Synthesis and activity of a novel class of tribasic macrocyclic antibiotics: the triamilides

The stereoselective synthesis of two novel series of tribasic macrocyclic antibiotics with potent in vitro activity against Pasteurella multocida and Escherichia coli strains of bacteria is described. The in vitro activity can be significantly influenced by the nature of the substituents on the C-4" aminoalcohol, with the stereochemistry of the C-4" alcohol playing a less critical role. The effect of substitution and stereochemistry on the in vivo activity in a murine model of respiratory infection is also described.     

Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors

The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).     

Synthesis and structure-activity relationships of 4-hydroxy-4-phenylpiperidines as nociceptin receptor ligands: Part 2

A series of 4-[2-(aminomethyl)phenyl]-1-[bis(2-chlorophenyl)methyl]-4-hydroxypiperidine analogs has been identified as nociceptin receptor ligands. These compounds display high affinity and functional activity at the nociceptin receptor. The synthesis and structure-activity relationships at the C-4 phenyl and N-1 positions are described and the antitussive activity of a selected compound is reported.     

Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential

The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.     

Effect of natural and synthetic benzyl benzoates on calmodulin

The present investigation describes the effect of the spasmolytic benzylbenzoates 1-9 from Brickellia veronicifolia on CaM using a functional in vitro enzymatic assay. Bovine brain PDE1 was used as a monitoring enzyme. The most active natural inhibitors of the system CaM-PDE1 were benzyl benzoates 3-5, which inhibited the activity of PDE1 in a concentration-dependent manner. In addition, three series of analogs of compound 4, compounds 10a-32a, were prepared and assayed. The benzyl benzoates from the first series, namely 10a-24a, possess no substituents on ring B but different number and position of hydroxyl or methoxy groups in ring A. The second group (25-32a), on the other hand, possesses an A ring identical to that on compound 4, but different substituents in Ring B. The most active compounds were 14a, 15a and 30a. These compounds were two to six times more potent than chlorpromazine, a well known CaM inhibitor. Benzyl benzoates 14a and 15a have methoxyl groups at C-2/C-4 and C-3/C-4 in ring A, respectively; while 30a, in addition to the methoxyl groups at C-2/C-6 of ring A, hold a benzoyloxy moiety at C-3' of ring B. Kinetic studies revealed that compounds 3, 4, 14a, 15a and 30a behave as competitive CaM antagonists.     

Synthesis of oligosaccharides as potential inhibitors of mycobacterial arabinosyltransferases. Di- and trisaccharides containing C-5 modified arabinofuranosyl residues

The synthesis of a panel of oligosaccharides containing C-5 arabinofuranosyl residues (9-20) is described. These compounds are of interest as potential inhibitors of the alpha-(1-->5)-arabinosyltransferase involved in the assembly of mycobacterial cell-wall arabinan. In the series of compounds prepared, the 5-OH group on the nonreducing residue(s) is replaced, independently, with an amino, azido, fluoro, or methoxy functionality. The synthesis of the target compounds involved the preparation of a series of C-5 modified arabinofuranosyl thioglycosides (24-26) and their subsequent coupling to the appropriate acceptor species (21-23). Deprotection of the glycosylation products afforded the azido, fluoro, or methoxy analogs directly. The amino derivatives were obtained in one additional step by reduction of the azido compounds.     

Degraded limonoids from Melia azedarach and biogenetic implications

The unique series of C-2'-acylated C-glycosylflavones is extended by the discovery of the C-8-glucosyl derivatives 2'-O-galloylvitexin and 2'-O-galloylorientin and their C-6 analogues 2'-O-galloylisovitexin and 2'-O-galloylisoorientin, representing the first described O-galloyl-C-glycosylflavones. They are accompanied in the aerial parts of Pelargonium reniforme by the known non-galloylated parent analogues vitexin, orientin, isovitexin and isoorientin, as well as several known flavonoid-O-glycosides. The structures of these compounds were established from spectroscopic studies. Differentiation between C-glycosylation at C-6 and C-8 is discussed on the basis of the effects of dynamic rotational isomerism.     

Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 3. Enhancing activity by imposing conformational restriction in the C-4" side chain

The preparation and biological evaluation of a series of benzo[b]thiophene diamine thrombin inhibitors possessing conformationally restricted C-4" linkers are reported. Compared to the parent compounds 1a/b, the unsaturated derivatives 3a/b exhibited a modest twofold increase in thrombin inhibitory activity, while the more lipophilic carbocyclic ring containing analogs 4a/b affected an eightfold enhancement in potency.     

Substrate interaction with 5alpha-reductase enzyme: influence of the 17beta-chain chirality in the mechanism of action of 4-azasteroid inhibitors

A series of steroidal compounds were synthesized in order to evaluate the possible influence of the configuration of a stereocenter in the 17beta-side chain on the inhibitory activity on the enzyme 5alpha-reductase (5AR). For this purpose diastereomerically pure 4-azasteroids epimers at C-22 were prepared (compounds 1-11) and tested as inhibitors of 5AR in "in vitro" tests. The obtained data showed that in most cases the couples of epimers possess a significant difference in their biological activity. We also considered, for the tested molecules, a series of chemico-physical parameters in order to find a possible correlation with their biological activity. The findings allowed us to propose a model of the binding site of 5AR which comprises also, for 4-azasteroid inhibitors, the configurational aspect of the 17beta-side chain.     

Pyrimidine benzamide-based thrombopoietin receptor agonists

A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.     

Novel azalides derived from 16-membered macrolides. III. Azalides modified at the C-15 and 4″ positions: Improved antibacterial activities

The design and synthesis of 16-membered azalides modified at the C-15 and 4″ positions are described. The compounds we report here are characterized by an arylpropenyl group attached to the C-15 position of macrolactone and a carbamoyl group at the C-4″ position in a neutral sugar. Introduction of alkylcarbamoyl groups to the C-4″ position was regioselectively achieved by unique and convenient methods via acyl migration. As a result of optimization at the C-3 and 15 positions, several compounds were found to have potent activity against mef- and erm-resistant bacterial strains. These results suggest that 16-membered azalides could be promising compounds as clinical candidates.     

Synthesis and biological evaluation of new 4beta-anilino- and 4beta-imido-substituted podophyllotoxin congeners

A series of C-4-anilino- and C-4-imido-substituted new podophyllotoxin congeners have been designed, synthesized, and evaluated for their cytotoxicity and DNA topoisomerase-II (topo-II) inhibition potential. Some of these compounds have exhibited promising in vitro anticancer and topo-II inhibition activity.     

Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: optimization of BX-517

Based on the lead compound BX-517, a series of C-4' substituted indolinones have been synthesized and evaluated for PDK1 inhibition. Modification at C-4' of the pyrrole afforded potent compounds (7b and 7d) with improved solubility and ADME properties. In this letter, we describe the synthesis, selectivity profile, and pharmacokinetic data of selected compounds.     

Synthesis and biological properties of new 1beta-methylcarbapenems having tetrazolothioether moiety

The synthesis and biological activities of a series of new 1beta-methylcarbapenems 1a-l having tetrazolothioether moiety at C-5 position of pyrrolidine were described. Among these compounds, 1c showed the most potent antibacterial activity and advanced pharmacokinetics compared with imipenem and meropenem.     

