Current Bioactive Compounds - Volume 15, Issue 1, 2019

Background: Pyrrolizidine alkaloids (PAs) are a group of plant secondary metabolites which protect the plants from biotic stresses by stimulating defense mechanisms as well as adaptability. The pyrrolizidine alkaloids widely occur in members of Boraginaceae family. This review paper describes about the structural properties of various PAs isolated from various Indian Heliotropium species and their biological and pharmacological activities. Methods: Authors surveyed the per-reviewed research, review papers and bibliographic databases and incorporated in this review paper. We have focused our attention on the answers of reviewed questions. The main themes and characteristics of reviewed papers have been described in this review paper. Results: Twenty three species of Heliotropium genus were reviewed critically and have included in this review paper. The review paper contains the critical information of ethnomedicinal properties of each species of Heliotropium genus, the occurrence of pyrrolizidine alkaloids, the biological and pharmacological properties of pyrrplizidine alkaloids. So many pyrrolizidine alkaloids and their N-oxides possess anticancer activity. Some PAs have demonstrated cytotoxic effects also. Conclusion: The findings of this review paper validate the significance of pyrrolizidine alkaloids, their occurrence and biosynthesis in Heliotropium species, as well as their biological and pharmacological properties.

Background: Bioactive compounds from microorganisms have been widely studied for several biological, therapeutic and pharmaceutical importances. Bacterial secondary metabolites have proven their worth as a prolific source of antibiotics, antifungal, antiviral, anticholesterol and immunosuppressant. The majority of inhibitors are secondary metabolites of varying chemical moieties produced by microorganisms among which actinomycetes are most important due to their tremendous diversity. Actinomycetes are most economically and commercially important prokaryotes known for their metabolic versatility. They have gained attention due to their ability to produce novel bioactive compounds with many applications. This review provides an overview on well-established actinobacterial bioactive compounds used as enzyme inhibitors for the treatment and management of diseases and their future perspectives. Objective: We focused on actinobacterial bioactive compounds which were reported to possess enzyme inhibition activity. An extensive search on well-acknowledged enzyme inhibitors was done by referring to peer-reviewed research papers. The papers were screened on the basis of the significance of research work done. Results: The research papers referred in this review article suggest the potential of bioactive compounds as therapeutically important enzyme inhibitors. The actinobacterial compounds were found to possess enzyme inhibition potential and could be developed into an antibacterial, antifungal, antimetastatic, antidiabetic and antihypertensive agent. These inhibitors were structurally elucidated and belonged to the class of peptides, proteins and pseudotrisaccharides. Conclusion: The findings of this review paper highlight the enormous potential of actinomycetes and bioactive compounds as enzyme inhibitors of therapeutic and pharmaceutical importance.

Bacterial infections remain a major threat to the world community in terms of both morbidity and mortality. Indeed, bacterial infections are accountable for millions of fatalities around the globe. Additionally, these bacterial infections represent a notable burden, in particular, for children living in less-developed regions of the world. There are a numbers of classes of antibiotics for the treatment of these complicated and uncomplicated infections. But most of them are struggling with the current challenge of resistance. Obviously, resistance to current antibiotic is a global issue as greatly caused therapeutic outcome and patient compliance. The current researchers are looking towards natural product specially plant-based product for effective and long term solutions. In this regard, alkaloids represent a very important therapeutic class of natural products with clinical significance. The review describes the antibacterial profile of plant based alkaloids. Alkaloid acts as an emerging therapy for bacterial infections by inhibiting a broad range of gram positive and gram negative bacteria that were mostly resistant to current therapies. It was concluded that these alkaloids could be useful and effective therapeutic alternative to existing therapies that are extensively facing challenges of resistance. The current need is to focus on the clinical and safety aspects of these reported preclinical studies. Thus, it could be expected that plant alkaloids will be the popular drugs of future.

