Synthesis and Anti-HIV Activity of Some S-Acyl-2-thioethyl (SATE) Phosphoramidate Derivatives of 3′-Azido-2′,3′-dideoxythymidine

Abstract

The synthesis and in vitro anti-HIV activity of tBuSATE phosphoramidate derivatives of AZT incorporating several methyl-esterified α-aminoacids are reported. The biological evaluation strongly supports the hypothesis that such compounds exert their anti-HIV effects via intracellular delivery of the corresponding 5′-mononucleotide.     

Novel pyrazole–pyrazoline hybrids endowed with thioamide as antimalarial agents: their synthesis and 3D-QSAR studies

Abstract

One of the most viable options to tackle the growing resistance to the antimalarial drugs is hybrid molecules. It involves combination of different scaffolds in one frame that may lead to compounds with diverse biological profiles. In this context, new hybrids of three different scaffolds viz pyrazole, pyrazoline and thiosemicarbazone moiety were incorporated into one single compound and evaluated for their in vitro schizontocidal activity against the CQ-sensitive 3D7 strain of Plasmodium falciparum. Compounds with significant in vitro antimalarial activity were further evaluated for cytotoxicity against VERO cell lines. The best active compound 48 exhibited an IC₅₀ of 1.13?µM. The in vitro results were further validated by quantitative structure–activity relationship (QSAR).     

Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease

Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer’s disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure–activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid β-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC₅₀?=?10.2?±?1.2, 16.5?±?1.7, and 15.3?±?1.8?nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.     

In vitro activity of the antimicrobial peptide AP7121 against the human methicillin-resistant biofilm producers Staphylococcus aureus and Staphylococcus epidermidis

Abstract

In vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis biofilm producers from blood cultures of patients with prosthetic hip infections was evaluated. The Minimum Inhibitory Concentration (MIC) for AP7121 was determined and the bactericidal activity of AP7121 (MICx1, MICx4) against planktonic cells was studied at 4, 8 and 24?h. The biofilms formed were incubated with AP7121 (MICx1, MICx4) for 1 and 24?h. The anti-adhesion effect of an AP7121-treated inert surface over the highest MIC isolate was studied with scanning electron microscopy (SEM). The bactericidal activity of AP7121 against all the planktonic staphylococcal cells was observed at 4?h at both peptide concentrations. Dose-dependent anti-biofilm activity was detected. AP7121 (MICx4) showed bactericidal activity at 24?h in all isolates. SEM confirmed prevention of biofilm formation. This research showed the in vitro anti-biofilm activity of AP7121 against MRSA and S. epidermidis and the prevention of biofilm formation by them on an abiotic surface.     

The In Vitro and In Vivo Inhibitory Effects of Some Sulfonamide Derivatives on Rainbow Trout (Oncorhynchus Mykiss) Erythrocyte Carbonic Anhydrase Activity

The in vitro and in vivo inhibitory effects of 5-(3α, 12α-dihydroxy-5-β-cholanamido)-1,3,4-thiadiazole-2-sulfonamide (1), 5-(3α, 7α, 12α-trihydroxy-5-β-cholanamido)-1,3,4-thiadiazole-2-sulfonamide (2), 5-(3α, 7α, 12α-triacetoxy-5-β-cholanamido)-1,3,4-thiadiazole-2-sulfonamide (3) and acetazolamide on rainbow trout (Oncorhynchus mykiss) (RT) erythrocyte carbonic anhydrase (CA) were investigated. The RT erythrocyte CA was obtained by affinity chromatography with a yield of 20.9%, a specific activity of 422.5?EU/mg protein and a purification of 222.4-fold. The purity of the enzyme was confirmed by SDS-PAGE. Inhibitory effects of the sulfonamides and acetazolamide on the RT erythrocyte CA were determined using the CO₂-Hydratase method in vitro and in vivo studies. From in vitro studies, it was found that all the compounds inhibited CA. The obtained I₅₀ value for the sulfonamides (1), (2) and (3) and acetazolamide were 0.83, 0.049, 0.82 and 0.052?μM, respectively. From in vivo studies, it was observed that CA was inhibited by the sulfonamides (1), (2) and (3) and acetazolamide.     

Synthesis and In Vitro Antiviral Activity of Some Symmetrical Phosphoramidate Dimers of AZT

Abstract

The synthesis of some symmetrical phosphoramidate dimers of AZT is presented. The synthetic scheme includes the formation of the symmetrical H-phosphonate diester of AZT, followed by its conversion to several dinucleoside phosphoramidate analogues. The compounds were evaluated for their anti-retroviral activity.     

