Antimycobacterial activity of basic ethyl esters of alkoxy-substituted phenylcarbamic acids

A series of 124 basic ethyl esters of alkoxy-substituted phenylcarbamic acids with the alkoxy group in position 2, 3 or 4 on the phenyl ring, and basic substituents attached to the ethyl moiety in position 2, were evaluated for in vitro antimycobacterial activity against strains of Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. In vitro antimycobacterial activity becomes higher with increasing hydrophobic properties of the alkoxy groups. The p- and m-substituted derivatives were more active than the o-substituted ones. Direct relationship between the structure of the basic substituents and the activity was not found.     

Conventional and microwave assisted synthesis of 2-oxo-4-substituted aryl-azetidine derivatives of benzotriazole: a new class of biological compounds

We report herein the synthesis and biological activity of a new kind of azetidinone derivatives of benzotriazole. The reaction was carried out by both conventional and microwave methods. The chemical structures of all the synthesized compounds were deduced according to FTIR, (1)H NMR, (13)C NMR and FAB-mass spectral along with microanalytical data. All the synthesized compounds of series 5a-i were evaluated for their antitubercular activity against Mycobacterium tuberculosis H37RV and antimicrobial activity against some selected microorganism. Unexpectedly, some azetidinone derivatives of benzotriazole displayed better activities.     

Hydrogen bond equilibrium constants for the complexes of benzotriazole and some nucleoside derivatives. A near infrared study

Approximate hydrogen bond association constants were determined by near infrared spectroscopy for pairs formed by benzotriazole and a number of nucleoside derivatives. The molecule of benzotriazole forms, in chloroform, hydrogen bonds with inosine, uridine and adenosine derivatives. The order of decreasing association constants for complexes formed by benzotriazole and uridine or inosine derivatives is the opposite of the one observed for pairs formed by adenosine and uridine or inosine derivatives.     

Hydrogen Bond Equilibrium Constants for the Complexes of Benzotriazole and some Nucleoside Derivatives. A Near Infrared Study

Abstract

Approximate hydrogen bond association constants were determined by near infrared spectroscopy for pairs formed by benzotriazole and a number of nucleoside derivatives.

The molecule of benzotriazole forms, in chloroform, hydrogen bonds with inosine, uridine and adenosine derivatives.

The order of decreasing association constants for complexes formed by benzotriazole and uridine or inosine derivatives is the opposite of the one observed for pairs formed by adenosine and uridine or inosine derivatives.     

A new group of potential antituberculotics: Hydrochlorides of piperidinylalkyl esters of alkoxy-substituted phenylcarbamic acids

A group of 31 of alkoxy-substituted phenylcarbamic acids with the alkoxy group in ortho, meta or para position, and methyl or ethoxymethyl attached to the ethylene moiety in position 1, including both basic ethyl esters and derivatives branched on ethylene, were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, and M. avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on a combination of the Free-Wilson analysis was used to express the influence of the substituents on the ethylene group as well as the position of the alkoxy groups on the phenyl ring and of the hydrophobicity of alkyls. In vitro antimycobacterial activity becomes higher with increasing hydrophobic properties of the alkoxy groups. The para- and meta-substituted derivatives were more active than the ortho-substituted ones. Substitution of ethylene in position 1 by methyl increased the activity against M. tuberculosis, a similar substitution by ethoxymethyl increased the activity against M. kansasii. The most active compounds were piperidinyl-1-(ethoxymethyl)ethylesters of heptoxyphenylcarbamic acids.     

Preparation and activity of metal complexes with heteroatomic organic ligands. Preliminary note

Various coordination compounds were prepared between transition metals (in particular copper, zinc, silver and cobalt) and benzotriazole 5-methylbenzotriazole, 2-methylbenzotriazole and 2-methylbenzimidazole. Compounds of this type present a significant herbicidal capacity both on monocotyledons and dicotyledons and some of them also present an antimicrobic activity. The method of preparation, the principal chemical characteristics and the analyses to determine the formulae are reported. It was observed that metal can coordinate with benzotriazole and its derivatives either as a neutral molecule (BTAH) or as a deprotonated anion (BTA-), or as a combination of both (BTAH and BTA-).     