Objective: Firstly, Deflazacort was synthesized in 1969 and has the structural similarity with cortisol. The present review is an attempt to summarize the updated information related to chemistry and pharmacology of Deflazacort. Development: Deflazacort a synthetic compound synthesized by derivatization in the chemical structure of prednisolone with an aim to improve its potency. Deflazacort is under global development with Marathon Pharmaceuticals, was approved by the U.S. Food and Drug Administration in year 2017 to treat patients with Duchenne muscular dystrophy (DMD). Chemistry and Pharmacology: DMD is one of the rare and genetic disorders with the symptoms of progressive degeneration of muscle tissue. Chemically, it is deacetylated at position 21 to produce active metabolite 21-desacetyl deflazacort (21-desDFZ), which acts through the glucocorticoid receptor. The predominant side effects are cushingoid appearance, increased appetite, upper respiratory tract infection (URTI), pollakiuria, hirsutism, and nasopharyngitis. Conclusion: The present article summarizes the available updated information and work done so far on Deflazacort with special emphasis on its chemistry, pharmacology with detailed mechanism of action, pharmacodynamics, pharmacokinetics, metabolism and clinical trials etc.

Background: Garlic (Allium sativum) possesses health enhancing abilities due to the presence various phytoceutics moities. The current research was deigned to explore the phytochemicals and antioxidant capacity of Pakistani garlic. Methods: Garlic extracts were obtained using methanol, hexane and ethyl acetate at different time intervals (35, 50 and 65 min) followed by their polyphenols and flavonoid content determination. Afterwards, the antioxidant potential was also determined. Results: The outcomes revealed that the methanolic extracts obtained at 50 min extraction time showed maximum total phenolics as 60.38±0.23 mg GAE/100g and flavonoids as 58.45±1.24 mg/100g. Similarly, the highest DPPH activity (61.59±1.58%) and β-carotene and linoleic acid potential (64.96±1.72%) were also observed for methanolic extract. Conclusion: Inferences were made that Pakistani garlic contains myriad of phenolics and flavonoids but the extraction of these components depends upon the solvent/time combination. In this study, methanol proved to be the ideal solvent for the maximum extraction of phytochemicals from garlic.

Background: Cancer is a disease of high mortality. The therapeutic agents currently available are insufficient to cure it and are associated with serious side effects. 4-methylumbelliferone is a natural product containing benzo-α-pyrones as a central nucleus. Benzo-α-pyrone is a privileged moiety having multifarious biological activities including anticancer activity. A series of compounds were synthesized taking 4-methylumbelliferone as a core nucleus and screened for their anticancer activity against HeLa cancer cell line. Methods: The 4-methylumbelliferone was linked with aminoacids using chloroacetyl chloride or ethyl chloroacetate as linker. The N-methylmorpholine and isobutylchloroformate protocol was used for amidic coupling. The final compounds were tested against the HeLa cancer cell lines using SRB assay protocol. Results: Three compounds have shown significant anticancer activity viz 9a, 12f and 15l having GI50 (μg/ml) value of, 56.1, 30.9 and 50.9, respectively. Other compound 9f and 13 showed weak anticancer activity having GI50 (μg/ml) value of 97.2 and 71.1, respectively. Conclusion: It has been found that the synthesized derivatives have inhibitory effect on the growth of cancer cell line. Compound 12f has been found as the most active compound of the synthesized series.

