Green synthesis and biomedicinal applications of silver and gold nanoparticles functionalized with methanolic extract of Mentha longifolia.

This study deals with facile and rapid synthesis of silver nanoparticles (AgNPs) and Gold nanoparticles (AuNPs) using Mentha longifolia leaves extracts (MLE). The synthesized AgNPs and AuNPs were characterized by UV-visible spectroscopy (UV-Vis), Fourier transformed infra-red spectroscopy (FT-IR), atomic force microscopy (AFM) and transmission electron microscopy (TEM) techniques. The phytochemical analysis showed the presence of bioactive secondary metabolites, which are involved in the synthesis of nanoparticles (NPs). The surface plasmon resonance (SPR) observed at 435 and 550 nm, confirmed the green synthesis of AgNPs and AuNPs, respectively. The TEM images showed poly dispersed and round oval shapes of Ag and Au NPs with an average particles size of 10.23 ± 2 nm and 13.45 ± 2 nm, respectively. TEM results are in close agreements with that of AFM analysis. The FT-IR spectroscopy revealed the presence of OH, -NH2 and C = O groups, which involved in the synthesis of NPs. The MLE and their AgNPs and AuNP exhibited good in vitro antibacterial and anti-oxidant activities. Moreover, MLE and NPs also showed in vivo analgesic activities in mice, and excellent sedative properties in open field test paradigm.

Pharmacophore model-based virtual screening, docking, biological evaluation and molecular dynamics simulations for inhibitors discovery against α-tryptophan synthase from Mycobacterium tuberculosis.

Discovery of new anti-tuberculosis drugs with novel mode of action is urgently needed. The tryptophan synthase is a genetically validated enzyme that catalyzes last step of tryptophan biosynthetic pathway required for growth and survival of Mycobacterium tuberculosis. Here, a ligand-based pharmacophore model was built using molecular operating environment (MOE) software (version 2010.12) and validation of generated pharmacophoric features was done using active, inactive and decoy set of molecules. The generated pharmacophore model was used for screening of 7,523,972 drug-like molecules of ZINC database. The best matches (RMSD < 1) retrieved as a result of screening were subjected to molecular docking studies into active pocket of α-subunit of tryptophan synthase from M. tuberculosis. The five hits were selected and validated through anti-tuberculosis activity analysis. Finally, a new inhibitor ZINC09150898 has been identified with best binding score -32.07 kcal/mol, showing 100% growth inhibition of M. tuberculosis (H37Rv strain) at 50 µg/mL. This identified inhibitor-protein complex was further subjected to MD simulations studies (50 ns) involving root mean square deviation, root mean square fluctuation, secondary structure analysis and pocket interaction analysis to explore its binding mode stability inside active pocket. The binding free energies of inhibitor-protein complex through MM-PBSA analysis suggested that van der Waals interactions play a vital role for retention of identified inhibitor inside the protein pocket. All these analyses confirmed retention of ligand inside pocket and no unfolding in protein structure was observed over explored time scale.Communicated by Ramaswamy H. Sarma.

Facile synthesis and antiproliferative activity of new 3-cyanopyridines.

BACKGROUND: Pyridines have been reported to possess various pharmacological activities. RESULTS: Sodium 3-oxo-3-(2-oxo-2H-chromen-3-yl)prop-1-en-1-olate (2) and sodium 3-oxo-3-(3-oxo-3H-benzo[f]chromen-2-yl)prop-1-en-1-olate (7) were prepared and reacted with 2-cyano-N'-(1-aryl(heteryl)ethylidene)acetohydrazides 3a-d to produce 2-oxo-1,2-dihydropyridine-3-carbonitrile derivatives 5a-d and 9a-d, respectively, in good yields. Also, 3a-d reacted with sodium (2-oxocyclopentylidene)methanolate (11a) or sodium (2-oxocyclohexylidene) methanolate (11b) to yield 2-oxo-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitriles 13a-d and 2-oxo-hexahydroquinoline-3-carbonitriles 13e-h, respectively. The mechanisms that account for the formation of the products are discussed. Additionally, the structures of all the newly synthesized products are confirmed, based on elemental analysis and spectral data. Several of the newly synthesized compounds are evaluated for their antitumor activity against HEPG2 and their structure activity relationship (SAR) was studied. CONCLUSIONS: The results revealed that the pyridine derivatives 5c and 5d (IC50 = 1.46, 7.08 µM, respectively) have promising antitumor activity against liver carcinoma cell line (HEPG2), compared to the reference drug, doxorubicin.

