beta-Lactam derivatives as enzyme inhibitors: 1-peptidyl derivatives of 4-phenylazetidin-2-one as inhibitors of elastase and papain

N-Peptidyl substituted azetidin-2-ones were synthesized and evaluated as inhibitors of the serine protease elastase, and the cysteine protease papain. All compounds were synthesized from 4-phenylazetidin-2-one, either from the racemate or from the pure enantiomers. The (S)-enantiomer was prepared by enantioselective synthesis from (S)-beta-phenyl-beta-alanine, while the (R)-enantiomer was obtained by enzymatic resolution with alpha-chymotrypsin. N-Alkylation with bromoacetates introduced a spacer group which, after hydrolysis to the free acid, was acylated with amino acid esters or di- or tripeptide esters. The enzymatic assays proved some derivatives to be effective inhibitors of PPE and/or papain. N-BOC protected amino acid derivatives without a spacer group inhibited PPE reversibly, while derivatives with spacer group showed either weak or no inhibitory properties. On the other hand, papain was inactivated irreversibly by ethyl (RS)-2-oxo-4-phenylazetidin-1-acetate. The highest inhibitory activity against papain was found for the diastereomers of N-(2-oxo-4-phenylazetidin-1-acetyl)-L-alanyl-L-valine benzyl ester, a compound with a spacer group.     

L-酒石酸衍生物的合成及其抑制-分泌酶活性

摘 要: 目的 设计并合成&;#61538;-分泌酶(BACE1)的小分子抑制剂。方法 基于BACE1的晶体结构及其配体的关键结构特征，设计并合成新结构的BACE1配体。结果与结论 合成了26个酒石酸衍生物。筛选结果表明，部分化合物对BACE1有一定的抑制作用。     

New celecoxib derivatives as anti-inflammatory agents

A series of 1,5-diarylpyrazoles with a substituted benzenesulfonamide moiety was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Some compounds, for example, (+/-)-2-[4-(5- p-tolyl-3-trifluoromethyl-pyrazole-1-yl)-benzenesulfonylaminooxy]-propionic acid 16 and its disodium salt 21, had a higher in vivo anti-inflammatory activity compared to celecoxib, despite having no in vitro COX-1 or COX-2 inhibitory activity. Their gastrointestinal side effect profile is essentially more favorable than that of celecoxib.     

Synthesis and biological evaluation of new amino acid and dipeptide derivatives of neocryptolepine as anticancer agents

The syntheses of neocryptolepine derivatives containing an amino acid or a dipeptide at the C-9 position and their evaluation for antitumor activity in vitro and in vivo are reported. To establish the influence of an amino acid or a peptide on the physicochemical properties of 5H-indolo[2,3-b]quinoline (DiMIQ), lipophilic and hemolytic properties were investigated. Most of the compounds displayed a high antiproliferative activity in vitro and strongly inhibited growth of tumor in mice compared to cyclophosphamide. The attachment of the hydrophilic amino acid or the peptide to the hydrophobic DiMIQ increased its hydrophilic properties and decreased its hemolytic activity. The glycylglycine conjugate (7a) was the most promising derivative. It strongly inhibited the growth of the tumor in mice (at dose 50 mg kg(-1) day(-1) it inhibited the tumor growth by 46-63% on days 11-16 and by 29-43% on days 18-23) and significantly decreased hemolytic activity and lowered the in vivo toxicity compared to DiMIQ.     

N-acylated derivatives of cyclohexylaniline with potential antiallergic and analgesic-antiinflammatory activity

Some N-acylated derivatives of cyclohexylaniline were prepared. These can be considered as derived from oxarbazol (A), a carbazolic structure with antiallergic activity, by breaking the bond between carbon atom 4a and 4b. In the new molecule the following groups were introduced: benzoic acid, salicylic acid, acetylsalicylic acid and tetrazol. The synthesized compounds were studied for analgesic, antiedema and antiallergic activity. Some showed analgesic action (phenylquinone) comparable with that of naproxen. Antiinflammatory activity was slight and antiallergic activity nonexistent.     