In vitro antimicrobial activity of plant extracts against Pseudomonas syringae pv. actinidiae causal agent of bacterial canker in kiwifruit

Abstract

Pseudomonas syringae pv. actinidiae (Psa), the causal agent of bacterial canker of kiwifruit, is considered the main pathogen of yellow-, green- and red-fleshed kiwifruit. All major kiwifruit producing countries in the world have been affected by this bacterial pathogen, leading to substantial economic losses. The control of bacterial canker of kiwifruit is based only on preventive methods or on the use of copper compounds that can cause phytotoxicity problems. In this study, the in vitro antibacterial activity of seven different plant extracts against eight Psa strains has been evaluated. The inhibition of 100% of the Psa growth was observed, after 24?h, for the extracts of Polygonum cuspidatum roots (POL-roots), Hypericum perforatum roots elicited with chitosan oligosaccharides (HYP-COS roots) and non-fermented grape pomace (ITA-pomace). The strongest antibacterial activity was exhibited by POL-roots, with a geometric mean of minimum inhibitory concentration of 100% of growth (GMMIC₁₀₀) of 105.11 µg/mL after 24?h, and with a GMMIC₁₀₀ value of 148.65 µg/mL after 48?h. Moreover, POL-roots extract showed the best bactericidal activity with a GMMBC of 210.22 µg/mL. No phytotoxic activity was observed up to 15 days in the leaves of Actinidia chinensis “Belen” treated with plant extracts at 500 µg/mL.     

In vitro inhibition effect of some coumarin compounds on purified human serum paraoxonase 1 (PON1)

Human serum paraoxonase 1 (PON1; EC 3.1.8.1) is a high-density lipoprotein associated, calcium-dependent enzyme that hydrolyses aromatic esters, organophosphates and lactones and can protect the low-density lipoprotein against oxidation. In this study, in vitro effect of some hydroxy and dihydroxy ionic coumarin derivatives (1–20) on purified PON1 activity was investigated. Among these compounds, derivatives 11–20 are water soluble. In investigated compounds, compounds 6 and 13 were found the most active (IC₅₀?=?35 and 34?µM) for PON1, respectively. The present study has demonstrated that PON1 activity is very highly sensitive to studied coumarin derivatives.     

Synthesis and anticancer activity of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidine analogs and their phosphoramidates

Abstract

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (20–49) was synthesized by means of phosphorylation of 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) with 4-chlorophenyl phosphoroditriazolide (14), followed by a reaction with the appropriate amine. The synthesized compounds 7–11 and 20–49 were evaluated along with four known anticancer compounds for their cytotoxic activity in human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), osteosarcoma (143B) (only selected compounds 20, 24, 28, 32–36, 38, 40, 46) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Among 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) the highest activity in all the investigated cancer cells was displayed by 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (9) (IC₅₀ in the range of 2.58–3.61?μM) and its activity was higher than that of cytarabine. Among phosphoramidates 20–49 the highest activity was demonstrated by N-n-propyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (35) in all the cancer cells (IC₅₀ in the range of 0.97–1.94?μM). Also N-ethyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (33) exhibited good activity in all the used cell lines (IC₅₀ in the range of 4.79–4.96?μM).     

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).     

Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides

A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P–N bond cleavage and free nucleoside 5′-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.     

Synthesis of organometallic-based biologically active compounds: In vitro antibacterial,antifungal and cytotoxic properties of some sulfonamide incorporated ferrocences

Sulfonamides incorporated ferrocene (SIF) have been synthesized by the condensation reaction of sulfonamides (sulfanilamide, sulfathiazole or sulfamethaxazole) with 1,1′-diacetylferrocene. The synthesized compounds (SIF¹–SIF⁴) have been characterized by their physical, spectral and analytical properties and have been screened for their in vitro antibacterial properties against pathogenic bacterial strains e.g., Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis Staphylococcus aureus and Salmonella typhi and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata using Agar-well diffusion method. Most of the compounds showed good antibacterial activity whereas, all the compounds exhibited significant antifungal activity. Brine shrimp bioassay was also carried out for in vitro cytotoxic properties against Artemia salina.     

Synthesis,Biophysical and Biological Evaluations of Novel Antisense Oligonucleosides Containing Dephosphono-Internucleosidic Linkages

Abstract

Efficient large-scale syntheses of methylene(methylimino) (MMI) linked mixed base nucleosidic dimers have been accomplished. These dimers were successfully incorporated into deoxyoligonucleotides by automated solid-support synthesis. The hybridization properties, nuclease stability, RNase H mediated cleavage and in vitro biological activity of novel chimeric oligomers have been studied. The biophysical and biological evaluation of these chimeric oligomers containing MMI linkages suggests that MMI is a promising chemical modification of the backbone linkage for the construction of antisense molecules useful as therapeutics.     

Urease inhibitors from Hypericum oblongifolium WALL.

The bioassay-guided fractionation of H. oblongifolium has led to the isolation of potent urease inhibitors 1–3. The structures were elucidated by NMR and mass spectroscopic techniques. Compound 2 showed a potent enzyme inhibition activity (IC₅₀ 20.96?±?0.93), which is comparatively higher than that for the standard thiourea (IC₅₀ 21.01?±?0.51 μM). Compounds 1 and 3 also showed a significant activity, with IC₅₀ 37.95?±?1.93 and 138.43?±?1.23 μM, respectively. The sub crude fractions (F1, F2, F3, and F4) were tested in vitro for their urease inhibition activity. Fractions F2 and F4 showed significant activity with IC₅₀ 140.37?±?1.93 and 167.43?±?3.03 μM, respectively.     

