Showing papers in "Medicinal Chemistry Research in 2017"

Hydrazide-hydrazones as potential antimicrobial agents: overview of the literature since 2010.

Abstract: Hydrazide-hydrazone derivatives are present in many bioactive molecules and display a wide variety of biological activities, such as antibacterial, antitubercular, antifungal, anticancer, anti-inflammatory, anticonvulsant, antiviral, and antiprotozoal action. Therefore, many medicinal chemists synthesize various hydrazide-hydrazones and evaluate them for biological activities. Among biological properties of this class of compounds, antimicrobial activity is the most frequently encountered in scientific literature. This paper is focused on the overview of the literature findings of the last six years (2010-2016) covering the research on antimicrobial activity of hydrazide-hydrazone derivatives. This review may also serve as a useful guide for the development of new hydrazide-hydrazones as potential antimicrobial agents.

Synthesis and antimicrobial activity of novel quinoline derivatives bearing pyrazoline and pyridine analogues

Abstract: The present investigation is in the interest of some synthesized novel derivatives containing (5-(2-chloroquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanones (4a–o) moieties incorporated with different biological active heterocycles such as quinoline, pyrazoline and pyridine derivatives. For the determination of the compounds reported in this paper was based on IR, 1H NMR, 13C NMR and mass spectral data and same compounds were screened for their antibacterial and antifungal activity on four bacteria (Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa) and three fungi (Candida albicans, Aspergillus niger, Aspergillus clavatus) using ampicillin and griseofulvin as the standard drugs. Cytotoxicity study was carried out using MTT colorimetric assay (HeLa cell line). Among the screened compounds, 4e, 4f and 4n showed most potent antibacterial activity, while compounds 4d and 4g emerged as the most active against fungal strains. The results demonstrated that compound 4o was remarkably active against all microbial strains. From the viewpoint of SAR studies, it was observed that the presence of electron withdrawing groups remarkably enhanced the antimicrobial activity of synthesized compounds. Additionally, preliminary MTT cytotoxicity studies on HeLa cells suggested that effective antimicrobial activity of 4e–g, 4n and 4o was accompanied by low cytotoxicity.

Synthesis and biological evaluation of pyrazolo[1,5- a ]pyrimidine-3-carboxamide as antimicrobial agents

Abstract: Exploring novel classes of antimicrobial therapeutics is an excellent approach to face the challenge of microbial resistance. In this context, a novel series of pyrazolo[1,5-a]pyrimidines 5a–d, 10a–f, 15a, d and 16a–d were synthesized and characterized by their spectral data. The structure of 10f was confirmed by X-ray diffraction analysis of its single crystal. The antimicrobial activities of the newly synthesized compounds showed that, compounds 5a and 16d were more potent than tetracycline against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. In addition, most of the newly synthesized compounds displayed a significant antifungal activity when compared with amphotericin B. Moreover, compound 16d (27.0 ± 0.41 mm, minimum inhibitory concentration: 7.81 µg/ml) displayed excellent and the highest antifungal activity than amphotericin B (18.0 ± 0.17 mm, MIC: 15.62 µg/ml) against Fusarium oxysporum.

Triphenylphosphonium cations of betulinic acid derivatives: synthesis and antitumor activity

Abstract: A series of lupane triterpenoid conjugates with the triphenylphosphonium cation, in which the terpenoid molecules are linked to one or two triphenylphosphonium moieties at the С-2, С-28, or С-30 positions by carbon–carbon or ester bonds, have been designed and synthesized as potential anti-cancer agents. The pharmacological results showed that all of the prepared triphenylphosphonium salts displayed considerable antitumor activities against the tested cancer murine tumor (Ehrlich ascites carcinoma, (Р-815), and human tumor (MCF-7) (IC50 < 2 μg/mL)) cell lines. The presence of the triphenylphosphonium cation in the triterpenoid conjugates markedly enhanced the cytotoxic action as compared to the parent compound (betulinic acid) (IC50 24.7 μg/mL for Ehrlich cells and 18.7 μg/mL for Р-815 cells), while the correlation between the cytotoxic activity and the chemical structure of phosphonium salts was not observed.