Synthesis and in vitro activity of new cephalosporin derivatives containing a benzoxazolone ring

New cephalosporin derivatives containing a benzoxazolone ring in the side acylamino chain are synthesized using chlorides of non-substituted and halogen substituted (2-benzoxazolone-3-yl) acetic acids for the acylation of the 7-aminodesacetoxy-cephalosporanic acid and 7-amino-cephalosporanic acid amino group. Some of these new compounds exhibit a biological activity higher than that of cephalexin and cephazolin against clinical strains of Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus group A and B.     

1,2,3-Triazole derivatives of aryloxyalanoic acids

Several 1,2,3-triazolederivatives of aryloxyalcanoic acids of general formula (II) were synthesized. Some derivatives were obtained by the cycloaddition reaction of 4-azidophenoxyacetic acid (III) to activated methylene compounds, but the largest part were prepared by nucleophilic substitution reactions of three new (4-hydroxyphenyl)triazole derivatives and alyphatic bromoesters. Some compounds, tested as prostaglandin-synthetase inhibitors of rat spleen in vitro, showed practically no activity; moderate activities as herbicides, insecticides and antimicrobials were detected.     

Synthesis of new compounds derived from metronidazole and amino acids and their esters as antiparasitic agents

A number of new compounds derived from metronidazole and amino acids and their esters have been synthesized through a reaction between 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetic acid and a number of amino acid esters in the presence of N,N′carbonyldiimidazole (CDI). Hydrolysis of the esters derivatives with sodium hydroxide (4%) followed by acidification with hydrochloric acid (3?M) afforded the corresponding acids. The newly synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, and mass spectrometry. Some of the prepared compounds exhibited lethal activity against pathogenic protozoan parasites.     

Synthesis and anti-HIV activity of new C2 symmetric derivatives designed as HIV-1 protease inhibitors

The synthesis of several new anti-HIV-1 compounds is described. The new compounds contain a C(2) symmetry axis and a dihidroxyethylene moiety based on the D-tartaric acid back bone. The synthesis of these compounds was achieved in 36-69% overall yields from D-tartaric acid. The protocol included: acetylation of hydroxyl groups, followed by diamide formation and deacetylation or reduction with LiAlH(4). The anti-HIV 1 activities of these substances were evaluated in PM-1 cells, using Indinavir as standard (IC(50) = 0.2 microM). Two amino alcohol derivatives showed good inhibitory activity against the virus, with IC(50) = 2.0 and 4 microM.     

Synthesis of some new benzothiazole derivatives as potential antimicrobial and antiparasitic agents

Several thiazolidinonyl benzothiazoles 8a-b and thiazolinylbenzothiazoles 9a-j were synthesized by the reaction of 2-(N-substituted thiocarbamoyl hydrazino) benzothiazoles 7a-d with chloroacetic acid or phenacyl bromide respectively. The intermediate compounds 7a-d were prepared in a good yield by the reaction of 2-hydrazinobenzothiazole (6) with phenylisothiocyanates. Synthesis of hydrazones 10a-c were performed by the reaction of 6 with the corresponding aldehydes. Trials to cyclize the obtained hydrazones 10a-c into the corresponding triazolo derivatives 11a-c were unsuccessful. Addition of 4-morphylino carbonyl chloride to compound 6 yielded the corresponding 2-acid hydrazide derivative 12. Some of the prepared compounds were screened for their anti-parasitic activity. Most of them showed reasonable antinematodal or schistosomicidal activity. In addition, antimicrobial screening of all of the prepared new compounds was performed against Staphylococcus aeurus ATCC 6538, Escherichia coli ATCC 8735 and Candida albicans ATCC 10321 but non of them was active.     