Drug Design of Inhibitors of Alzheimer's Disease (AD): POM and DFT Analyses of Cholinesterase Inhibitory Activity of ß-amino di-Carbonyl Derivatives.

BACKGROUND: Since deficit of acetylcholine has been evidenced in the Alzheimer's disease (AD) patients, cholinesterase inhibitors are currently the most specified drug category for the remediation of AD. METHOD: In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 µg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity. RESULTS AND CONCLUSION: All the investigated dicarbonyl compounds exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition towards BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good harmonization with experimental data.

Muscle relaxant activities of pistagremic acid isolated from Pistacia integerrima.

The aim of the current work was to explore the muscle relaxant effect of pistagremic acid (PA) isolated from Pistacia integerrima in various animal paradigms. In a rotarod test, PA caused a significant (p<0.05) muscle relaxant potential in a dose-dependent manner. When studied in the inclined plane test, pretreatment with PA (5 and 10 mg/kg) caused promising activity (p<0.05) after treatment for 30, 60 and 90 min. The muscle relaxant potential of PA was strongly complimented by the traction and chimney tests, showing a dominant effect after 60 min of treatment. In conclusion, PA possesses strong muscle relaxant activity in various animal-based models.

Multidrug resistance reversal activity of extract and a rare dimeric naphthoquinone from Diospyros lotus.

A dimeric naphthoquinone namely dihydrodyspyrole R (1) was purified once more from Diospyros lotus. Dihydrodyspyrole R and chloroform fractions were evaluated for their effects on the reversion of multidrug resistance (MDR). The compounds (1) and extract exhibited promising MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Molecular docking of compound 1 revealed the correlation between in-silico with in-vitro results. The molecular docking results showed that compound 1 is bind closely where co-crystal ligand of P-gp is present. But usually, computational investigation predicts that, if a compound gives lesser score then compound will exhibit good activity. Hence, the docking scores of compound 1 are the near to the Rhodamine. It is conclude that there are certain important structural features of compound 1which are responsible for the inhibiting potency of P-gp from mice. The computational Petra/Osiris/Molinspiration (POM) analysis confirms the possibility of use of compound 1 without side effect or less toxicity risks.

Better agonist for the opioid receptors.

This commentary highlights the recent work published in journal Nature on the structural based discovery of novel analgesic compounds for opioid receptors with minimal effects. Manglik et al. selectively targeted the Gi based µOR pathway instead of the ß-arrestin pathway of the opioids. The computational screening of millions of compounds showed a list of several competent ligands. From these ligands they synthesized the compounds with the best docking score, which were further optimized by adding side residues for better interaction with the µOR. A promising compound, PZM21, was a selective agonist of µOR. It has better analgesic properties with minimal side effects of respiratory depression and constipation. This work is a step towards better drug designing and synthesizing in terms of efficacy, specificity with least side effects of targeted GPCR proteins present in the human proteome.

Bioactive chromone constituents from Vitex negundo alleviate pain and inflammation.

BACKGROUND: Vitex negundo L. has been widely studied for its beneficial effect in inflammatory and pain conditions. The present study describes the isolation of two new bioactive chromone constituents from V. negundo and their in vivo evaluation for anti-inflammatory and antinociceptive activities. METHODS: Two new chromone derivatives, namely, methyl 3-(2-(5-hydroxy-6-methoxy-4-oxo-4H-chromen-2-yl)ethyl)benzoate (1) and 3-(1-hydroxy-2-(5-hydroxy-6-methoxy-4-oxo-4H-chromen-2-yl)ethyl)benzoic acid (2) were isolated from V. negundo and their structures were determined through various spectroscopic techniques including mass spectrometry, UV, IR, 1H NMR, 13C NMR, and two-dimensional-NMR like correlation spectroscopy and heteronuclear multiple bond correlation techniques. The isolated compounds (1-2) were tested for their prospective antinociceptive activity in acetic acid-induced abdominal constriction assay and anti-inflammatory activity in the carrageenan-induced paw edema assay in mice. RESULTS: Significant attenuation (P<0.001) of tonic visceral nociception was demonstrated by compound 1 and 2 at doses of 50 and 100 mg/kg. At similar doses, these compounds (1-2) also showed potent amelioration (P<0.001) of carrageenan-induced paw swelling. CONCLUSION: The isolated chromone derivatives (1-2) from V. negundo are able to alleviate nociception and inflammation and the findings corroborated that V. negundo may be used as a potential source of antinociceptive and anti-inflammatory candidates.