The pharmacological activities and mechanisms of artemisinin and its derivatives: a systematic review

Abstract: Artemisinin and its derivatives have now become essential antimalarial drugs for increasingly widespread drug-resistant malaria strains. Although artemisinin was first used for the treatment of malarial ailments, lots of subsequent studies have demonstrated it possesses other multiple pharmacological functions such as antitumor, antiarrhythmic, anti-fibrosis, as well as the activity against schistosomiasis. A wide array of the molecular mechanisms based on above-mentioned functions of artemisinin and its derivatives have also been explored. Experimental evidences suggest that artemisinin compounds may exert its functions via mechanisms like regulating key factors such as apoptosis-related BAX, FASL and caspase-3, multi-drug resistence genes, cytokines such as CD4+ and CD8+, inflammation-related NF-κB and COX2, telomerase, oxidative stress molecules, and so on. In this article, the proposed mechanisms of action of artemisinins are reviewed with the hope of gaining more insight into the multiple actions of these potent drugs and how they work.

Cyclic peroxides as promising anticancer agents: in vitro cytotoxicity study of synthetic ozonides and tetraoxanes on human prostate cancer cell lines

Abstract: Synthetic ozonides and tetraoxanes were shown to have high cytotoxicity in vitro when tested on androgen-independent prostate cancer cell lines DU145 and PC3, which is in some cases was higher than that of doxorubicin, cisplatin, etoposide, artemisinin, and artesunate. Activity of ozonide stereoisomers differs from each other. This difference in activity and absence of correlation between activity of stereoisomers and their oxidative properties allow us to suggest existence of a quite specific mechanism of cytotoxicity of these endoperoxides different from a traditional mechanism based mainly on oxidative properties of peroxides.

Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids

Abstract: A series of rhodanine 3-carboxyalkanoic acid derivatives possessing 4'-(N,N-dialkyl-amino or diphenylamino)-benzylidene moiety as a substituent at the C-5 position were synthesised and their antibacterial activity was screened. All the rhodanine derivatives showed bacteriostatic or bactericidal activity to the reference gram-positive bacterial strains, but lack of activity to the reference Gram-negative bacterial strains and yeast strains was observed.

De novo computational design of compounds virtually displaying potent antibacterial activity and desirable in vitro ADMET profiles

Abstract: In this work, we introduce the first multitasking model for quantitative structure-biological effect relationships focused on the simultaneous exploration of antibacterial activity against Gram-negative pathogens and in vitro safety profiles related to absorption, distribution, metabolism, elimination, and toxicity (ADMET). The multitasking model for quantitative structure-biological effect relationships was created from a data set containing 46,229 cases, and it exhibited accuracy higher than 97% in both training and prediction (test) sets. Several molecular fragments present in the compounds of the data set were selected, and their contributions to multiple biological effects were calculated, providing useful insights toward the detection of 2D pharmacophores, toxicophores, etc. Here, we used a fragment-based philosophy known as puzzle approach, where different fragments with positive contributions against all the biological effects (antibacterial activity and ADMET properties) were assembled as pieces of a puzzle, leading to the creation of six new molecules. Such assembly was dictated by the physicochemical interpretations of the different molecular descriptors of the model. The new molecules were predicted to exhibit potent activity against Gram-negative bacteria, and desirable ADMET properties. The druglikeness of these new molecules was in agreement with the Lipinski’s rule of five, making them promising candidates for future biological testing in the framework of collaborative drug discovery.

Synthesis, computational studies and biological evaluation of new 1-acetyl-3-aryl thiourea derivatives as potent cholinesterase inhibitors

Abstract: A new series of 1-acetyl-3-aryl thioureas (3f1–15) was synthesized by the reaction of acetyl isothiocyanate with a variety of suitably substituted aromatic anilines. The acetyl isothiocyanate was freshly prepared by reaction of corresonding acid chloride with potassium thiocyanate. The structural confirmation of all compounds was carried out by spectroscopic techniques and in case of 3a by X-ray diffraction study. The newly prepared compounds were subjected to computational studies and evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition studies. Except 3f9 and 3f15, all the derivatives were found as selective inhibitor of acetylcholinesterase. Compound 3f2 (IC50 ± SEM = 1.99 ± 0.11 µM) was found to be the most potent inhibitor of acetylcholinesterase exhibited ≈11 times greater inhibitory potential than reference inhibitor i.e. neostigmine (IC50 ± SEM = 22.2 ± 3.2 µM). Compound 3f9 was found to be most potent butyrylcholinesterase inhibitor (IC50 ± SEM = 1.33 ± 0.11 µM), exhibiting ≈four times greater selectivity for butyrylcholinesterase over acetylcholinesterase. Molecular docking studies were carried out to determine the binding site interactions of these potent inhibitors with cholinesterases and also supported the experimental observations.