Dual‐protected amino acid derivatives as new antitubercular agents

Tuberculosis is an infectious disease with high incidence and growing drug‐resistant rates. In an attempt to develop new antitubercular agents, 35 compounds were synthesized, most of them bearing a carbamate and enantiopure amino acid moiety. These compounds had their activity evaluated toward a Mycobacterium tuberculosis strain (ATCC 27294) and cytotoxicity against fibroblast MRC‐5 cells (ATCC CCL‐171). Three of the prepared derivatives presented a good antimicrobial inhibition and two of them a moderate cytotoxicity. The lipophilicity seems to play a vital role in the cell growth activity, with best results for the derivatives with a higher logP.     

Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents

The key intermediate octahydroquinazoline (1) was obtained in one pot synthesis by a modification of the Biginelli reaction. Compound 1 was allowed to react with phenacyl bromide and bromomalononitrile to furnish thiazolo[2,3-b]quinazoline 3 and 12, respectively. Interaction of compound 12 with formamide, formic acid and phenyl isothiocyanate yielded the corresponding pyrimidino[4',5':4.5]thiazolo[2,3-b] quinazolines 13, 14 and 17, respectively. The structure of the synthesized compounds were elucidated by elemental analyses and spectroscopic analyses. Some of the prepared compounds were tested for their antifungal activity in comparison with tioconazole as a reference fungicide.     

Polycyclic peptide and glycopeptide antibiotics and their derivatives as inhibitors of HIV entry

Antiviral activity and other biological properties of two groups of polycyclic peptides are discussed. Antibiotics of the complestatin-kistamycin group have a structural motif similar to that of the peptide core of antibacterial antibiotics of the vancomycin-teicoplanin group though no amino acid component in the chloropeptin-kistamicin antibiotics is identical to an amino acid incorporated in the peptide core of the antibiotics of the vancomycin-teicoplanin group. Chloropeptins and the hydrophobic several derivatives of antibacterial antibiotics are inhibitors of HIV and some other viruses. They interfere with the viral (i.e. HIV) entry process. Chemical modifications of natural glycopeptide antibiotics led to the compounds with antiviral properties whereas antibacterial properties were lost. These glycopeptide aglycons derivatives can be envisaged as potential lead compounds for application as microbicides against sexual HIV transmission.     

Tyrosine-like condensed derivatives as tyrosinase inhibitors

Objectives We report the pharmacological evaluation of a new series of 3‐aminocoumarins differently substituted with hydroxyl groups, which have been synthesized because they include in their structures the tyrosine fragment (tyrosine‐like compounds), with the aim of discovering structural features necessary for tyrosinase inhibitory activity. Methods The synthesized compounds 4 and 7–9 were evaluated in vitro as mushroom tyrosinase inhibitors. Key findings Two of the described compounds showed lower IC50 (concentration giving 50% inhibition of tyrosinase activity) than umbelliferone, used as a reference compound. Conclusions Compound 7 (IC50 = 53 µm ) was the best tyrosinase inhibitor of this small series, having an IC50 value 10‐fold lower than umbelliferone. Compound 7 (3‐amino‐7‐hydroxycoumarin) had amino and hydroxyl groups precisely mimicking the same positions that both groups occupy on the tyrosine molecule.     

New 5H-pyridazino[4,5-b]indole derivatives. Synthesis and studies as inhibitors of blood platelet aggregation and inotropics.

Some fused 5H-pyridazino[4,5-b]indoles (7-10), substituted in positions 1 and 4 by hydrazine and/or amino groups, have been synthesized. These new compounds present a planar topography, a dipole with an adjacent acidic proton, and a basic hydrogen-acceptor site opposite the dipole. These compounds have some resemblance to carbazeram and other pyridazino agents with cardiotonic activity. Some of the new compounds here described possess inotropic activity (Table I and II), with a complementary effect as inhibitors of platelet aggregation (Table III and IV). 1-Hydrazino-4-(3,5-dimethyl)-1-pyrazolyl-5H-pyridazino[4,5-b ]indole hydrochloride (7a.HCl) is the first compound described in the literature with activities as inhibitor of PDE-IV and as selective inhibitor of TXA2 synthetase (Table V).     

