Anti-tubercular activity of novel 4-anilinoquinolines and 4-anilinoquinazolines

We screened a series of 4-anilinoquinolines and 4-anilinoquinazolines and identified novel inhibitors of Mycobacterium tuberculosis (Mtb). The focused 4-anilinoquinoline/quinazoline scaffold arrays yielded compounds with high potency and the identification of 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (34) with an MIC₉₀ value of 0.63–1.25 µM. We also defined a series of key structural features, including the benzyloxy aniline and the 6,7-dimethoxy quinoline ring, that are important for Mtb inhibition. Importantly the compounds showed very limited toxicity and scope for further improvement by iterative medicinal chemistry.     

Coupling of 2,6-disubstituted purines to ribose-modified sugars

1,2,3-Tri-O-acetyl-N-ethyl-beta-D-ribofuranuronamide was synthesized in three steps starting from 1-O-methyl-(2,3-O-isopropylidene)-beta-D-ribofuranuronic acid. Both the triacetyl and the 1-O-methyl-2,3-di-O-acetyl derivatives were coupled to the 2,6-dichloropurine to obtain the acetylated 1-(2,6-dichloro-9H- purin-9-yl)-1-deoxy-N-ethyl-beta-D-erythro-pentofuranuronamide. 1H NMR and n.O.e. data accounted for both anomeric and N-7/N-9 isomeric configuration.     

2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK)

6-aryl-2-morpholin-4-yl-4H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones were synthesised and evaluated as potential inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). Several compounds in each series exhibited superior activity to the chromenone LY294002, and were of comparable potency to the benzochromenone NU7026 (IC(50)=0.23 microM). Importantly, members of both structural classes were found to be selective inhibitors of DNA-PK over related phosphatidylinositol 3-kinase-related kinase (PIKK) family members. A multiple-parallel synthesis approach, employing Suzuki cross-coupling methodology, was utilised to prepare libraries of thiopyran-4-ones with a range of aromatic groups at the 3'- and 4'-positions on the thiopyran-4-one 6-aryl ring. Screening of the libraries resulted in the identification of 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones bearing naphthyl or benzo[b]thienyl substituents at the 4'-position, as potent DNA-PK inhibitors with IC(50) values in the 0.2-0.4 microM range.     

Antibacterial effect of some substituted tricyclic quinazolines and their synthetic precursors

Eleven substituted tricyclic quinazolines and their synthetic precursors were tested for antibacterial effects. 3-Chloromethylcarbonyl-2-methylquinazolin-4-thione and 5-phenyl-2,3-dihydro-1,2,4-triazolo[4,3-c]quinazolin-3-one had the highest antibacterial effect againstBacillus subtilis, the MIC values being 50 mg/L. Two tested derivatives were more active againstPseudomonas aeruginosa than ampicillin, the IC₅₀ values being 80 and 100 mg/L. The most effective derivatives contained in the structure generally pharmacologically active chromophores—methyl group in position 2 and a chloromethyl configuration on the carbonyl group in position 3.     

The preparation of 2,6-disubstituted pyridinyl phosphine oxides as novel anti-cancer agents

A series of 2,6-dimethoxylpyridinyl phosphine oxides have been synthesized and examined for their antitumor activity. 2,6-Dimethoxy-3-phenyl-4-diphenylphosphinoylpyridine 2 has been employed as the lead compound for this study. We found out that the presence of phosphine oxide on the 2,6-dimethoxylpyridine ring is important for the antitumor activity; the presence of bromine on this core leads to a further enhancement of its antitumor activity. This is the first reported work on the antitumor activity of the 2,6-dimethoxy-3,5-dibromopyridinyl phosphine oxide 5b towards MDAMB-231 breast cancer and SKHep-1 hepatoma cell lines.     

Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5

A high-throughput cell-based screen identified a series of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of metabotropic glutamate receptor 5 (mGlu₅). This Letter describes the SAR of this series and the profile of selected compounds in selectivity and radioligand binding assays.     

Antibacterial effect of some essential oils administered alone or in combination with Norfloxacin

The objective of the present study was that of verifying a possible synergistic antibacterial effect between Pelargonium graveolens [Lis-Balchin, M., Deans, S.G., Hart, S., 1996. Bioactive Geranium oils from different commercial sources. J. Essential Oil Res. 8, 281-290.] essential oil (and its main components) and Norfloxacin antibiotic. As a first step growth inhibition by some types of essential oils was assessed in five microbial species. The antimicrobial effects of P. graveolens oil, as well as those of its components, were evaluated by means of the agar dilution method (ADM) against Bacillus cereus ATCC 11778, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 35218, Staphylococcus aureus ATCC 6538 and S. aureus ATCC 29213. The results obtained highlighted the occurrence of a pronounced synergism between P. graveolens essential oil and Norfloxacin against three of the five bacterial species under study with a FIC index in the 0.37-0.50 range. Such antibacterial effects were also shown to increase, although to a lesser extent, when Norfloxacin was given with the main components of P. graveolens essential oil. SIGNIFICANCE AND IMPACT OF THE STUDY: The combination of Norfloxacin with either P. graveolens essential oil, or with some of the main components of this latter, in the treatment of infections caused by some bacterial species is likely to reduce the minimum effective dose of Norfloxacin thus minimizing the side effects of the antibiotic.     

