Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC₅₀ 0.037, 0.044 and 0.042?μM, respectively, while IC₅₀ of thiourea is 20.9?μM.     

Inhibition of fatty acid synthase by ginkgolic acids from the leaves of Ginkgo biloba and their cytotoxic activity

Fatty acid synthase (FAS) has been proposed to be a new drug target for the development of anticancer agents because of the significant difference in expression of FAS between normal and tumour cells. Since a n-hexane-soluble extract from Ginkgo biloba was demonstrated to inhibit FAS activity in our preliminary test, we isolated active compounds from the n-hexane-soluble extract and evaluated their cytotoxic activity in human cancer cells. Three ginkgolic acids 1–3 isolated from the n-hexane-soluble extract inhibited the enzyme with IC₅₀ values 17.1, 9.2 and 10.5 µM, respectively, and they showed cytotoxic activity against MCF-7 (human breast adenocarcinoma), A549 (human lung adenocarcinoma) and HL-60 (human leukaemia) cells. Our findings suggest that alkylphenol derivatives might be a new type of FAS inhibitor with cytotoxic activity.     

Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer,anti-cancer and anti-inflammatory activities

Abstract

In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC₅₀?=?10.4?µM) was obtained for harmine 1 and cytotoxic activities (IC₅₀?=?0.2?µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC₅₀?=?29.2 and 55.5?µM, respectively).     

Indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents

A new series of indolylhydrazones (6) and indole-based 4-thiazolidinones (7, 8) have been designed, synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. 4-Thiazolidinone derivatives 7g–7j, 8g, 8h and 8j displayed notable antituberculosis (anti-TB) activity showing 99% inhibition at MIC values ranging from 6.25 to 25.0?µg/ml. Compounds 7g, 7h, 7i, 8h and 8j demonstrated anti-TB activity at concentrations 10-fold lower than those cytotoxic for the mammalian cell lines. The indolylhydrazone derivative 6b has also been evaluated for antiproliferative activity against human cancer cell lines at the National Cancer Institute (USA). Compound 6b showed an interesting anticancer profile against different human tumor-derived cell lines at sub-micromolar concentrations with obvious selectivity toward colon cancer cell line COLO 205.     

Conferin,potent antioxidant and anti-inflammatory isoflavone from Caragana conferta Benth

Conferin (1), a new isoflavone, has been isolated from the ethyl acetate soluble fraction of Caragana conferta Benth. along with seven known compounds, namely biochanin A (2), p-hydroxybenzoic acid (3), 3,5- dimethoxybenzoic acid (4), ursolic acid (5), erythrodiol (6), pinoresinol (7), and syringresinol (8), reported for the first time from this species. The structure of the new isoflavone was deduced on the basis of spectroscopic studies. Compounds 1 and 2 were investigated for biological activities and showed significant anti-inflammatory activity in carrageenan induced paw edema of rats. Evaluation of antioxidant activity by the radical scavenging method indicated that compound 1 is a potent antioxidant while 2 is moderately active. It was also shown that the reducing capability of compound 2 was remarkably increased in a concentration dependent manner as compared to 1. Compound 1 showed moderate inhibitory activity against the enzyme lipoxygenase, while 2 showed weak activity.     

Definitive Solution Structures for the 6-Formylated Versions of 1-(βD-Ribofuranosyl)-, 1-(2′-Deoxy-β-D-Ribofuranosyl)-, and 1-β-D-Arabinofuranosyluracil,and of Thymidine

Abstract

ROESY and NOESY NMR spectroscopic analyses of the ribofuranosyl (1a), 2′-deoxyribofuranosyl (1b), and arabinofuranosyl (1c) derivatives of 6-formyluracil in (CD₃)₂SO and D₂O solutions have established that each exclusive 7,05′-cyclic hemiacetal diastereomer of 1a,b and the major 7,O2′-cyclic hemiacetal diastereomer of 1c possess the 7R configuration. In addition, (7R)-1c has been shown to be thermodynamically more stable than (7S)-1c, contrary to our previous indication. A new, higher yielding synthetic route to 1a has been developed, 1b has been obtained for the first time in crystalline form, the route to 1c has been modified to better accommodate large scale preparations, and a new, fourth member of this class, 6-formylthymidine (1d), has been synthesized and its solution structures in (CD₃)₂SO, D₂O, and CD₃OD have been determined. Antitumor and antiviral evaluations of 1a-c have revealed no significant levels of activity.     