Background: Thienopyrimidines are the bioisoster of quinazoline and unlike quinazoline exist in three isomeric forms corresponding to the three possible types annulation of thiophene to the pyrimidine ring viz thieno[2,3-d] pyrimidine, thieno[3,2-d] pyrimidine and thieno[3,4-d]pyrimidine. Heterocyclic containing the thienopyrimidinone moiety exhibits various pronounced activities such as anti-hypertensive, analgesic and anti-inflammatory, antiviral, platelet aggregation inhibitory, antiprotozoal bronchodilatory, phosphodiesterase inhibitory, antihistaminic, antipsychotic and antimicrobial activity. Objective: Synthesis of novel 3(N,N-dialkylamino)alkyl/phenyl substituted thieno[2,3-d]pyrimidinones as H1-anti-histaminic and antimicrobial agents. Methods: A series of 3-[(N,N-dialkylamino)alkyl/phenyl]-2-(1H)thioxo-5,6,7,8-tetrahydrobenzo(b) thieno(2,3-d)pyrimidine-4(3H)-ones[4a-d], their oxo analogous [5a-d] and 3-[(N,N-dialkylamino)alkyl]- 2-chlorophenyl-5,6,7,8-tetrahydrobenzo(b)thieno(2,3-d)pyrimidine- 4 (3H)-ones[6a-d]derivative were synthesized from 2-amino-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylic acid by nucleophilic substitution of different N,N-dialkyl alkylene/phenylene diamines on activated 3-acylchloride moiety followed by cyclocondensation with carbon disulfide and ethanolic potassium hydroxide to get [4a-d] and in second reaction by condensation with 4-chlorobenzoyl chloride to get [6a-d] by single pot novel innovative route. The oxo analogous [5a-d] were prepared by treating derivatives [4a-d] with potassium permagnate in ethanolic KOH. The synthesized compound were evaluated for H1-antihistaminic and antimicrobial activities. Results: All synthesized compounds exhibited significant H1-antihistaminic activity by in vitro and in vivo screening methods and data were verified analytically and statistically. The compound 4a, 4b, 5a and 5b showed significant H1-antihistaminiic activity than the reference standard chlorpheniramine maleate. The compound 6d, 6c, 5c and 4c exhibited significant antimicrobial activity.

Background: Coumarin and modified nitrogen heterocyclic nuclei show biological activity. Combining these into a hybrid molecule could lead to new pharmacological agents. A series of hybrid compounds combining coumarin and piperidine, piperazine, purine or tetrahydroisoquinoline moieties were synthesized and evaluated for anti-arrhythmic activity. Methods: The Mannich reaction of coumarins (peurutenicin, peucenol and 6-cyanoumbelliferrone) with formaldehyde and various amines, including several alkaloids – anabasine, theophylline or tetrahydroisoquinolines, proceeds by heating under reflux in dioxane in the presence of 4-dimethylaminopyridine. The Suzuki reaction of 6,8-disubstituted umbelliferone triflate was used for the introduction of an aryl substituent in position 7 of the the coumarin framework. Results: Twenty two novel coumarin-based Mannich bases were synthesized via introduction of functional aminomethyl group at position 8 of 6 substituted 7-hydroxy-2H-chromen-2-ones by Mannich reaction. The results illustrated that the C-6 and C-8 substituents’ effect was obvious in our designed system and there was a relationship between the structures and the anti-arrhythmic activity of the 6,7,8- trisubstituted coumarins. 8-(6,7-dimethoxy-1-(3,4,5-trimethoxyphenyl)-tetrahydroisoquinolinylmethyl)- substituted peucenol derivatives shown in vivo a pronounced and selective anti-arrhythmic activity on epinephrine arrhythmias in comparison with natural coumarin peucenol. The moderate toxicity of the new compound encouraged further design of therapeutically relevant analogues based on this novel type of coumarin- tetrahydroisoquinoline hybrids. Conclusion: We have developed a mild reaction protocol to synthesize new mannich products on the basis of substituted coumarins. The anti-arrhythmic activity of coumarin-tetrahydroisoquinoline hybrids was revealed. We report for the first time that coumarin containing 8-(1-(3,4,5-trimethoxyphenyl) tetrahydroisoquinolinyl)methyl) substituent offer a suitable scaffold for the development of novel anti-arrhythmic agents.