Anticancer activities, molecular docking and structure–activity relationship of novel synthesized 4 H -chromene, and 5 H -chromeno[2,3- d ]pyrimidine candidates

Abstract: In the present study, a series of 4H-chromene and 5H-chromeno[2,3-d]pyrimidine derivatives was synthesized and evaluated as potential cytotoxic agents. The cytotoxic activities of the target compounds were evaluated against four cancer cell lines MCF-7, HCT-116, HepG-2, and A549 in comparison with vinblastine and colchicine as reference drugs. We explored the structure–activity relationship of 4H-chromenes with modification at the 2-,4- or 7-position, and fused pyrimidine ring at 2,3-position. Most of the screened compounds showed marginal antitumor activity against the different cell lines in comparison to the standard drugs. The structure–activity relationship study revealed that the antitumor activity of the synthesized compounds was significantly affected by the lipophilicity of the substituent at the 2-,4- or 7-position for the 4H-chromenes, and 5,8-position or fused pyrimidine ring at 2,3-positions for 5H-chromeno[2,3-d]pyrimidines. Structure–activity relationship was elaborated with the help of molecular docking studies. The structures of the synthesized compounds were established on the basis of the spectral data, infrared, proton nuclear magnetic resonance, 13-Carbon nuclear magnetic resonance and mass spectroscopic data.

Design, characterization, in vitro antibacterial, antitubercular evaluation and structure–activity relationships of new hydrazinyl thiazolyl coumarin derivatives

Abstract: Herein, we describe the synthesis of 11new thiazolyl coumarin derivatives and evaluation of their potential role as antibacterial and antituberculosis agents. The structures of the synthesized compounds were established by extensive spectroscopic studies (Fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance, 13C-nuclear magnetic resonance, 2D-nuclear magnetic resonance and liquid chromatography–mass spectrometry) and elemental analysis. All synthesized compounds were assayed for their in vitro antibacterial activity against a few gram positive and gram negative bacteria and antituberculosis activity against Mycobacterium tuberculosis H37Rv ATCC 25618 by using colorimetric microdilution assay method. Nine derivatives showed moderate anti-bacterial and anti-tuberculosis activities against all the tested strains. The highest activity against all the pathogens including Mycobacterium tuberculosis was observed by compound 7c with MIC values ranging between 31.25–62.5 μg/mL, indicating that coumarin skeleton could indeed provide useful scaffold for the development of new anti-microbial drugs.

Synthesis and anti(myco)bacterial activity of novel 5,5-diphenylpyrrolidine N-aroylthiourea derivatives and a functionalized hexahydro-1H-pyrrolo[1,2-c]imidazole

Abstract: In this paper, five novel 5,5-diphenylpyrrolidine N-aroylthiourea derivatives were synthesized by stereoselective cycloaddition of N-diphenylmethylene-protected glycine methyl ester and methyl acrylate, and subsequent coupling with aroylisothiocyanates. The cis-stereochemistry of one of the heterocyclic thiourea derivatives was characterized by single crystal X-ray diffraction studies. The compounds showed antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Aeromonas hydrophila, Escherichia. coli and Acinetobacter baumannii with minimum inhibitory concentration values in the range of 62.5–1000 μg/mL against these bacterial strains. Antimycobacterial activity of the compounds was investigated against the M. tuberculosis H37Rv strain and all compounds exhibited antimycobacterial activity with a minimum inhibitory concentration value of 80 μg/mL. Additionally, methyl 5,5-diphenylhexahydro-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate was synthesized by cyclization reaction of the 5,5-diphenylpyrrolidine N-aroylthiourea derivatives in the presence of hydrazine monohydrate and exhibited antibacterial activity with a minimum inhibitory concentration value of 62.5 μg/mL against the same bacterial strains and exhibited antimycobacterial activity with a minimum inhibitory concentration value of 80 μg/mL against the M. tuberculosis H37Rv strain.