Novel EGFR inhibitors prepared by combination of dithiocarbamic acid esters and 4-anilinoquinazolines

On the basis of combination strategy, a novel series of EGFR inhibitors were designed and synthesized by combination of dithiocarbamic acid esters and 4-anilinoquinazolines. The effect of the synthesized compounds on cell proliferation was evaluated by MTT assay in three human cancer cell lines: MDA-MB-468, SK-BR-3 and HCT-116. Two compounds (11d and 11f) were found more potent against all three cell lines and five compounds (11a, 11d-11g) were found more potent against both MDA-MB-468 and SK-BR-3 than Lapatinib. SAR studies revealed that the substituents on C6 and C7 positions of quinazoline, the amine component of dithiocarbamate moiety and the linker greatly affected the activity. This work provides a promising new strategy for the preparation of potent tyrosine kinase inhibitors.     

Discovery of 2,6-disubstituted pyrazine derivatives as inhibitors of CK2 and PIM kinases

The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f).     

Synthesis of 2,6-disubstituted benzylamine derivatives as reversible selective inhibitors of copper amine oxidases

In order to obtain substrate-like inhibitors of copper amine oxidases (CAOs), a class of enzymes involved in important cellular processes as well as in crosslinking of elastin and collagen and removal of biogenic primary amines, we synthesized a set of benzylamine derivatives properly substituted at positions 2 and 6 and studied their biological activity towards some members of CAOs.With benzylamines 6, 7, 8 containing linear alkoxy groups we obtained reversible inhibitors of benzylamine oxidase (BAO), very active and selective toward diamine oxidase (DAO), lysyl oxidase (LO) and monoamine oxidase B (MAO B) characterized by a certain toxicity consequent to the crossing of the brain barrier. Poorly toxic, up to very active, reversible inhibitors of BAO, very selective toward DAO, LO and MAO B, were obtained with benzylamines 10, 11, 12 containing hydrophilic ω-hydroxyalkoxy groups. With benzylamines 13, 14, 15, containing linear alkyl groups endowed with steric, but not conjugative effects for the absence of properly positioned oxygen atoms, we synthesized moderately active inhibitors of BAO reversible and selective toward DAO, LO and MAO B.The cross examination of the entire biological data brought us to the conclusion that the bioactive synthesized compounds most likely exert their physiological role of reversible inhibitors in consequence of the formation of a plurality of hydrogen bonds or hydrophobic non-covalent interactions with proper sites in the protein. Accordingly, the reported inhibitors may be considered as a set of research tools for general biological studies and the formation of enzyme complexes useful for X-ray structure determinations aimed at the design of more sophisticated inhibitors to always better modulate the protein activity without important side effects.     

Antibacterial effect, plasmid curing activity and chemical structure of some tricyclic compounds.

Diethazine, amitriptyline and imipramine showed bacteriostatic and bactericidal effect on different bacteria. Chlorpromazine sulphoxide and fluorescein were ineffective even at 1000 microgram/ml. The antibacterial compounds deleted at 40-70% frequency the F'lac plasmid of Escherichia coli K12 LE-140.     

Inhibitors of src tyrosine kinase: the preparation and structure-activity relationship of 4-anilino-3-cyanoquinolines and 4-anilinoquinazolines

Src is a nonreceptor tyrosine kinase involved in signaling pathways that control proliferation, migration, and angiogenesis. Increased Src expression and activity are associated with an increase in tumor malignancy and poor prognosis. Several quinolines and quinazolines were identified as potent and selective inhibitors of Src kinase activity.     

Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors

It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.     

Antibacterial action of ether oils of some plants

Inhibitory effect of clove oil on Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Shigella dysenteriae and Candida albicans was detected. Mint ether oil had the high antibacterial action on S. aureus, however against other microorganisms mint oil had a reliably low effect then clove oil. Fennel oil had high antibacterial effect on C. albicans, and bactericidal action on S. typhimurium and S. dysenteriae.     

Exploring the PI3Kα and γ binding sites with 2,6-disubstituted isonicotinic derivatives

A homology model of the p110α catalytic subunit of PI3Kα was generated from the p110γ crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kα and γ binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs.     

Antibacterial effects of some 1-substituted 1,2,4-triazoles

Seventeen synthetic 1-substituted 1,2,4-triazoles exerted a significant effect on the bacteriaB. subtilis, S. aureus, E. coli andP. aeruginosa. The least sensitive to the effects of the triazoles wasS. aureus. With all triazole derivatives and their combinations,B. subtilis andP. aeruginosa exhibited IC₅₀ and MIC values several times higher than with ampicillin. The most effective triazoles have a N-phenyl ring or benzimidinoyl ring substituted with one or several chlorine atoms. The highest tested concentration of the three most effective triazoles influenced the specific growth rate.     

Structural determinants for potent, selective dual site inhibition of human pp60c-src by 4-anilinoquinazolines

The kinetic mechanisms for the inhibition of pp60(c-src) tyrosine kinase (Src TK) by 4-anilinoquinazolines, an important class of chemicals as protein kinase inhibitors, were investigated. 4-Anilinoquinazolines with a bulky group at the 4'-position of the anilino group were shown to be competitive with both ATP and peptide, whereas molecules lacking such a bulky group only displayed an inhibition pattern typical of those competitive with ATP and noncompetitive with peptide. Modifications of the substituents on the carbocyclic ring did not perturb the inhibition pattern although the affinities of these modified inhibitors for Src TK were affected. Structural modeling of Src TK with inhibitor and peptide substrate bound indicated a direct atomic conflict between the bulky 4-position group and the hydroxy of the peptide tyrosyl to which the gamma-phosphate of ATP is transferred during the kinase reaction. This atomic conflict would likely prevent simultaneous binding of both inhibitor and peptide, consistent with the observed kinetic competitiveness of the inhibitor with peptide. The dual site inhibitors appeared to have both enhanced potency and selectivity for Src TK. One such inhibitor, 4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, had a 15 nM potency against Src TK and was selective over receptor tyrosine kinases VEGFR2 by 88-fold and C-fms by 190-fold.