Background: The neuroleptic chlorpromazine has been reported for antitubercular activity but the associated antipsychotic activity restricted its clinical presentation. Objectives: Novel derivatives of carbazole having structural similarity with chlorpromazine were designed, in an attempt to reduce the associated side effects, while retaining the antitubercular activity. Materials and Methods: The designed molecules were synthesized and screened for antitubercular and antibacterial activities. The blood-brain barrier (BBB) permeability and mammalian cell (VERO) cytotoxicity (CC50) were examined to determine the safety of compounds. Results: Among the developed compounds, 14c, 15c, 16c and 17c were found to be promising against Mtb H37Rv at MIC of 1.56 μg/ml. They were also effective against S. aureus and E. coli at MIC of 0.98 and 7.81 μg/ml, respectively. The BBB permeability of the compounds was found to be less than chlorpromazine. Therefore, the developed compounds are expected to have diminished antipsychotic effect. The compounds were further marked safe against mammalian VERO cells at CC50 > 90 μg/ml. Conclusion: The profound antitubercular activity with a concomitant reduction in BBB permeability of carbazole derivatives can pave new vista in the discovery of antitubercular drugs.

Background: Using constantly and widely chemistry insecticides has resulted in a selection burden and favored tolerance development in various insect species. Particularly, pyrethroids are the only one which can be used for net impregnation either ITNs or LLIN as yet, however, the excessive use of pyrethroids has led to many cases of insect resistance in worldwide. Therefore, it is urgent to develop novel insecticides fighting against this sort of resistance. Methods: Based on the preliminary studies, we explored a straightforward highly stereoselective method to achieve the novel chiral ester derivatives by using Oppolzer’s 10,2-camphorsultam as chiral controlling reagent. Results: A series of tetrafluorobenzyl alcohol oriented (S)-enantiomeric esters were designed and synthesized by the asymmetric synthesis. All the compounds exhibited moderate yields, and the original synthesized compounds have been evaluated for their potential insecticidal activity against Plutella xylostella compared with those of fenvalerate and D-trans-phenothrin, and some compounds presented excellent insecticidal activities. Conclusion: The bioassay illustrated that some of the compounds exhibit obviously insecticidal activities against Plutella xylostella, especially, the insecticidal activity of compound 5i was as good as commercial fenvalerate and D-trans-phenothrin, which can be used as a lead compound for further optimization.

Background: During last two decades, good progress has been made for the flavonoids in metabolic and infectious diseases. However, expectations have not been fulfilled when these compounds were extended to the in vivo studies, particularly in humans. This could due to low bioavailability and less absorption of flavonoids in the biological systems. A recent study revealed that methylation of flavonoids can bring about dramatic changes in pharmacokinetic and biochemical properties. Often, the partially methylated flavonoids show better activities by improving their metabolic stability, membrane transport capacity, facilitating absorption and for oral bio-availability. Though, partial methyl ethers occupy a large chemical space, their biological properties has not been well established. Azaleatin (quercetin-5-O-methyl ether) is one of such group of naturally occurring molecules. Methods: In the present study, we have utilized methoxymethyl (MOM) protecting groups for the preparation of azaleatin. Synthesized compounds and their derivatives were subjected for α-Amylase and DPPH activities. α-Amylase activity can be measured in vitro by hydrolysis of starch in presence of α-amylase enzyme. Antioxidant capacity was evaluated by measuring the scavenging activity of azaleatin and related compounds on the 2,2- diphenyl-l-1-picrylhydrazil (DPPH) radical. In order to identify the binding mode of the compound azaleatin, Auto Dock Tools (http://mgltools.scripps.edu) were used. Results: Quercetin, along with their derivatives, monomethyl ethers i.e. azaleatin, isorhamnetin, tamarixetin; dimethyl ether i.e. quercetin-3,7-dimethyl ether; quercetin-3,3',7-trimethyletherpachypodol; quercetin-3,3',4'7-tetramethyl ether and quercetin pentamethyl ether were taken for α- amylase inhibitory activity. The study showed that azaleatin was found to be comparable with the standard for the inhibition of α-amylase amongst the tested compounds. Since, azaleatin is a best for the inhibition of α-amylase, this compound was taken for the in-silico molecular modelling studies. Azaleatin, showed a good docking energy (-8.8 Kcalmol-1) with the α-amylase receptor. Similarly, other closely related derivatives were studied for their antioxidant capacity. It was found that amongst the compound tested quercetin was found to be best (EC50 of 30μg/mL) for their antioxidant capacity and second best compound was azaleatin; which showed EC50 of 36.1μg/mL. Conclusion: An efficient synthesis of azaleatin, a lesser known flavone has been achieved from quercetin. Amongst the compounds tested, azaleatin was found to inhibit α-amylase with the acceptable radical scavenging activity. Further, in-silico modelling studies indicated that azaleatin found to have very good affinity with the key residues i.e. Gln63, Asp197 and Arg195 of α-amylase receptor. Since, azaleatin has other free hydroxyls in their template, it can be effectively utilized for the activity improvement through further structural modifications.