Binding of anti-Trypanosoma natural products from African flora against selected drug targets: a docking study

Abstract: Recent publications have suggested that African medicinal plants and their derived products could be viable source of new and better trypanocidal drugs. Nowadays, in silico methods are often used in drug discovery processes to identify new potential drug leads. In this study, we have developed a small library named Afrotryp, comprising three-dimensional chemical structures of potential trypanocidal compounds derived from medicinal plants in Africa (a total of 321 unique chemical structures). We have predicted the pharmacokinetic properties of the library using Qikprop software and employed the three docking/scoring methods implemented in Molecular Operating Environment Dock Tool to assess the affinity of the library dataset towards the binding site of six selected validated anti-Trypanosoma drug targets. It was observed that about 42% of the compounds contained in the Afrotryp dataset were predicted to show a good overall performance in terms of predicted parameters for absorption, distribution, metabolism, elimination and toxicity properties. Docking calculations identified 15 compounds with lowest theoretical binding energies toward the studied proteins, nine of which are suited for the treatment of stage 2 human African trypanosomiasis, due to their low polar surface area. Analysis of their binding modes gave basis for the observed unique molecular interactions which exist between the Afrotryp dataset and the six studied drug targets. The results lay the foundations for the rational development of novel trypanocidal drugs with improved potency.

Cytotoxic activity of genistein-8-C-glucoside form Lupinus luteus L. and genistein against human SK-OV-3 ovarian carcinoma cell line

Abstract: Genistein belongs to isoflavones, which are a subclass of flavonoids, a large group of polyphenolic compounds widely distributed in plants. Numerous in vitro studies suggest that isoflavones, particularly genistein, have both chemopreventive and chemotherapeutic potential in multiple tumor types. However, the molecular and cellular mechanisms of genistein effects on human ovarian cancer cells are still little known. In the present study, we investigated anticancer activity of genistein and its natural glucoside, genistein-8-C-glucoside isolated from flowers of Lupinus luteus L. We examined the effects of the two isoflavones alone or in combination on cultured human SK-OV-3 ovarian carcinoma cells. The cells were exposed to genistein and genistein-8-C-glucoside at various concentrations (1–90 µM) for 24 and 48 h. The cytotoxic and apoptotic properties of compounds were studied by the colorimetric 3-[4,5-2-yl]-2-5-diphenyltetrazolium bromide assay and the acridine orange/ethidium bromide staining technique. The morphological features of SK-OV-3 cells were examined by Nomarski differential interference contrast combined with a confocal laser scanning microscope. The level of ROS was evaluated with fluorescence probes: dichlorofluorescein-diacetate by flow cytometry. Changes in mitochondrial membrane potential were determined using 5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolcarbocyanine iodide. Genistein-treatment and genistein-8-C-glucoside-treatment resulted in the inhibition of cell proliferation, induction of apoptotic cell death and loss of mitochondrial membrane potential. The present data provide the first evidence in vitro that genistein-8-C-glucoside and combination genistein-genistein-8-C-glucoside could be a potential chemotherapeutic candidate for ovarian cancer therapy.

Inhibitors of multidrug efflux pumps of Pseudomonas aeruginosa from natural sources: An in silico high-throughput virtual screening and in vitro validation

Abstract: Pseudomonas aeruginosa is resistant to a wide range of antibiotics, thus making troublesome the infection treatment. Efflux systems are the main mechanisms involved; among these, MexAB-OprM is a tripartite efflux pump responsible for resistance to ciprofloxacin, aztreonam, gentamicin, tetracycline and tobramycin. In an attempt to contrast antibiotic efflux, databases of natural compounds were tested for their ability to bind MexB, the inner membrane channel, using a high-throughput virtual screening approach. The comparison of their common pharmacophoric features was the basis for inhibitor identification and selection process. In silico screening against the MexB protein was performed by Autodock/Vina and further refined using a minimization/focused docking protocol on the obtained complexes. The compounds showing the best docking and resulting potentially active at nanomolar concentration have been selected and used in combination with antibiotics usually exported by MexAB-OprM in antimicrobial in vitro synergy tests (checkerboard and time kill assays) against multidrug-resistant P. aeruginosa clinical isolates. The combinations morelloflavone and pregnan-20-one-derivative/ciprofloxacin showed a four-fold MIC decrease and 100-fold increase of the bacterial killing compared to the antibiotic alone. The two chosen hits were validated by ethidium bromide accumulation assay for their efflux inhibition potency. These compounds showed the ability to increase the accumulation of ethidium bromide inside the bacterial cells as evidenced by the increase of its fluorescence in the presence of the each of them. Finally, their toxicity has been preliminary tested through hemolysis assay. The observed good correlation between in silico docking and in vitro synergy tests, indicates these two compounds as promising drugs to be used in combination therapy against MDR and MexAB-OprM overexpressing P. aeruginosa.