Molecular docking and biological evaluation of some thioxoquinazolin-4(3H)-one derivatives as anticancer, antioxidant and anticonvulsant agents.

BACKGROUND: The quinazoline are an important class of medicinal compounds that possess a number of biological activities like anticancer, anticonvulsant and antioxidant etc. RESULTS: We evaluated the previously synthesized quinazoline derivatives 1-3 for their anticancer activities against three cancer cell lines (HepG2, MCF-7, and HCT-116). Among the tested compounds, quinazolines 1 and 3 were found to be more potent than the standard drug Vinblastine against HepG2 and MCF-7 cell lines. All the tested compounds had less antioxidant activity and did not exhibit any anticonvulsant activity. Also, molecular docking studies were performed to get an insight into the binding modes of the compounds with human cyclin-dependent kinase 2, butyrylcholinesterase enzyme, human gamma-aminobutyric acid receptor. These compounds showed better docking properties with the CDK2 as compared to the other two enzymes. CONCLUSIONS: The overall study showed that thioxoquinazolines are suitable antitumor agents and they should be explored for other biological activities. Modification in the available lot of quinazoline and synthesis of its novel derivatives is essential to explore the potential of this class of compounds. The increase in the threat and with the emergence of drug resistance, it is important to explore and develop more efficacious drugs.

Antimicrobial activity of thiophene derivatives derived from ethyl (E)-5-(3-(dimethylamino)acryloyl)-4-methyl-2-(phenylamino)thiophene-3-carboxylate.

BACKGROUND: The thiophene nucleus has been recognized as an important entity in the synthesis of heterocyclic compounds with promising pharmacological characteristics. RESULTS: A number of new heterocyclic compounds incorporating thiophene species have been prepared from the titled enaminone via the reaction with different nucleophiles and electrophiles. The structure elucidation of the designed compounds was derived from their spectral information. The results of antimicrobial activity of the prepared compounds revealed that derivatives 7b and 8 exhibited activity comparable to the standard drugs ampicillin and gentamicin for all tested bacteria species. Additionally, compound 3 displayed potent activity against Aspergillus fumigates, whereas compounds 5, 6, and 7a showed good activity against Syncephalastrum racemosum. CONCLUSIONS: We have synthesized a number of new thiophene-containing compounds. The results of antimicrobial activity of the prepared compounds revealed that changing the substituents at position-2 of thiophene ring significantly affect their biological activity. The pyridine side chain derivatives in compounds 7a, 7b and 8 showed excellent antimicrobial activity.

Isolation and characterization of three new anti-proliferative Sesquiterpenes from Polygonum barbatum and their mechanism via apoptotic pathway.

BACKGROUND: The emergence of chemoresistant cancers and toxicity related to existing chemotherapeutic agents, demand the search for new pharmacophore with enhanced anti-cancer activity and least toxicity. For this purpose, three new sesquiterpenes were isolated from ethyl acetate fraction of the aerial parts of the plant Polygonum barbatum and evaluated for their anti-cancer potential. METHODS: The structural elucidation and characterization of the isolated compounds 1-3 were performed using various spectroscopic techniques such as mass, UV, IR, and extensive 1D/2D-NMR spectroscopy. Furthermore, the compounds 1-3 were subjected to screening of anti-cancer activity against different cell lines followed by brief analysis of apoptotic and anti-angiogenic potentials of the potent hit against non-small cell lung carcinoma cell line. RESULTS: All the compounds 1-3 were subjected to anti-proliferative potential against non-small cell lung carcinoma (NCI-H460), breast cancer (MCF-7), cervical cancer (HeLa) and normal mouse fibroblast (NIH-3 T3) cell lines. Among these, compound 3 was found to be more cytotoxic against NCI-H460 and MCF-7 cells (IC50 = 17.86 ± 0.72 and 11.86 ± 0.46 µM respectively). When compared with the standard drug cisplatin compound 3 was found to have more potent activity against NCI-H460 (IC50 = 19 ± 1.24 µM) as compared to MCF-7 cell lines (IC50 = 9.62 ± 0.5 µM). Compound 3 induced apoptosis in NCI-H460 cells in a dose dependent manner. It significantly downregulated, the expression of anti-apoptotic (BCL-2 L1 and p53) and increased the expression of pro-apoptotic (BAK and BAX) genes. Besides apoptosis, it also significantly reduced the cell migration and downregulated the angiogenic genes (i.e. VEGF and COX-2), thereby, inhibiting angiogenesis in NCI-H460 cells. CONCLUSION: Compound 3 possesses potent anti-proliferative potential as well as induced apoptosis and inhibited the cell migration of the cancerous cells by altering the gene expression, responsible for it.

