithelialization in burn wounds, compared to that treated with SSD. After treatment with Salvia verbenaca extracts the epidermis was close to the normal structure. Conclusion: Our results indicate thus that Salvia verbenaca has good healing effects in burning animals. The plant extracts accelerated the wound healing rate and shortens healing time compared to those treated with SSD in burned rats. The results of this study raise the possibility of a potential efficacy of the Salvia verbenaca extracts in accelerating the healing of burn injuries. Based on the results of this study, it is likely that extracts of Salvia verbenaca could lead to shorter treatment of burned patients compared to SSD.

Background: The benzofused six membered ring lactams is the part of the core structure of various pharmaceuticals, natural products, agrochemicals and active components of various dyes. The failure to control the microbial infections and the rise in the rate of resistant to antimicrobial agents, there is a strong need to develop new antimicrobial agents. In the current study, we synthesized some benzofused six membered ring lactams as a trial to obtain valuable precursors for the discovery of future antimicrobial drugs. Method: Syntheses of benzofused six membered ring lactams (4a-c and 5a-c) were reported via Beckmann rearrangement on indanones oximes as well as on indanones oxime tosylate. Structures of all products were well characterized by the rigorous analysis of their IR, 1H NMR, MS and elemental analysis. The in vitro antimicrobial activities of all the synthesized compounds 4 and 5 were determined against Gram-positive, Gram-negative bacteria and the fungal species Candida albicans using broth macrodilution method. Results: The Beckmann rearrangement of 3-substituted indanone oximes and indanone oxime tosylate were studied and thionyl chloride in case of indanone oximes as well as AlCl3 with oxime tosylate were identified the best catalyst. Bacterial growth inhibition was observed with bicyclic lactams although their MIC values were higher than ampicillin. The significant inhibitory effects were shown by majority of compounds with MIC values 125-250 μg/ml. Antifungal activity of bicyclic lactam derivatives was observed against C. albicans. However, MICs values of all tested compounds were higher compared to standard antifungal agent miconazole. Conclusion: After screening many Beckmann conditions, thionyl chloride condition in case of indanone oximes was found the best Beckmann condition whereas with oxime tosylate, AlCl3 was found the excellent catalyst. All synthesized benzofused six membered ring lactams were screened against Grampositive, Gram-negative bacteria and the fungal species Candida albicans using broth macrodilution method and concluded that new bicyclic lactams seem to be valuable precursors for the discovery of future antimicrobial drugs.

Background: The synthesis of novel Mannich bases of nitro alkanes utilizing mono- and diamino sugar is abundant in the literatures. The new bases have been successfully synthesized and fully characterized. Biological investigations, particularly cytotoxic activity of our novel compounds were made against some cancer cell lines. With an attempt to improve the anticancer activity we decide to include the indole moieties (well known as anticancer agent) along with nitro function. Method: Investigation of the synthesized derivatives and studying their cytotoxicity against a range of cancer cell lines; such as Hep G2 (liver hepatocellular carcinoma), PC3 (human prostate cancer cells), HCT116 (human colorectal carcinoma), MCF-7 (breast cancer cell lines) and A549 (human lung carcinoma) revealed an inhibitory effect ranged from potent to weak activity in comparison with Doxorubicin; a well-known currently used drug for treatment of several types of cancer. DNA-damage determination was further explored for HepG2 cell lines that previously treated with the most active derivatives using Comet assay (SCGE). Results: Accordingly some compounds showed good activity against A-549 and HepG2 cancer cell lines in comparison with the well-known cytotoxic drug [Doxorubicin]. As a result the current research introduces novel compounds expected to serve as lead structures of potential therapeutics for cancer. Conclusion: The present paper deals with Mannich reaction of nitro methane and/or nitro ethane with formaldehyde and well known sugar mono-/di- amines result in novel nitro-heterocycles polyhydroxy Mannich basses of type 4, 5 and 9-12. Some new polyhydroxy nitro-Mannich basses have been investigated for its reactivity such as reduction, acetylation and condensation afforded structures variety. Indole ring has been introduced with the nitro functional to enhance the anticancer activity through some condensation reactions with nitro alkanes. The synthesized compounds have been confirmed by different means of analytical and spectral data. Biological investigations, particularly cytotoxic activity of our novel compounds were made against some cell lines [A-549, MCF-7, HCT-116, HepG2 and PC3], in comparison with the well-known cytotoxic drug [Doxorubicin] to discover their impact as new inhibitors in cancer therapy. DNA-damage determination was further explored for HepG2 cell lines that previously treated with the most active derivatives 6 and 7, using Comet assay (SCGE). As a result of all preceding examinations, we introduce novel compounds which expected to serve as lead structures for new series of potential therapeutics for cancer.