Synthesis, characterization, preliminary SAR and molecular docking study of some novel substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as antifungal agents

Abstract: The aim of this study was to synthesize imidazo[2,1-b][1,3,4]thiadiazole derivatives, characterize them with various spectroscopic methods and investigate their antifungal activities. 2-Αmino-1,3,4-thiadiazole derivatives 2a, b were synthesized by reacting nitrile compounds 1a, b with thiosemicarbazide (yields 75 and 88%). We then synthesized imidazo[2,1-b][1,3,4]thiadiazole derivatives 4–21, the target compounds, from the reactions of 2-amino-1,3,4-thiadiazole derivatives 2a, b with phenacyl bromide derivatives 3 (yields 52–69%). The structures of all synthesized compounds were characterized by infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, elemental analysis and mass spectroscopy and X-ray diffraction analysis was also used for the compounds 7, 8, 10, and 17. Subsequently, in vitro antifungal activity tests were applied to all synthesized compounds. Inhibition zones, percentages of inhibition and LD50 doses were determined. Most of the synthesized compounds exhibited good antifungal activity against plant pathogens. Molecular docking and electronic properties calculations were carried out in order to see the potential binding conformations of the ligands and the effect of the substituents on the activities. Docking score successfully reflects the activity of the most active compound 10, which was found to have the lowest octanol/water partition coefficient and high HOMO energy value. The combination of experimental and computational work show that all the synthesized compounds have promising activities and might serve as novel drug candidates.

Exploring the possible binding mode of trisubstituted benzimidazoles analogues in silico for novel drug designtargeting Mtb FtsZ

Abstract: FtsZ, an essential cytokinesis protein, was a highly promising target for antibacterial agents. Following up the identification of trisubstituted benzimidazoles targeting Mycobacterium tuberculosis FtsZ (Mtb FtsZ) in previous studies and in order to explore the possible binding mode of these analogues, in silico methodologies such as 3D-QSAR, ProFunc analysis, molecular docking and molecular dynamic simulation were performed. They corroborated well with each other and gave credence to the proposed binding mechanism of trisubstituted benzimidazoles in the interdomain cleft region of Mtb FtsZ. The benzimidazole scaffold and cyclohexyl group of trisubstituted benzimidazoles were orthogonal to each other in low energy state and inclosed in a most hydrophobic environment formed by residues from the C-terminal β sheets and H7 helix. The carbamate groups at the 5-position extended outward form the cleft cavity to the hydrophilic surface. The substituents at the 6-position fitted into the top portion of the cleft by directly interacting with the T7 loop. It was believed that the hydrophobic interactions and the polar contacts were major contributors to the stabilization of the ligand binding in the interdomain cleft. The binding mechanism provided useful clues to design new trisubstituted benzimidazoles inhibitors of Mtb FisZ with promising activity. The work presented here may even be expanded tremendously to screen novel Mtb FtsZ inhibitors with different scaffolds by using the molecular dynamic refined Mtb FtsZ structure and docking based 3D QSAR CoMFA.

Synthesis and evaluation of 2,3-indolotriterpenoids as new α-glucosidase inhibitors

Abstract: A series of ring-A fused heterocycles of lupane, oleanane, ursane and dammarane triterpenoids were synthesized and evaluated for their inhibitory activity against α-glucosidase. An influence of the different types of triterpenoids with indole and pyrazine cycles on the activity was revealed. Among them, 2,3-indolo-lup-20(29)-en-28-oic acid with an IC50 of 1.8 µM was the most active compound being 221-fold more active than the market drug acarbose. In the most cases, the replacement of the indole by the pyrazine fragment provided the decreasing of activity (except dammarane type pyrazine derivative).

New acetylenic derivatives of betulin and betulone, synthesis and cytotoxic activity

Abstract: Betulin 1 and its semisynthetic derivatives exhibit a cytotoxic activity toward various cancer cell lines. These compounds are a promising and potential anticancer candidates. A series of betulin derivatives was prepared and tested for the antiproliferative activity in vitro against T47D breast cancer, CCRF/CEM leukemia, HL-60 promyelocytic leukemia, SW707 colorectal, murine P388 leukemia, as well as BALB3T3 normal fibroblasts cell lines. Cisplatin and betulin 1 were used as a reference compounds. Some derivatives of betulin showed a higher cytotoxic activity than the parent compound 1. Two derivatives (5 and 17) were 24-fold potent than betulin 1 against the human promyelocytic leukemia cell line (HL-60), with an IC50 value of 0.3 µg/mL.