Plant bioactive molecules bearing glycosides as lead compounds for the treatment of fungal infection: A review.

Despite therapeutic advancement in the treatment of fungal infections, morbidity and mortality caused by these infections are still very high. There are approximately 300 fungal species that are infectious and can cause a variety of diseases. At present, several synthetic antifungal drugs are in clinical practice, many of them, however, are vulnerable to multidrug-resistant strains of microbes, and thus compromising the overall treatment outcomes. Glycosides are naturally occurring plant secondary metabolites with important therapeutic potential and clinical utility. The aim of this review was to focus on the antifungal effects of glycosides in preclinical studies with possible mechanism(s) wherein described. Published research show significant susceptibility of different fungi towards phytoglycosides, mediated through multiple mechanisms. Further detailed studies are needed to explain the clinical applications and limitations of these glycosides.

Microwave-Assisted Synthesis of some Novel Azoles and Azolopyrimidines as Antimicrobial Agents.

In this study, new derivatives of pyrazole, isoxazole, pyrazolylthiazole, and azolopyrimidine having a thiophene ring were synthesized under microwave irradiation. Their pharmacological activity toward bacteria and fungi inhibition was screened and compared to the references Chloramphenicol and Trimethoprim/sulphamethoxazole. The antimicrobial results of the investigated compounds revealed promising results and some derivatives have activities similar to the references used.

Facial Regioselective Synthesis of Novel Bioactive Spiropyrrolidine/Pyrrolizine-Oxindole Derivatives via a Three Components Reaction as Potential Antimicrobial Agents.

This article presents the synthesis of new derivatives of spirooxindole-spiropiperidinone- pyrrolidines 6a-j and spirooxindole-spiropiperidinone-pyrrolizines 8a-j, through a 1,3-dipolar cycloaddition reaction of azomethineylides generated from isatin, sarcosine, and l-proline, through a decarboxylative route with dipolarophile 4a-j. All of the newly synthesized compounds were evaluated for their antimicrobial activities and their minimum inhibitory concentration (MIC) against most of the test organisms. The tested compounds displayed excellent activity against all of the tested microorganisms.

Sedative-hypnotic-like effect and molecular docking of di-naphthodiospyrol from Diospyros lotus in an animal model.

BACKGROUND: Diospyros lotus Linn commonly known as date-plum, or Caucasian persimmon has multiple uses in folk medicine. Various parts of this plant is used for alleviating lumbago, dysponea, hemorrhage, insomnia, and hiccup. The plant extracts possess a variety of biological activities, such as anti-inflammatory, sedative, febrifuge, anti-microbial, vermifuge, and anti-hypertensive. AIM/HYPOTHESIS: The aim of the present work is to investigate the sedative-hypnotic effect of a rare dimeric napthoquione 1 obtained from the chloroform soluble fraction of D. lotus extracts. METHODS: Compound 1, di-naphthodiospyrol at 5, 10, and 15mg/kg intraperitoneal doses was assessed for its in vivo sedative effect in an open-field using a phenobarbitone-induced sleeping time model. The geometry of di-naphthodiospyrol was also optimized with the aid of density functional theory. In addition, molecular docking of compound 1 was performed with the receptor GABAA. RESULTS: The animal protocol-based assay showed significant sedative-hypnotic-like effects of compound 1 at various test doses (5, 10, and 15mg/kg i.p.). Docking studies indicated that this compound interacts strongly with important residues in receptor GABAA. CONCLUSIONS: Results from this investigation reveal that compound 1 possesses sedative-hypnotic- like properties which can be of interest in therapeutic research.

Urease inhibition potential of Di-naphthodiospyrol from Diospyros lotus roots.