The novel pyrimidine and purine derivatives of l-ascorbic acid: synthesis, one- and two-dimensional 1H and 13C NMR study, cytostatic and antiviral evaluation

The syntheses of the novel C-5 substituted pyrimidine derivatives of l-ascorbic acid containing free hydroxy groups at C-2' (6-10) or C-2' and C-3' (11-15) positions of the lactone ring are described. Debenzylation of the 6-chloro- and 6-(N-pyrrolyl)purine derivatives of 2,3-O,O-dibenzyl-l-ascorbic acid (16 and 17) gave the new compounds containing hydroxy groups at C-2' (18) and C-2' and C-3' (19 and 20). Z- and E-configuration of the C4'C5' double bond and position of the lactone ring of the compounds 6-9 were deduced from their one- and two-dimensional (1)H and (13)C NMR spectra and connectivities in NOESY and HMBC spectra. Compounds 15 and 18 showed the best inhibitory activities of all evaluated compounds in the series. The compound 15 containing 5-(trifluoromethyl)uracil showed marked inhibitory activity against all human malignant cell lines (IC(50): 5.6-12.8 microM) except on human T-lymphocytes. Besides, this compound influenced the cell cycle by increasing the cell population in G2/M phase and induced apoptosis in SW 620 and MiaPaCa-2 cells. The compound 18 containing 6-chloropurine ring expressed the most pronounced inhibitory activities against HeLa (IC(50): 6.8 microM) and MiaPaCa-2 cells (IC(50): 6.5 microM). The compound 20 with 6-(N-pyrrolyl)purine moiety showed the best differential inhibitory effect against MCF-7 cells (IC(50): 35.9 microM).     

Synthesis and biological properties of new 1beta-methylcarbapenems containing heteroaromatic thioether moiety

The synthesis and biological activities of a series of new 1beta-methylcarbapenems 1a-h having heteroaromatic thioether moiety at C-5 position of pyrrolidine were described. Among these compounds, 1,2,3-thiadiazole derivative 1h showed the most potent antibacterial activity and advanced pharmacokinetics in comparison with meropenem.     

Synthesis and biological evaluation of novel 1beta-methylcarbapenems having a new moiety at C-2.

The synthesis and biological activity of the novel series of 1 beta-methylcarbapenems 1a-f, bearing a variety of 3",4"-disubstituted pyrrolidinamides as substituents at C-2, are described. Of these carbapenems, diol 1a showed the most potent and well balanced antibacterial activity against Gram-positive and Gram-negative. 1a was also evaluated for pharmacokinetics and in vivo therapeutic efficacy in systemic infections.     

Structure-affinity relationships of the affinity of 2-pyrazolyl adenosine analogues for the adenosine A2A receptor

The structure-affinity relationships of two novel 2-substituted adenosine series containing a substituted pyrazole attached at the N-1 or C-4 position for the adenosine (ADO) A2A receptor are described. Compounds in the 2-(N-1-pyrazolyl) adenosine series IV provided the highest affinity for the ADO A2A receptor as compared to the 2-(C-4-pyrazolyl) series V. The main structural differences between the two series point to the N-1 nitrogen of series IV imparting more favorable binding interactions with the receptor than those of series V.     

Synthesis and antioxidant activities of 3,5-dialkoxy-4-hydroxycinnamamides

A series of 3,5-dialkoxy-4-hydroxycinnamamides 6 and 7 was synthesized, and their antioxidant activity was assessed using the thiobarbituric acid reactive substance (TBARS) assay. Interestingly, cinnamamides with longer alkoxy groups on the C-3 and C-5 positions display enhanced inhibition, and most of the compounds in the series tested exhibit excellent lipid peroxidation inhibitory activities. Some cinamamides bearing hexyloxy or 2,6-di-tert-butyl-4-methyl phenol groups have submicromolar inhibitory activities.     

Synthesis and biological evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR inhibitors

A series of C-6 or C-3' alkynyl-substituted 4-anilinoquinazoline derivatives was prepared straightforwardly by a Sonogashira reaction of the corresponding bromo-substituted 4-anilinoquinazolines. Bioactive assay of these compounds for in vitro EGFR kinase inhibition demonstrated that the novel 6-hydroxypropynyl-4-anilinoquinazoline 5e was a very potent EGFR kinase inhibitor with an IC(50) of 14 nM.