Albizia harveyi: phytochemical profiling, antioxidant, antidiabetic and hepatoprotective activities of the bark extract

Abstract: Profiling the polyphenols in the methanol extract from the bark of Albizia harveyi was performed by HPLC–PDA–ESI–MS/MS analysis. The phytochemical analysis identified 39 compounds, the majority of them were flavan-3-ol derivatives and condensed tannins. Total phenolic content, determined by the Folin–Ciocalteu method amounted to 489 mg gallic acid equivalents/g extract. The extract showed promising antioxidant activities with an EC50 of 3.6 µg/mL and 18.32 mM FeSO4 equivalent/mg extract in radical scavenging assay and ferric reducing antioxidant power assays, respectively. The hepatoprotective potential of the extract in rats was determined in vivo in a d-galactosamine-induced liver toxicity model. A dose of 100 mg/kg (body weight) of the bark extract reduced levels of aspartate aminotransferase, gamma-glutamyltransferase and total bilirubin by 35.7, 65.3, and 23.8% (p < 0.05), respectively whereas glutathione was increased by 59.1%. These effects were similar to silymarin which was used as positive control. The extract (100 mg/kg (body weight) mediated a substantial antidiabetic response in streptozotocin-induced diabetic rats manifested by a significant reduction in serum glucose and lipid peroxides and significant increase of serum insulin. Docking of d-(+) catechin and the dimer (epi)catechin-(epi)catechin into the active site of the enzymes human pancreatic α-amylase, maltase-glucoamylase, and aldol reductase revealed that these enzymes may be possible targets via which, the studied Albizia harveyi extract could exert its antidiabetic effect.

Determination of antioxidant capacity, phenolic acid composition and antiproliferative effect associated with phenylalanine ammonia lyase (PAL) activity in some plants naturally growing under salt stress

Abstract: Being a considerable abiotic stress factor particularly for arid and semi-arid regions, salt stress may significantly limit the plant growth and yield. Plant’s response to salt stress involves secondary metabolites and especially phenylpropanoids that significantly contribute to the antioxidant activity of plant tissues. In addition to their important role in the control of cancer, phenylpropanoid compounds act as quenchers of singlet oxygen formation, free radical scavengers and reducing agents. One of the important gateway enzymes in the secondary metabolic pathway leading to the synthesis of phenylpropanoids is phenylalanine ammonia lyase (PAL). The aim of this study is to determine the phenolic acid composition, antioxidant capacity and antiproliferative effect associated with PAL activity in some plants that grow naturally under salt stress. The PAL activities of Salsola nitraria, Salvia halophila and Cyathobasis fruticulosa were evaluated. The antioxidant content of the extracts was studied and they were evaluated for their antioxidant activity. MTT assay was used to determine the antiproliferative effects of the extracts on HT-29 cells. Also, phenolic acids in extracts, namely p-coumaric acid, vanillic acid, gallic acid, caffeic acid, chlorogenic acid and syringic acid were screened using LC-MS/MS. Considering all results, C. fruticulosa with its highest PAL activity (62.85 μmol.min−1.mg−1 protein) has become prominent among the three plants. C. fruticulosa extract exhibited the highest antioxidant content with total phenolic content (120.36 mg/g) as the major antioxidant component. It was also found to be the plant extract richest in p-coumaric acid, vanillic acid, gallic acid, caffeic acid, chlorogenic acid and syringic acid as phenolic acids. Besides its marked antiproliferative activity against HT-29 cells, C. fruticulosa extract had the highest antioxidant activity compared with other extracts. In conclusion, the antioxidant and anticancer properties of plants naturally growing under salt stress may partly arise from their high PAL activities. Therefore, compounds obtained through plants exhibiting high levels of PAL activities could be used in the development of new pharmaceuticals as an antioxidant and anticancer agent.