Pyrazole Related Nucleosides 5.1 Synthesis and Biological Activity of 2′-Deoxy- 2′, 3′-dideoxy- and Acyclo-analogues of 4-Iodo-1-β-D-ribofuranosyl-3-carboxymethyl Pyrazole (IPCAR)

Abstract

Continuing our studies on the structure-activity relationships (SAR) of 4-iodo-1-β-D-ribofuranosyl-3-carboxymethyl pyrazole (IPCAR), the ribofuranosyl moiety has been substituted with acyclic chains, namely 1-[(2-hydroxyethoxy)methyl]- and 1-[(1,3-dihydroxy-2-propoxy)methyl]-pyrazole derivatives (4, 5 and 8, 9 respectively), with the 2′-deoxy-β-D-ribofuranosyl group (12 and 13) and finally with the 2′,3′-dideoxy-D-glycero-pentofuranosyl-moiety (16 and 17). None of the new compounds display any interesting biological activity.     

Synthesis and Antiviral Evaluation of Adenosine-N1-Oxide and 1-(Benzyloxy) Adenosines

Abstract

The antiviral activity of adenosine-N¹-oxide (1) and a variety of substituted 1-(benzyloxy) adenosines (2) has been re-investigated and significant in vitro activity vs. Vaccinia virus has been shown. In vivo activity in mice has also been demonstrated.     

A new potential spreading factor: Streptomyces koganeiensis hyaluronidase. A comparative study with bovine testes hyaluronidase and recombinant human hyaluronidase of the HA degradation in ECM

BackgroundRecombinant human hyaluronidase has been used in the interstitial matrix to promote the dispersion of therapeutics. The production and isolation of an extracellular hyaluronidase from Streptomyces koganeiensis (rHyal_Sk) has recently been described.MethodsThe specificity of rHyal_Sk has been assessed against heparan sulfate, chondroitin sulfates and sulfated HAs. The oligomers generated by HA degradation have been investigated by MALDI-TOF MS analysis. rHyal_Sk has been compared with BTH and PH20 in vitro, against cross-linked HA (ACP) and HA–aggrecan complex, and in vivo, by means of a diffusion assay in nude mice.ResultsDepolymerization of HA by rHyal_Sk gave tetra-, hexa- and octasaccharides in high yields. The reaction mechanism and the high HA specificity were demonstrated. The in vivo diffusion assay, supported by the in vitro tests, evidenced an initially enhanced enzymatic activity of rHyal_Sk compared to BTH and PH20.ConclusionsrHyal_Sk, compared to BTH and PH20, showed higher substrate specificity and no inhibition from GAGs sulfate, together with a superior performance for HA depolymerization in ECM. As better predictive tests for the in vivo activity of hyaluronidase we developed two assays based on the degradation of ACP or of the HA–aggrecan complex.General significancerHyal_Sk is a new potential spreading factor for intradermal drug administration. Hyaluronidases of distinct classes, that show equivalent activities in a common turbidimetric assay, could have different potencies and dose-efficacies in vivo which influences the therapeutic effect. The new proposed in vitro tests are designed to obtain a predictive characterization of the enzyme activity in vivo.     

Characterization of β-lactamase activity using isothermal titration calorimetry

BackgroundHydrolysis of β-lactam antibiotic by β-lactamase is the most common mechanism of β-lactam resistance in clinical isolates. Timely detection and characterization of β-lactamases are therefore of utmost biomedical importance. Conventional spectrophotometric method is time-consuming and cannot provide thermodynamic information on β-lactamases.MethodsA new assay was developed for the study of β-lactamase activity in protein solutions (Metallo-β-lactamase L1) and in clinical bacterial cells, based on heat-flow changes derived from enzymatic hydrolysis of β-lactams using isothermal titration calorimetry.Results(1) The thermokinetic parameters of three antibiotics (penicillin G, cefazolin and imipenem) and the inhibition constant of an azolylthioacetamide inhibitor were determined using the calorimetric assay. The results from the calorimetric assays were consistent with the data from the spectrophotometric assay. (2) The values of heat change in the calorimetric assay using two clinical Escherichia coli strains correlated well with their antibiotic susceptibility results from the broth dilution experiment. The subtypes of β-lactamase were also determined in the calorimetric assay.ConclusionsThe ITC assay is a reliable and fast method to study β-lactamase enzyme kinetics and inhibition. It can also provide thermodynamic information on antibiotic hydrolysis, which has been taken advantage of in this work to study β-lactamase activity in two clinical Escherichia coli isolates.General significanceAs the first calorimetric study of β-lactamase activity, it may provide a new assay to assist biomedical validation of new β-lactamase inhibitors, and also has potential applications on rapid antibiotic susceptibility testing and screening β-lactamase producing bacteria.     

