Series Of N1 Research Articles

Targeting Mycobacterium tuberculosis: Synthesis, in vitro and in silico evaluation of novel N1 -(benzo[d]oxazol-2-yl)-N4 -arylidine compounds.

The development of novel antimycobacterial agents is an urgent challenge to eradicate the increasing emergence and rapid spread of multidrug-resistant strains. Filamentous temperature-sensitive protein Z (FtsZ) is a crucial cell division protein. Alteration of FtsZ assembly leads to cell division inhibition and cell death. To find novel antimycobacterial agents, a series of N1 -(benzo[d]oxazol-2-yl)-N4 -arylidine compounds 5a-o were synthesized. The activity of the compounds was evaluated against drug-sensitive, multidrug-resistant, and extensive-drug-resistant Mycobacterium tuberculosis. Compounds 5b, 5c, 5l, 5m, and 5o showed promising antimycobacterial activity with minimum inhibitory concentrations (MIC) in the range of 0.48-1.85 µg/mL and with low cytotoxicity against human nontumorigenic lung fibroblast WI-38 cells. The activity of the compounds 5b, 5c, 5l, 5m, and 5o was evaluated against bronchitis causing-bacteria. They exhibited good activity against Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumonia, and Bordetella pertussis. Molecular dynamics simulations of Mtb FtsZ protein-ligand complexes identified the interdomain site as the binding site and key interactions. ADME prediction indicated that the synthesized compounds have drug-likeness. The density function theory studies of 5c, 5l, and 5n were performed to investigate E/Z isomerization. Compounds 5c and 5l are present as E-isomers and 5n as an E/Z mixture. Our experimental outcomes provide an auspicious lead for the design of more selective and potent antimycobacterial drugs.

Exploring the molecular determinants for subtype-selectivity of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid analogs as betaine/GABA transporter 1 (BGT1) substrate-inhibitors

We have previously identified 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (ATPCA) as the most potent substrate-inhibitor of the betaine/GABA transporter 1 (BGT1) (IC50 2.5 µM) reported to date. Herein, we characterize the binding mode of 20 novel analogs and propose the molecular determinants driving BGT1-selectivity. A series of N1-, exocyclic-N-, and C4-substituted analogs was synthesized and pharmacologically characterized in radioligand-based uptake assays at the four human GABA transporters (hGATs) recombinantly expressed in mammalian cells. Overall, the analogs retained subtype-selectivity for hBGT1, though with lower inhibitory activities (mid to high micromolar IC50 values) compared to ATPCA. Further characterization of five of these BGT1-active analogs in a fluorescence-based FMP assay revealed that the compounds are substrates for hBGT1, suggesting they interact with the orthosteric site of the transporter. In silico-guided mutagenesis experiments showed that the non-conserved residues Q299 and E52 in hBGT1 as well as the conformational flexibility of the compounds potentially contribute to the subtype-selectivity of ATPCA and its analogs. Overall, this study provides new insights into the molecular interactions governing the subtype-selectivity of BGT1 substrate-inhibitors. The findings may guide the rational design of BGT1-selective pharmacological tool compounds for future drug discovery.

Copper-Catalyzed Three-Component Reaction of Alkynes, TMSN3, and Ethers: Regiocontrollable Synthesis of N1- and N2-Oxyalkylated 1,2,3-Triazoles.

A new copper-catalyzed selective synthesis of N1- and N2-oxyalkylated 1,2,3-triazoles has been developed through a three-component reaction of alkynes, TMSN3, and ethers. Through this methodology, a series of N1- and N2-oxyalkylated 1,2,3-triazoles could be efficiently and regioselectively obtained from simple and readily available starting materials with favorable functional group tolerance.

Uracil Hydroxybenzamides as Potential Antidiabetic Prodrugs

A series of N1, N3-bis-hydroxybenzoyl, -acetoxybenzoyl, and -methoxybenzoyl uracil derivatives were synthesized. All compounds were screened for the ability to rupture protein cross links and antiglycating, chelating, and antiaggregant properties, which are most significant for pharmacological treatment of thrombosis and angio-, nephro-, encephalo-, and cardiopathies. 1,3-bis-(4-Methoxybenzoyl)pyrimidine-2,4(1H,3H)-dione was a promising antidiabetic agent with all studied activities.

Design, synthesis, and preliminary bioactivity evaluation of N1 -hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors.

Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1 -hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50 =0.074μm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC50 =0.131μm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.

Construction of New Insensitive Explosives: Fused N5-Chain N1,N3,N5-(1,2,3,4-Tetrazole -5-Nitro)-1,3,5-Triamino-2,4,6-Trinitrobenzene Derivatives

A series of N1,N3,N5-(1,2,3,4-tetrazole-5-nitro)-1,3,5-triamino-2,4,6-trinitrobenzene derivatives containing fused N5-chain were investigated theoretically. Density functional theory has been employed to calculate their geometric, electronic structures, band gaps, and heats of formation at the B3LYP/6-31G** level. The detonation performance was evaluated by using Kamlet-Jacobs equations based on the calculated densities and HOFs. The thermal stability of these compounds was investigated by bond dissociation energies, energy gaps and molecular electrostatic potentials. Results show that there are good linear relationships between detonation velocity, detonation pressure and the number of nitro groups. Most of the designed derivatives have higher detonation velocity (D), detonation pressure (P), and specific impulse (Isp) than those of RDX. D and Isp of molecule L even outperform those of CL-20. Some of the title molecules have higher h50 (impact sensitivity) than RDX (except for D, H, L). According to the quantitative standard of energy and stability as insensitive high energetic materials (IHEMs), molecules I and J essentially satisfy this requirement. These results provide basic information for molecules design of novel IHEMs.

Synthesis and Antitumor Activities of Some New N1‐(Flavon‐6‐yl)amidrazone Derivatives

A new series of N1-(flavon-6-yl)amidrazones were synthesized by reacting the hydrazonoyl chloride derived from 6-aminoflavone with the appropriate sec-cyclic amines. The antitumor activities of these compounds were evaluated on breast cancer (MCF-7) and leukemic (K562) cell lines. Among the compounds tested, the N-morpholine derivative was the most active against the MCF-7 and K562 cell lines, with IC50 values of 5.18 and 2.89 μM, respectively. Our docking studies showed that the N-morpholino derivative fits and blocks the oncogenic tyrosine kinases bcr/abl and epidermal growth factor receptor (EGFR) in a similar fashion to that of the potent anticancer agent imatinib.

Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors

A novel series of N1-(3-fluoro-4-(6,7-disubstituted-quinolin-4-yloxy)phenyl)-N4-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50=1.4nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.

Conventional and Microwave Induced Synthesis of 4-Oxo-Thiazolidine Derivatives and Their Biological Activities

An efficient route for the synthesis of new series of N1-[2-{2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine}-iminoethyl]-1,2,3-benzotriazoles 5a–5j has been developed. The cycloaddition reaction of thioglycolic acid with N1-{2-(substituted benzylidenehydrazino)-ethyl}-1,2,3-benzotriazoles 3a–3j in the presence of anhydrous ZnCl2 afforded new heterocyclic compounds N1-[2-{2-(substituted phenyl)-4-oxo-1,3-thiazolidine}-iminoethyl]-1,2,3-benzotriazoles 4a–4j. The latter product on treatment with several selected substituted aromatic aldehydes in the presence of C2H5ONa undergoes Knoevenagel reaction to yield 5a–5j. The structure of compounds 1, 2, 3a–3j, 4a–4j and 5a–5j were deduced by IR, 1H NMR, 13C NMR, FAB-Mass and chemical analysis. All the compounds were screened for their antimicrobial activity against some selected bacteria and fungi and antituberculosis study against M.tuberculosis.

Regioselective synthesis and cannabinoid receptor binding affinity of N-alkylated 4,5-diaryl-1,2,3-triazoles

A series of N1- and N2-substituted 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1,2,3-triazoles were regioselectively synthesized to explore the binding motifs of the diaryl-1,2,3-triazole scaffold at CB1 receptors. The N1 analogs were regioselectively constructed via Click chemistry to furnish analogs with modest CB1 receptor affinity (Ki < 200 nM). The regioselective N2-alkylation of the 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1,2,3-triazole afforded analogs that exhibited good affinity for CB1 receptors (Ki < 100 nM).