Quantum chemical, ADMET and molecular docking studies of ferulic acid amide derivatives with a novel anticancer drug target

Abstract: Cancer is among the major health problems and leading cause of deaths worldwide. As per the World Health Organization report, the number of cancer patients will increase up to ≥30% by the year of 2030. So there is a necessity to invent new and effective anticancer agents. Peptide deformylase, a member of hydrolases family which removes the formyl group from initiating methionine of nascent peptides, recently proved as novel target for anticancer drugs. Here, theoretical studies of ferulic acid amide derivatives have been performed for geometry optimization, calculation of electronic properties and structural parameters by using density functional theory employing B3LYP correlation at 6–311 G** basis set by Gaussian 09 suite. Calculations of highest occupied molecular orbital and lowest unoccupied molecular orbital energies showed the eventual charge transfer interaction within the molecules. The absorption, distribution, metabolism, excretion and toxicity parameters were prediction and found satisfactory. Further, the molecular docking of all the ferulic acid amide derivatives with human peptide deformylase (Homo sapiens; HsPDF; PDB ID: 5G5K) have been carried which confirmed the inhibition of HsPDF and the data were also found in line with the previously reported experimental results by our research group. Results of docking studies manifest Va–Vg (containing acridine moiety) as the top five HsPDF inhibitors as most potent efficacious and selective drugs in the form of docking score as compared to their parent molecule. The in vitro and in silico studies performed for these proposed inhibitors showed the potentials to become a vital anticancer candidate and in future possibly be either used alone or in combination with known existing drugs which can together act synergistically more effectively to treat different type of cancer.

Design, synthesis and biological evaluation of new 4-(4-substituted-anilino)quinoline derivatives as anticancer agents

Abstract: A new series of 4-(4-substituted-anilino)quinoline derivatives 6a–f was synthesized from amine derivatives via Gould–Jacobs reaction. All synthesized compounds were evaluated for their cytotoxic activity against two human cancer cell lines; breast carcinoma (MCF-7) and non-small cell lung cancer (A549). The tested compounds showed a broad range of activities (IC50 = 3.42–23.32 and 5.97–22.01 µM) in comparison with doxorubicin (IC50 = 2.07 and 0.02 µM) and erlotinib (IC50 = 1.14 and 19.26 µM) for MCF-7 and A549 respectively. The 4-(4-chloroanilino)quinoline derivative (6c, IC50 = 3.42 and 5.97 µM) was the most potent among all compounds against both MCF-7 and A549 cell lines respectively. In addition, molecular docking studies were performed and the results were in agreement with the in vitro cytotoxic data.

Synthesis, antitubercular and antimicrobial potential of some new thiazole substituted thiosemicarbazide derivatives

Abstract: The increase in antibiotic resistance due to multiple factors has warranted the need for search of new compounds which are active against multidrug resistant pathogens. In this context a small focused library of thiosemicarbazide derivatives of 2-arylthiazole-4-carbaldehyde, 4-methyl-2-arylthiazole-5-carbaldehyde and 1-(4-methyl-2-arylthiazol-5-yl) ethanone, (5a–l) has been synthesized. The title compounds were screened for inhibitory activity against Mycobacterium tuberculosis H37Ra (ATCC 25177) and Mycobacterium bovis Bacille Calmette Guerin (ATCC 35743) strains. The synthesized compounds, 5a–l were further assayed for their cytotoxic activity against the two human cancer cell lines, HeLa and human colon carcinoma 116 cell lines and showed no significant cytotoxic activity against these two cell lines at the maximum concentration evaluated. Further, the synthesized compounds were found to have potential antibacterial activity against Gram-negative bacteria, Escherichia coli, Pseudomonas flurescence and Gram-positive bacteria, Staphylococcus aureus, Bacillus subtilis. Most of the synthesized compounds showed moderate activity against fungal strain Candida albicans. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antimycobacterial agent.

Synthesis, anti-inflammatory and neuroprotective activity of pyrazole and pyrazolo[3,4-d]pyridazine bearing 3,4,5-trimethoxyphenyl

Abstract: A new series of 3,4,5-trimethoxyphenyl bearing pyrazole (4a–g) and pyrazolo[3,4-d]pyridazine (5a–g) scaffolds were synthesized in good yield. The newly synthesized compounds were characterized on the basis of elemental and spectroscopic analyses. Their inhibitory activity against the pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2 proteins expression in lipopolysaccharide-stimulated murine RAW 264.7 macrophages were assessed and showed various potencies. All pyrazolo[3,4-d]pyridazine compounds (5a–g) strongly down regulated lipopolysaccharide inducible nitric oxide synthase expression to the range of 20.3 ± 0.6–51.3 ± 3.5% relative to the bioactive pyrazole derivatives 4b, 4c, 4e and 4g. With the exception of inactive compounds 4c and 4d, all other synthesized compounds inhibited cyclooxygenase-2 expression below 100% in the lipopolysaccharide-stimulated cells, which being declined maximally to 42.8 ± 1.4% by one of the pyrazolo[3,4-d]pyridazine compounds (5d). Moreover, the neuroprotective activity of the less cytotoxic compounds 4b, (4e–g) and (5a–g) were evaluated against 6-hydroxydopamine (6-OHDA)-induced neuroblastoma SH-SY5Y cell death and exhibited significant (p < 0.05) cell protection. The pyrazolo[3,4-d]pyridazine compound (5e) exhibited more than 100% of relative neuroprotection (110.7 ± 4.3%) with an additional advantage of having the highest cell viability index (107.2 ± 2.9%).