Background: It has been decades since natural biomaterials, including mushrooms, are examined for antioxidant capacity to put them in the place of the synthetic antioxidants causing cancer. Ganoderma lucidum Karst is an annual fungus reputed for possessing medicinal properties. The fungus has a high potential to be used as a dietary supplement or a source of nutrients and antioxidant agents. It has not been more than a decade since the scientists are working on the different medicinal properties of the endemic Ganoderma lucidum in Iran. This study was conducted, in order to complete a part of this goal and comparing the antioxidant potential of the endemic specimen from Iran with findings from other countries. The aim of this investigation was to test the antioxidant properties, total flavonoid and phenolic contents of various extracts of Ganoderma lucidum in the form of fruit bodies. Methods: Mushroom samples were extracted with chloroform, methanol and water by maceration method. Ferric Reducing Antioxidant Power, DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'- azino-bis[3-ethylbenzothiazoline-6-sulphonic acid]) were methods used for antioxidant studies in this work. Also, total flavonoid and phenolic contents of these extracts were evaluated. Results: The methanol extraction illustrated the highest radical scavenging capacity 21.51±0.90 μmoL Trolox/g Ferric reducing assay. The best activities in ABTS and DPPH tests were obtained by chloroform extracts with the 31.36±2.30 μmoL Trolox/g and 6.07±0.08 μg/mL, respectively. Also the chloroform extraction of this fungus displayed the highest total phenolic and flavonoid content 167.75±1.27 GAE/g and 38.00±0.75 mg quercetin equivalents/g, respectively. Conclusion: The results displayed that Reishi might be proposed as a source of natural antioxidant compounds and can be used as excellent food supplement.

Background: Diseases caused by microbial infections are very common worldwide. Although the search of innovative antimicrobial agents is the current focus for the researchers, the treatment of infectious diseases remains an important public health issue and a challenging problem in front of medicinal chemist. Methods: A series of 2-(4-hydroxyphenyl)-3-(4-(4-nitrophenyl) thiazol-2-yl)thiazolidin-4-one derivatives (T1-T10) was designed and synthesized. All the titled compounds were evaluated for their antimicrobial potential. Antimicrobial activity was performed by tube dilution methods against Gram negative Escherichia coli MTCC 443 (E. Coli), Gram positive bacteria: Staphylococcus aureus MTCC 3160 (S. aureus) and Bacillus subtilis MTCC 441 (B. Subtilis), and fungal strains: Aspergillus niger MTCC 281 (A. niger) and Candida albicans MTCC 227 (C. albicans). Results: Among the synthesized derivatives, compounds 2, 4 and 10 were found to be most active antimicrobial agents. Conclusion: In conclusion, a series of 2-(phenyl)-3-(4-(phenyl)thiazol-2-yl)thiazolidin-4-ones have been designed and synthesized. All the titled compounds were evaluated for their in vitro antimicrobial activity against five representative microorganisms. The results of antimicrobial study indicated that the presence of nitro and chloro groups in aromatic ring improved antibacterial activity, whereas the presence of hydroxy group improved antifungal activity of substituted 4-thiazolidinone derivatives.