N 1-{4-[(10S)-Dihydroartemisinin-10-oxyl]}phenylmethylene-N 2-(2-methylquinoline-4-yl)hydrazine derivatives as antiplasmodial falcipain-2 inhibitors

A series of N1-{4-[(10S)-dihydroartemisinin-10-oxyl]}phenylmethylene-N2-(2-methylquinoline-4-yl) hydrazine derivatives 9a–9n possessing 4-quinolylhydrazone and artemisinin cores were herein synthesized and evaluated for their activities against cysteine protease falcipain-2 of Plasmodium falciparum. The structures were clearly confirmed by elemental analysis, 1H NMR, and mass spectra. The pharmacological results indicated that all compounds showed excellent activity against recombinant falcipain-2 (IC50 = 0.15–2.28 μM). The best one of this series was compound 9d (IC50 = 0.15 μM). The molecular docking results showed that the compound 9d made close contact with the key active site of cysteine protease falcipain-2.

On the anomalous sorption behaviour of chlorhexidine with poly(2-hydroxyethyl methacrylate).

General observations of solute: plastic interactions would suggest that the sorption of the cationic preservative, chlorhexidine, with poly (2-hydroxyethyl methacrylate) (PHEMA) is not only unexpected but also atypical in its properties. The polymer and preservative were investigated independently and the sorption of PHEMA with simple solutes, namely benzoic acid, benzocaine and aniline found to exhibit conventional properties. The single exception was the uptake of small amounts of benzocaine and aniline cations at acidic pH's. In order to elucidate the sorption characteristics of chlorhexidine a series of N1-(p-chlorophenyl)-N5-alkylbiguanide acetates were synthesized. The anomalous sorption behaviour observed between PHEMA and the bis biguanide, chlorhexidine, was also found to be characteristic of these monofunctional biguanide derivatives. The extent of the interactions increased with increasing alkyl chain length (R = methyl to n-octyl), this being interpreted in terms of an interaction binding mechanism via the biguanide functional group stabilized by van der Waal's forces between the alkyl chain and the polymer backbone. Atypical sorption behaviour was observed for simple organic cations, biguanide and N2-phenylbiguanide acetate with PHEMA, a possible inference being that this is a general characteristic of all cationic sorption with PHEMA.

Topological descriptors in modelling antimalarial activity: N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype

The QSAR of antimalarial activity of two distinct series of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl) piperazine analogues are investigated with DRAGON descriptors in order to rationalize their activity. Of these two series of compounds, one has amide characteristics and the other has amine characteristics. Both the analogues have shared radial centric information (ICR) as common modelling descriptor with increased centricity in the molecules as preferred feature for antimalarial activity. Apart from this, the models of amide analogues suggested in favor of distantly placed nitrogen(s) and unfavorable nature of carbonyl moieties adjacent to nitrogen in the varying portion of the molecule for the activity. Moreover, for these analogues, the regression models have preferred the lone pair electrons on heteroatoms (N and O) for purposes other than H-bonds for better activity. In case of amine analogues, the models suggested in favor of compact structural moieties in the varying parts of the molecule for improved activity. Also, for these analogues, hydrophobicity of the compound is an important factor for influencing activity. The variations in the models of amide and amine analogues are attributed to the characteristic functional differences of these analogues.

Design, synthesis and pharmacological screening of a series of N1-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists

A series of N1-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-one was designed on the basis of the triangular pharmacophoric requirement of histamine H1-receptor antagonists. The designed series was synthesized by cyclo-condensation of monoaryl thiourea with ethyl cyanoacetate in the presence of dry HCl gas to give N1-(substituted aryl)-2-mercaptopyrimidine-4(3H)-one, which on cyclo-condensation with acetylacetone gave the pyridopyrimidinone. Further methylation of the mercapto group at C-2 with methyl iodide followed by nucleophilic displacement of the methylmercapto group by various amines gave the targeted compounds. All the synthesized compounds were screened for histamine H1-receptor antagonistic activity by the in vitro method of inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum using cetirizine as a standard drug. All the compounds exhibited potent histamine H1-receptor antagonistic activity with pA2 values from 7.30– 9.75 (cetirizine, pA2 value 9.40). The potent compounds were screened for their in vivo antihistaminic activity by protection of animal from asphyxic shock. The sedative potential of potent compounds was checked on albino mice by photoactometer and they had comparative sedative potential to the standard drug cetirizine. None of the compound exhibited anticholinergic activity in the in vitro rat ileum model.