New α-Pyrone derivatives from the endophytic fungus Embellisia sp

Abstract: Two new α- Pyrone derivatives (1,2) have been isolated from the endophytic fungus Embellisia sp. The isolated compounds were chemically identified as 5-(3-S-hydroxybutyl)-4-methoxy-6-methyl-2H-pyran-2-one (1) and 4-(4-methoxy-6-methyl-2-oxo-2H-pyran-5-yl)butanoic acid (2). The chemical structures of 1 and 2 were determined based on one and two dimensional NMR spectroscopy and high resolution mass spectrometry. Absolute configuration of compound 1 was determined using modified mosher ester reaction. In vitro antileishmanial, antifungal, antibacterial and antimalarial activities of 1 and 2 were examined but they didn’t show promising activities.

Halogenated 2-amino-4 H -benzo[ h ]chromene derivatives as antitumor agents and the relationship between lipophilicity and antitumor activity

Abstract: Several halogenated 2-amino-4H-benzo[h]chromene derivatives were synthesized and evaluated their cytotoxicity. The structures of the synthesized compounds were established on the basis of spectral data. The in vitro antitumor activity of the synthesized compounds against the cell lines MCF-7, HCT-116, and HepG-2 was investigated in comparison with the reference drugs vinblastine, colchicine, and doxorubicin using microculture tetrazolium colorimetric assay. It was found that some halogenated 4H-benzo[h]chromene derivatives showed the highest antitumor activity as compared with the reference drugs. The structure–activity relationship studies reported that the substitution at 4-position in the 4H-benzo[h]chromene nucleus with the specific halogen groups and lipophilicity increases the ability of the molecule against the different cell lines.

N -acylhydrazones containing thiophene nucleus: a new anticancer class

Abstract: In this study, we present a series of N-acylhydrazones containing thiophene nuclei as a new anticancer class. Fifty-seven compounds in this series were evaluated for their activity against four human cancer cell lines. Cytotoxicity (IC50) ranged from 0.82 to 12.90 μM. The compound (E)-N′-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide displayed good cytotoxic activity in all cell lines (IC50 = 0.82–5.36 μM) and yielded the best result in this series; therefore, it is an important lead compound in this new class.

Synthesis and antimicrobial/antimalarial activities of novel naphthalimido trans -β-lactam derivatives

Abstract: This paper describes for the first time the synthesis and microbiological assessment of some new β-lactam derivatives containing a 1,8-naphthalimide functional group. These compounds were obtained through a [2 + 2] cyclocondensation (Staudinger reaction) of a ketene derived from 2-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl) acetic acid (Alrestatin) and various N-arylimines. The reaction was totally diastereoselective leading exclusively to the formation of trans-β-lactam adducts 3a–l, which were characterized by FT-Infra Red, 1H NMR, 13C NMR, mass spectrometry, elemental analyses, and X-ray crystallography, and then individually evaluated for antibacterial and antimalarial activities. Two of the β-lactams, 3c and 3l, afforded IC50 values of 3 and 5 µM, respectively, against Plasmodium falciparum K1 resistant strain.

Design, synthesis, and biological evaluation of 4-H pyran derivatives as antimicrobial and anticancer agents

Abstract: A series of pyran derivatives (5–27) were synthesized in good yields by utilizing Baylis–Hillman chemistry and were further investigated for their in vitro anticancer, antibacterial, and antifungal activities. Most of the tested compounds exhibited promising antibacterial activity as compared to the standard towards Gram-positive bacterial strains. The compounds 5–7, 11–13, and 17–19 displayed two-fold higher activity whereas compound 21 showed four-fold higher antibacterial activity against Staphylococcus aureus MTCC 96 as compared to the standard Neomycin. Some of these compounds exhibited moderate antifungal activity against all the tested fungal strains. Two compounds 16 and 23 showed promising anticancer activity against selected four human cancer cell lines such as A549, DU145, HeLa, and MCF7.