Design and synthesis of peptide derivatives of a 3-deoxy-D-manno-2-octulosonic acid (KDO) analogue as novel antibacterial agents acting upon lipopolysaccharide biosynthesis

On the basis of the knowledge that the amino acid 3 (8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid) is a potent inhibitor of 3-deoxy-manno-octulosonate cytidylyltransferase, attempts were made to design derivatives that would act as antibacterials against Gram-negative bacteria by inhibiting lipopolysaccharide biosynthesis. Compound 3 and the derivatives 15 and 16 containing an additional amino acid were not lethal to bacteria. However, compounds 17-22, which contain a N-terminally linked dipeptide, exhibited good antibacterial activity in vitro on testing against strains of the Gram-negative bacteria Escherichia coli and Salmonella typhimurium. They have no activity against Gram-positive bacteria such as Staphylococcus aureus.     

1H-indole derivatives as calcium antagonists

Two short series of compounds with 1H-indole skeleton, bearing hydantoin and piperazine nuclei respectively, were synthesized. Some compounds of these two series were tested for their calcium-antagonistic activity on K⁺-depolarized smooth muscle (rabbit auricolar artery and guinea-pig taenia caeci) and their negative inotropic action on atrial muscle from guinea-pig hearts.     

New alpha-amino phosphonic acid derivatives of vinblastine: chemistry and antitumor activity

A series of new amino phosphonic acid derivatives of vinblastine (1, VLB) has been synthesized and tested in vitro and in vivo for antitumor activity. The compounds were obtained from O4-deacetyl-VLB azide. All of the new products studied were capable of inhibiting tubulin polymerization in vitro. The most potent antitumor compounds bore an alkyl substituent on the phosphonate. In these compounds, the anti-tumor activity strongly depended on the stereochemistry of the phosphonate. The phosphonate (1S)-[1-[( O4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastin-3-yl] carbonyl]amino]-2-methylpropyl]phosphonic acid diethyl ester exhibited a remarkable activity against cancer cell lines both in vitro and in vivo.     

Effect of N-trifluoroacetyl derivatives of amino acids and amino acid analogs on microbial antitumor screen.

Eighteen trifluoroacetyl derivatives of amino acids and of amino acid analogs were prepared and tested for growth-inhibitory activity using a Lactobacillus casei system as a prescreen for antitumor activity. Of the compounds tested, the trifluoroacetyl derivatives of o-, m-, and p-fluorophenylalanine and of beta-3-thienylalanine showed modest activity; trifluoroacetyl derivatives of phenylalanine and of beta-2-thienylalanine showed marginal activity. The activity exhibited by the active trifluoroacetyl compounds was equal to that noted for most active chloroacetyl derivatives reported previously, as judged by comparison of their activity with that of chloroacetyl-m-fluorophenylalanine. No reversal of inhibition was noted when a representative of these inhibitors was challenged with a corresponding natural metabolite, both as a free amino acid and as a noninhibitory acylated compound.     

Synthesis of new piperidyl indanone derivatives as anticonvulsant agents

A series of 5,6-dimethoxy-2-{1-[arylamino/alkylamino(thioxo)methyl]-4-piperidyl-methyl}-1-indanones (4a–l) were designed and synthesized by the reaction of 5,6-dimethoxy-2-(piperidin-4-yl-methyl)-indan-1-one with aryl/alkyl isothiocyanates. The anticonvulsant activity was evaluated in animal models by maximal electroshock seizure and subcutaneous pentylenetetrazole tests. The neurotoxic effects were assessed by rotorod and ethanol potentiation tests. Gamma amino butyric acid (GABA) estimation of the selected compounds was performed in rat brain utilizing UV absorbance data. Compounds 4d, 4g, and 4j displayed encouraging anticonvulsant profile against both seizure models with remarkably lower neurotoxicity. These compounds were found to increase the GABA level in rat brain significantly.