Background: Cancer is one of the major health and socio-economic problems of the world even though extensive progress has been made in terms of early diagnosis and cure. The research for new anticancer drug development with more effective treatment is a field of utmost importance in current drug discovery. Method: Molecular Hybridization (MH) strategy has been adapted for the rational design of new ligands, where pharmacophoric sub-unities in the molecular structure of two bioactives will lead to the design of new hybrid architectures. All the synthesized compounds (3a-z) were evaluated in HeLa and MCF-7 cell lines for their anticancer activity and compared against H9C2 normal cells. Results: As expected, among the tested compounds, 3a, 3d, 3g, 3j, 3m and 3s exhibited highest activity with GI50 value of 1.72 μm, 2.10 μm, 4.26 μm, 2.43 μm, 5.11 μm and 4.34μm in HeLa cells and 1.86 μm, 2.50 μm, 5.20 μm, 4.40 μm, 6.14 μm and 5.30 μm in MCF-7 cells respectively. We also found that the compounds were non-toxic to H9C2 cells up to 20 μM. Conclusion: Preliminary structure-activity relationship studies revealed that compounds with para-Cl substituted phenyl and 5-Cl substituted indole on diazepine ring proved to be more potent.

Background: Tuberoinfundibular Peptide of 39 (TIP39) is a neuroendocrine hormone, potentially acting through parathyroid hormone receptor 2 receptor (PTH2R) abundantly expressed in brain. Objective: This study aimed to evaluate the neuroendocrine role of TIP39 in chronic unpredictable mild stress (CUMS) induced depression and to elucidate its underlying mechanism. Method: The depression was induced in rats by CUMS for a period of four weeks. TIP39 was administered through intracerebroventricular (ICV) route at doses (1 & 10 nmol/rat) for four weeks on alternate days, parallel with the daily exposure of stress. At the end of the treatment period, animals were evaluated for sucrose preference, behavioral, biochemical and oxidative changes. Further the molecular mechanism of anti-stress activity of TIP39 confirmed through gene expression study. Results: TIP39 administration significantly reversed the CUMS induced increased immobility time in depressive rats and increased plasma corticosterone as well as decreased open-field activity and sucrose consumption. CUMS lowers the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) and elevated the production of malondialdehyde (MDA) in hippocampus and prefrontal cortex, which was reversed by the administration of TIP39. Moreover, TIP39 could effectively reverse alteration in interleukin 6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in brain tissue. Conclusion: Chronic ICV administration of TIP39 alleviated the behavioral deficits of chronic unpredictable mild stress, consanguinity to its concurrent modulatory repercussion on hypothalamic pituitary adrenal axis, inflammation, and oxidative courses.

Background: DNA polymerases and topoisomerases are proteins that play a vital part in DNA metabolism such as replication, transcription, recombination, and chromosome segregation during mitosis. For this reason, these enzymes are appreciated targets for the development of cancer chemotherapeutic drugs. Method: All compounds evaluated in this work were obtained under the conditions and using the reagents described in the Schemes (1-3). Polymerase Chain Reaction (PCR): Sample stock solutions were prepared at a concentration of 10 mM in dimethyl sulfoxide (DMSO) using 1 ml as a final volume. The PCR master mix consisted of 2.5 μl of PCR Buffer (40 mM Tris-acetate, pH 8.3), 0.5 μl of MgCl2 at a concentration of 15 mM, 2.5 U Taq DNA polymerase, 2.5 μl of each oligonucleotide primer at a concentration of 100 mM, 0.5 μl of each deoxynucleotide triphosphates (dNTP) at a concentration of 10 mM and 0.1 μg/ml of DNA template. Topoisomerase I activity was determined by relaxation of supercoiled pBr 322 plasmid DNA. The reaction mixture in 20 ml contained 35 mM Tris-HCl, pH 8, 72 mM KCl, 5 mM MgCl2, 5 mM DTT, 5 mM spermidine, 0.01% bovine serum albumin, 0.64 mg/20 ml supercoiled pBr 322 DNA, 1.5 U human topoisomerase I and 1 ml of test compound diluted with DMSO. Results: Faithful replication of DNA molecules with the intervention of DNA polymerases and topoisomerases is essential for genome integrity and correct transmission of genetic information in all living organisms. For this reason, DNA polymerases and topoisomerases have emerged as important cellular targets for chemical intervention in the development of anti-cancer agents. Herein we report the semisynthesis of resveratrol derivatives and similar compounds and their biological activity against Taq DNA polymerase and topoisomerases. Compound 4 was the most active against both enzymes with IC50 values equal to 18.56 and 28.37 μM, respectively. Additionally, compounds 3 and 5 showed interesting activity against Taq DNA polymerase with IC50 values equal to 76.89 and 71.65 μM, respectively. Conclusion: In summary, one compound (4) was found to have excellent inhibitory activity against human topoisomerase I and Taq DNA polymerase. This compound can be a leading molecule for the development of original anticancer treatment and an excellent instrument to explore DNA polymerase and topoisomerase activity.