Background: Diabetes is a chronic metabolic syndrome that affecting millions of people around the world. There are several therapeutic options for the treatment of diabetes but adequate glycemic control is still a challenge. In this regard, daily food item has been focus to evaluate their effect on blood glucose control. Methods: Our study investigated the effect of oral consumption of crude extract and its subsequent solvent fractions (hexane, ethyl acetate and aqueous) of Green Tea purchased from local market in alloxan- induced diabetic rabbits. Plasma glucose level and overall affect on body weight was observed on daily basis up t 26th day at 25 and 50 mg/kg p.o. Results: The results showed significant (P<0.05) reduction in hyperglycemia-induced in rabbits. The crude extract was most dominant in its effect after 26th of administration, while hexane fraction did not produce any antihyperglycemic effect. However, the remaining fractions elicited moderate effects. When the effect of these extracts were studied on body weight of diabetic rabbits, marked recovery in body weight was observed. Conclusion: In short, it is concluded, that the various extracts of green tea possessed strong antidiabetic and weight regaining effects in alloxan-induced diabetic rabbits, and thus appeared as a significant biofunctional food in diabetes management. Furthermore, bioactivity guided isolation of secondary metabolites could provide chemical background.

Background: Thymol has been reported to have a variety of antimicrobial and insecticidal activities but it has irritation side effect due to its phenolic nature. Methods: A new series of potential non-irritant non-phenolic thymol derivatives were designed to hybridize the well-known biologically active thymol scaffold with various five membered heterocyclic antimicrobial and insecticidal pharmacophores like 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazole, thiazole and 4-thiazolidinone through different spacers. The target compounds were biologically evaluated for their in vitro antibacterial, antifungal and insecticidal activities. Results: Compounds 4b and 9c showed weak antibacterial activity against S. aureus and B.subtilis with the inhibition zone diameters ranging from 2 to 7 mm and 4 mm respectively compared with ciprofloxacin with the inhibition zone diameter of 21 mm. Compounds 9a, 7d and 13b showed weak antibacterial compounds against B. subtilis with inhibition zone diameters 4, 4 and 6 mm respectively. Compounds 12b, 9c and 7a showed 20% insecticidal activity at a concentration of 0.157 mg/cm2 for each compound against Tribolium castaneum (Herbst) and Sitophilus oryzae (L.). Compound 6 showed moderate larvicidal activity against Culex pipiens with 40% mortality at a concentration of 1000 ppm. Conclusion: Compound 9c showed weak dual antimicrobial and insecticidal activities.

Background: Funcionalized multi-walled carbon nanotubes (ox-MWCNTs) were used for the preparation of therapeutic nanoparticles for delivery of some bioactive compounds. Consequently, this work deals with the preparation of grafted MWCNTs with n-vinyl caprolactam in the presence of pomegranate peel extract (P. granatum), titanium dioxide (TiO2) and/or silver nanoparticeles and their toxic effects on male mice using in vivo biological examination (liver and kidney dysfunction biomarkers) and the histopathological analysis. Methods: P. granatum extract was immobilized onto functionalized MWCNTs using simple adsorption technique. Moreover, The prepared materials were analyzed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM). In vivo examination using liver and kidney dysfunction biomarkers was investigated. In addition, the histopathological study was carried out. Results: The ox-MWCNTs induced significant elevation in the liver enzymes including AST, ALT and ALP relative to the control group. While, the treatment with P. granatum extract only did not induce any change in the liver and kidney biomarkers. In other words, P. granatum extract loaded onto functionalized MWCNTs showed low effects on liver enzymes and kidney function biomarkers in the treated mice in comparison with ox-MWCNTs and extract separately. Moreover, histopathological analysis revealed that the P. granatum extract functionalized MWCNTs exhibited normal renal tissue with no histopathological alteration. Conclusion: The grafted MWCNTs with n-vinyl caprolactam in the presence of pomegranate peel extract (P. granatum), titanium dioxide (TiO2) and/or silver nanoparticeles were successfully prepared. SEM-micrographs showed complete coating of MWCNTs fiber with the extract. The prepared materials resulted in no toxic effects and the histopathological findings were confirmed by inflammation of the liver and kidney tissues.