Synthesis and biological activity of progesterone derivatives as 5α-reductase inhibitors,and their effect on hamster prostate weight

In this study, we report the synthesis and biological evaluation of four 6- and 17-substituted progesterone derivatives (7–10). These compounds were prepared from the commercially available 17α-acetoxyprogesterone. The biological effect of these steroids was demonstrated in in vivo as well as in vitro experiments. In the in vivo experiments, we measured the activity of 6–10 on the weight of the prostate glands of gonadectomized hamsters treated with testosterone (T). For the studies in vitro, we determined the IC₅₀ value by measuring the concentration of steroidal derivative that inhibited 50% of the activity of 5α-reductase present in the human prostate. The results from this work indicated that compounds 6–9 significantly decreased the weight of the prostate as compared to testosterone-treated animals and this reduction of prostate weight was comparable to that produced by finasteride. Steroid 8 was the most effective of the tested compounds. However, compound 10 did not exhibit this capacity. On the other hand, 6–9 exhibited a high inhibitory activity for the human 5α-reductase enzyme with IC₅₀ values of 10, 70, 22, and 19?nM, respectively. However, 10 was not effective for the inhibition of 5α-reductase activity. In conclusion, the compounds that contained the acetate ester moiety in the molecule (6, 7, 8, and 9) inhibited the activity of 5α-reductase and decreased the weight of the prostate. Nevertheless, the double bond in ring B seems to diminish the inhibitory potency (7 and 9), since 6, which does not possess a double bond at C-6, had the highest inhibitory activity (the lowest IC₅₀ value).     

Synthesis and biological evaluation of novel 3-substituted amino-4-hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents

A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC₅₀ of 0.10?mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC₅₀ of 0.18?mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4?μg/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents.     

Hypoglycemic activity of curcumin synthetic analogues in alloxan-induced diabetic rats

The currently available therapies for type 2 diabetes have been unable to achieve normoglycemic status in the majority of patients. The reason may be attributed to the limitations of the drug itself or its side effects. In an effort to develop potent and safe oral antidiabetic agents, we evaluated the in vitro and in vivo hypoglycemic effects of 10 synthetic polyphenolic curcumin analogues on alloxan-induced male diabetic albino rats. In vitro studies showed 7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione (4) to be the most potential hypoglycemic agent followed by 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (10). Structure activity relationship (SAR) of the tested compounds was elucidated and the results were interpreted in terms of in vitro hypoglycemic activities. Furthermore, oral glucose tolerance test (OGTT) with compounds 4, 10 and reference hypoglycemic drug glipizide showed that compound 4 and glipizide had relatively similar effects on the reduction of blood glucose levels within 2?h. Thus, compound 4 might be regarded as a potential hypoglycemic agent being able to reduce glucose concentration both in vitro and in vivo.     

In situ structural biology using in-cell NMR

BackgroundAccumulating evidence from the experimental and computational studies indicated that the functional properties of proteins are different between in vitro and living cells, raising the necessity to examine the protein structure under the native intracellular milieu. To gain structural information of the proteins inside the living cells at an atomic resolution, in-cell NMR method has been developed for the past two decades.Scope of reviewIn this review, we will overview the recent progress in the methodological developments and the biological applications of in-cell NMR, and discuss the advances and challenges in this filed.Major conclusionsA number of methods were developed to enrich the isotope-labeled proteins inside the cells, enabling the in-cell NMR observation of bacterial cells as well as eukaryotic cells. In-cell NMR has been applied to various biological systems, including de novo structure determinations, protein/protein or protein/drug interactions, and monitoring of chemical reactions exerted by the endogenous enzymes. The bioreactor system, in which the cells in the NMR tube are perfused by fresh culture medium, enabled the long-term in-cell NMR measurements, and the real-time observations of intracellular responses upon external stimuli.General significanceIn-cell NMR has become a unique technology for its ability to obtain the function-related structural information of the target proteins under the physiological or pathological cellular environments, which cannot be reconstituted in vitro.     

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.     

Design,synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer’s disease

A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Aβ (1–42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC₅₀, 12.1?nM for eeAChE, 8.6?nM for hAChE, 2.6?μM for eqBuChE and 4.4?μM for hBuChE) and the highest selectivity toward AChE over BuChE. It also showed good inhibition of Aβ (1–42) aggregation (64.7% at 20?μM) and good neuroprotection on PC12 cells against amyloid-induced cell toxicity. Finally, compound 5l could penetrate the BBB, as forecasted by the PAMPA-BBB assay and proved in OF1 mice by ex vivo experiments. Overall, compound 5l seems to be a promising lead compound for the treatment of Alzheimer’s diseases.