Synthesis and anticandidal evaluation of new benzothiazole derivatives with hydrazone moiety

In this study, we have performed the synthesis of new N′-(arylidene)-4-[(benzothiazol-2-yl)thio]butanoylhydrazide derivatives (3a–s) bearing azole moiety and hydrazone group in a lipophilic structural framework. The target compounds were prepared by a three step synthetic procedure starting from 2-mercaptobenzothiazole. The structures of the target compounds were elucidated by IR, ¹H NMR, ¹³C NMR spectra and elemental analysis. The antifungal activity of the obtained compounds has been determined against a number of clinic and fluconazole-resistant Candida strains by using microdilution method. Compounds (3a–3s) exhibited anticandidal activity in different ratios varying between the range of MIC: 50 and 200?µg/mL.     

2-Amino-3-cyanopyridine derivatives as carbonic anhydrase inhibitors

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous enzymes that catalyze the hydration of CO₂ to bicarbonate and protons. Inhibition of CAs has been clinically exploited for the treatment of various classes of diseases for decades, but investigating new classes of inhibitors continues to be important. We have synthesized a series of 2-amino-3-cyano-4-heteroaryl (5a–l) compounds and characterized the structures by NMR, IR and elemental analyses. We tested the ability of these compounds to inhibit two metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and hCA II. Compounds 5d and 5b showed the best inhibition activity against hCA I (IC₅₀: 33 and 34 µM, respectively), and compound 5d showed the best activity against hCA II (IC₅₀: 56 µM).     

Synthesis,molecular docking,binding free energy calculation and molecular dynamics simulation studies of benzothiazol-2-ylcarbamodithioates as Staphylococcus aureus MurD inhibitors

Abstract

A new series of benzothiazol-2-ylcarbamodithioate functional compounds 5a-f has been designed, synthesized and characterized by spectral data. These compounds were screened for their in vitro antibacterial activity against strains of Staphylococcus aureus (NCIM 5021, NCIM 5022 and methicillin-resistant isolate 43300), Bacillus subtilis (NCIM 2545), Escherichia coli (NCIM 2567), Klebsiella pneumoniae (NCIM 2706) and Psudomonas aeruginosa (NCIM 2036). Compounds 5a and 5d exhibited significant activity against all the tested bacterial strains. Specifically, compounds 5a and 5d showed potent activity against K. pneumoniae (NCIM 2706), while compound 5a also displayed potent activity against S. aureus (NCIM 5021). Compound 5d showed minimum IC₅₀ value of 13.37?μM against S. aureus MurD enzyme. Further, the binding interactions of compounds 5a-f in the catalytic pocket have been investigated using the extra-precision molecular docking and binding free energy calculation by MM-GBSA approach. A 30?ns molecular dynamics simulation of 5d/modeled S. aureus MurD enzyme was performed to determine the stability of the predicted binding conformation.     

Synthesis of some 4-arylidenamino-4H-1,2,4-triazole-3-thiols and their antituberculosis activity

The increasing clinical importance of drug-resistant mycobacterial pathogens has lent additional urgency to microbiological research and new antimycobacterial compound development. For this purpose, new triazoles were synthesized and evaluated for antituberculosis activity. A series of 4-arylidenamino-4H-1,2,4-triazole-3-thiol derivatives (2a–n) were synthesized from the treatment of 4-amino-4H-1,2,4-triazoles-3-thiol (1) with the respective aldehydes and were evaluated for antituberculosis activity against Mycobacterium tuberculosis H₃₇Rv (ATCC 27294), using the BACTEC 460 radiometric system and BACTEC 12B medium. Compound 2k showed an intereting activity at 6.25 μg/mL with a 87 percentage inhibition.     