Synthesis, biological evaluation, and structural studies on N1 and C5 substituted cycloalkyl analogues of the pyrazole class of CB1 and CB2 ligands

A series of N1 and C5 substituted cycloalkyl and C5 4-methylphenyl analogues of the N-(piperidin-1-yl)-4-methyl-1H-pyrazole-3-carboxamide class of cannabinoid ligands were synthesized. The analogues were evaluated for CB1 and CB2 receptor binding affinities and receptor subtype selectivity. The effects of pyrazole substitution on ligand conformation and as such receptor affinities was not readily apparent; therefore, the geometries of the N1 and C5 substituents relative to the pyrazole ring were studied using high field NMR spectroscopy and systematic molecular mechanics geometry searches. An analysis of the relative ring geometries and functional group orientations provides new insight into the structural requirements of the CB1 and CB2 ligand binding pocket.

Synthesis and Regioselective Ribosylation of 6,7-Dichloroimidazo[4,5-b]quinolin-2-one

The polyhalogenated benzimidazole nucleosides 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB) were synthesized in our laboratory and established as potent and selective antiviral agents against human cytomegalovirus (HCMV) with a novel mode of action. In an effort to study the behavior of the key substructure of these analogues in a dimensionally stretched-out manner and probe the spatial limitation of the target enzyme(s), a series of N1- and N3-ribonucleosides of imidazo[4,5-b]quinolines were designed as linear dimensional analogues. The nucleosides 6,7-dichloro-1-(β-d-ribofuranosyl)imidazo[4,5-b]quinolin-2-one and 6,7-dichloro-3-(β-d-ribofuranosyl)imidazo[4,5-b]quinolin-2-one were selected and prepared as the key intermediates in this study. During this study, a novel photoassisted annulation was developed for the synthesis of 6,7-dichloroimidazo[4,5-b]quinolin-2-one, which overcame several problems that were encountered with the literature annulation method. ...

ChemInform Abstract: SYNTHESIS AND ANTIINFLAMMATORY ACTIVITY OF N1‐(SUBSTITUTED PHENYL)PYRIDINECARBOXAMIDINES

AbstractAus den Nitrilen (I) und den Anilinen (II) werden die Amidine (III) hergestellt, die auf entzündungshenmwnde Wirkung geprüft werden.

Synthesis and antiinflammatory activity of N1-(substituted phenyl)pyridinecarboxamidines.

A series of N1-(substituted phenyl) pyridinecarboxamidines was synthesized by the condensation of substituted anilines with cyanopyridines in the presence of aluminum chloride or sodium amide and these compounds were evaluated for antiinflammatory activity by the carrageenin-induced rat paw edema assay. In the synthesis of N1-alkoxyphenyl pyridinecarboxamidines, it was found that o-alkoxyanilines reacted with aluminum chloride to afford o-aminophenol, while m- and p-alkoxyanilines were scarcely dealkylated. Sodium amide was successfully used for the condensation of o-alkoxyanilines with cyanopyridines. Among several active derivatives, N1-(2, 4-dichlorophenyl) pyridinecarboxamidine and N1-(4-chlorophenyl)-pyridinecarboxamidine exhibited significant antiinflammatory activities.

On the upper limits of some measures of variability

For a seriesPi ofn≧2 non negative terms the maximum value of therelative variability,\(V_r = \frac{{\Sigma |P_i - \bar P|}}{{\Sigma P_i }}\), is\(2\left( {1 - \frac{1}{n}} \right)\), the upper limit being 2.Schumann andMostert stated this theorem, showing that it holds for a series ofn-1 zeros and one other term of any value whatsoever. For such a series the maximum value of thecoefficient of variation,\(V_c = \frac{{\sqrt {n\Sigma (P_i - \bar P)^2 } }}{{\Sigma P_i }}\), is\(\sqrt {n - 1} \), the upper limit being ∞.Longley stated this theorem; its proof is given in this paper. The authorsstate and prove a theorem on the maximum value of another measure of variability, namely theintersequential variability: for a seriesPi ofn≧3 terms the maximum value of the intersequential variability,\(V_s = \frac{n}{{n = 1}} \frac{{\Sigma |P_i - P_{i + 1} |}}{{\Sigma P_i }}\), is\(\frac{{2n}}{{n - 1}}\) when there is at least one positive term in the series, provided before and after each positive term there is at least one zero; the highest maximum of this measure, 3, may be attained whenn=3.