The dimeric napthoquione 5,8,4'-trihydroxy-1'-methoxy-6, 6'-dimethyl-7,3'-binaphtyl-1,4,5',8'-tetraone (1) was isolated from the chloroform fraction of Diospyros lotus extract. Compound 1 was screened for its inhibitory effects against four enzymes: urease, phosphodiesterase-I, carbonic anhydrase-II and α-chymotrypsin, and showed selective activity against urease enzyme with an IC50 value of 254.1 ± 3.82 µM as compared to the standard thiourea (IC50 = 21 ± 0.11 µM). Furthermore, in silico docking study was carried out to explain the molecular mechanism of compound 1 against the target receptor.

The Search for Covalently Ligandable Proteins in Biological Systems.

This commentary highlights the recent article published in Nature, June 2016, titled: "Proteome-wide covalent ligand discovery in native biological systems". They screened the whole proteome of different human cell lines and cell lysates. Around 700 druggable cysteines in the whole proteome were found to bind the electrophilic fragments in both active and inactive states of the proteins. Their experiment and computational docking results agreed with one another. The usefulness of this study in terms of bringing a change in medicinal chemistry is highlighted here.

Synthesis and Structure-Activity Relationship of Some New Thiophene-Based Heterocycles as Potential Antimicrobial Agents.

Several new pyrazole, pyridine, [1,2,4]triazolo[1,5-α]pyrimidine, benzimidazo[1,2-a]pyrimidine and 1,2,4-triazolo[3,4-c][1,2,4]triazine derivatives incorporating a thiophene moiety were synthesized from (E)-ethyl 5-(3-(dimethylamino)acryloyl)-4-phenyl-2-(phenylamino)thiophene-3-carboxylate (1). The structures of the newly synthesized compounds were confirmed by IR, ¹H-, (13)C-NMR, mass spectral data and elemental analysis. The antibacterial and antifungal activities of all the synthesized compounds were evaluated. The results indicated that compounds 9, 12, and 19 were found to be more potent than the standard drug Amphotericin B against Aspergillus fumigates. Additionally, compound 12 exhibited higher activity than the standard drug Amphotericin B against Syncephalastrum racemosum.

Antinociceptive and anti-inflammatory activities of flavonoids isolated from Pistacia integerrima galls.

The present study deals with the anti-hyperalgesic and anti-inflammtory effects of flavonoids (1-4) isolated from the chloroform fraction of Pistacia integerrima galls. The structure of isolated compounds was elucidated by using advance spectroscopy analysis and comparing their physical spectral data with reported one. The pretreatment of compounds (1-4) caused significant anti-hyperalgesic effects in acetic acid induced writhing test in a dose dependent manner. The compounds strongly complimented the effects in both phases of formalin test. However, the administration of naloxone did not abolish the induced antinociceptive effects and therefore suggested the absence of opioid receptor involvement. The pretreatment of flavonoids (1-4) elicited marked anti-inflammtory effects in carrageenan induced paw edema test in mice during various assessment times (1-5 h). The effects were dose dependent and maximum results were observed after 3rd h of treatments which remained significant up to 5th hour. It is concluded that the isolated flavonoids (1-4) possessed strong anti-hyperalgesic and anti-inflammtory activity and thus are strong candidates for further detail studies.

Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses.

Tetrasubstituted 2-acetylthiophene derivative 5 was synthesized and then condensed with various nitrogen nucleophiles such as 5-amino-1,2,4-triazole, 2-aminobenzimidazole, aniline or p-chloroaniline to afford the corresponding iminothiophene derivatives 6-8a,b. Condensation of thiophene 5 with malononitrile as carbon nucleophile afforded compound 9, which underwent nucleophilic addition with DMF-DMA to afford compound 10. The newly synthesized products were characterized by elemental analysis, IR, MS, ¹H-(13)C-NMR and CHN analysis and then evaluated for their antimicrobial activity. Results of the in vitro antibacterial activity showed that thiophene derivative 7 was found to be more potent than the standard drug gentamicin against Pseudomonas aeruginosa. Some of these compounds showed potential antimicrobial activities. Molecular docking and Osiris/Molinspiration analyses show the crucial role and impact of substituents on bioactivity and indicate the unfavorable structural parameters in actual drug design: more substitution with electronic donor group doesn't guarantee more effective bioactivity. This study should greatly help in an intelligent and a controlled pharmacomodulation of antibiotics.