The pterocellins,bioactive alkaloids from the marine bryozoan <Emphasis Type="Italic">Pterocella vesiculosa</Emphasis>

Although comparatively little research has been undertaken into the secondary metabolites of bryozoans as compared with those of other marine invertebrates, bryozoans have proven to be an excellent source of novel and/or biologically active compounds. The majority of bryozoan metabolites isolated to date have been alkaloids. In our continuing search for bioactive and/or novel compounds from New Zealand marine bryozoans, we undertook an investigation of an extract of Pterocella vesiculosa (order Cheilostomatida, suborder Ascophorina, family Catenicellidae) which possessed activity against P388 murine leukaemia cells. Two alkaloids, pterocellins A–B (1–2) have been isolated from the bryozoan. The biological activity of these alkaloids was examined including their activities in the in vitro 60 cell line panel and in vivo hollow fibre assays at the National Cancer Institute (NCI). The isolation and characterisation of further pterocellin analogues is currently in progress and tentative structures for two new members of this series, pterocellins C–D (3–4) are proposed, based on NMR and mass spectral data.     

Evaluation of anti-inflammatory and antioxidant activities of Copper (II) Schiff mono-base and Copper(II) Schiff base coordination compounds of dien with heterocyclic aldehydes and 2-amino-5-methyl-thiazole

Highly reactive radicals are implicated in many pathological conditions. The quest for radical scavengers or antioxidants, spans the previous decades. A new series of complexes of the type [Cu (dien) (2a-2tzn) Y₂] and [Cu (dienXXY₂) (2a-5mt)] and of the type [Cu (dptaS) Cl₂] and [Cu (dptaS) Br₂] (dptaS = 1, 3-propanediamine) or Schiff mono-base of dipropylenetriamine with 2-thiophene-carboxaldehyde, has been tested for anti-inflammatory and antioxidant activity. The tested compounds inhibit the carrageenin-induced rat paw edema (52.0–82.6%) and present important scavenging activity. Compound 6 is the most potent (82.6%) in the in vivo experiment. Lipophilicity-as R_M values – has been determined. The results support that in general, adducts of the type [Cu (dienXXY₂) (2a-5mt)] exhibit increased activity compared to the starting material of type [Cu (dienXXY₂)]. An attempt to correlate the biological results with their structural characteristics and physicochemical parameters has been made     

Barlerisides A and B,new potent superoxide scavenging phenolic glycosides from Barleria acanthoides

Barlerisides A (1) and B (2), new phenolic glycosides, have been isolated from the n-butanol soluble sub-fraction of Barleria acanthoides along with two known compounds acteoside (3) and p-hydroxycinnamic acid (4). Their structures have been assigned on the basis of spectral studies. Both 1 and 2 showed significant activity in the superoxide scavenging assay while weak inhibitory activity was observed against the enzyme xanthine oxidase.     

Design,synthesis and in vitro bactericidal/fungicidal screening of some vanadyl(IV)complexes with mono- and di-substituted ONS donor triazoles

Abstract

A new series of anti-bacterial and anti-fungal mono- and di-substituted triazoles (L¹)–(L⁶) have been synthesized and characterized on the basis of their physical, spectral and analytical data. The ligands (L¹)–(L⁶) on reaction with vanadyl(IV) sulphate led to the formation of vanadyl(IV) metal complexes (1)–(4). The structure of the complexes has been established on the basis of their physical, spectral and elemental analyses data. The synthesized ligands and their vanadyl(IV) complexes have been screened in vitro for anti-bacterial activity against six bacterial species such as, Escherichia coli (ATCC 25922), Shigella flexneri (ATCC 12022), Pseudomonas aeruginosa (ATCC 27853), Salmonella typhi (ATCC 14028), Staphylococcus aureus (ATCC 25923) and Bacillus subtilis (ATCC 6051) and for in vitro anti-fungal activity against six fungal strains, Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata. The screening results showed the vanadyl complexes to be more bactericidal/fungicidal against one or more bacterial/fungal species. The synthesized compounds were also subjected to brine shrimp bioassay for scrutinizing their cytotoxicity.