Antimicrobial activity of some 2-amino-5-subsituted pyridine derivatives

A series of 2-amino-5-substituted pyridine derivatives were prepared and evaluated against phytopathogenic fungi and bacteria under laboratory conditions. Position 4 on the pyridine ring has notable fungicidal and bactericidal activity, greater than position 3 and/or position 6. Reaction of 1-hydroxymethyl benzotriazole with the amino group of the pyridine ring gave better fungicidal activity than substitution on the carbon of the pyridine ring (compound 4 versus 1c). Replacing the benzotriazole moiety with thiophenol exhibited the strongest fungicidal and bactericidal activity in this series (compound 3).     

Synthesis and antiplasmodial activity of lycorine derivatives

Twenty seven lycorine derivatives were prepared and evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. The best antiplasmodial activities were achieved with lycorine derivatives that present free hydroxyl groups at C-1 and C-2 or esterified as acetates or isobutyrates. The double bond C-2–C-3 is also important for the activity. Concerning to the antiplasmodial activity of the secolycorines, the higher values were obtained with the replacement of the methylenedioxy moiety by hydroxyl or acetate groups and with methyl substituent attached to the nitrogen atom.     

Antiproliferative activity of salinomycin and its derivatives

Antiproliferative activity of seven amides and one benzotriazole ester derivative of salinomycin, a polyether ionophore antibiotic, with recently reported antibacterial activity, are herein described. Salinomycin and the majority of derivatives exhibit potent antiproliferative activity against the drug-resistant cancer cell lines. Moreover almost all derivatives show stronger activity against LoVo/DX cell line than that of unmodified salinomycin.     

Microwave-assisted synthesis of N-alkylated benzotriazole derivatives: antimicrobial studies

Synthesis and characterization of N-alkylated benzotriazole derivatives 2(a-g) bearing pharmaceutically important bioactive substituents and their antimicrobial studies in vitro are described. The syntheses of the compounds were achieved by N-alkylation of the benzotriazole with different bioactive alkyl halides in presence of powdered K2CO3 in DMF solution and by microwave irradiation method with good yield compared to conventional method. The crystal structure analysis shows that compound 4'-benzotriazol-1-yl-methyl-biphenyl-2-carbonitrile 2a crystallizes in the space group P1 with cell parameters a = 8.526 (3) A, b = 12.706 (3) A, c = 7.966 (2) A, alpha = 100.89 (2) degrees , beta = 101.63 (3) degrees , gamma = 102.20(2) degrees, Volume = 801.7(4) A degrees , Z = 2 and the final R factor is 0.0559 for 6130 reflections with 218 parameters and zero restraint. This structure exhibits intermolecular hydrogen bonding. Compounds 2e, 2a showed significant antimicrobial activity.     

Design and synthesis of CK2 inhibitors

A series of new polybrominated benzimidazoles and benzotriazoles has been synthesized and their influence on the activity of protein kinase CK2 was evaluated. It was revealed that the most active inhibitors are those with methyl or ethyl substituent at benzene ring, namely 5,6,7-tribromo-4-methyl-1H-benzotriazole (38, IC(50) 0.51 μM) and 5,6,7-tribromo-4-ethyl-1H-benzotriazole (40, IC(50) 0.16 μM). The derivatives with large aromatic or heterocyclic substituents connected to benzimidazole or benzotriazole scaffold appeared to be less potent inhibitors.     

Benzotriazoles and indazoles are scaffolds with biological activity against Entamoeba histolytica

Parasitic infections caused by Entamoeba histolytica are still major threats against public health, especially in developing countries. Although current therapies exist, the problems associated with parasite resistance and negative side effects make it imperative to search for new therapeutic agents. A systematic scaffold analysis reported herein of a public database containing 474 antiamoebic compounds reveals that benzimidazole is the most active scaffold reported thus far. To gain insights into the antiamoebic activity of novel compounds, the authors report herein the biological activity of 12 compounds, including benzotriazole and indazole derivatives, scaffolds not previously tested against E. histolytica. Compounds with the benzotriazole and indazole scaffolds showed low micromolar activity (IC(50) = 0.304 and 0.339 μM) and are more active than metronidazole, which is the drug of choice used for the treatment of amebiosis. The novel compounds have similar properties to approved drugs. Compounds with novel scaffolds represent promising starting points of an optimization program against E. histolytica.     

Synthesis and in vitro antikinetoplastid activity of polyamine–hydroxybenzotriazole conjugates

Thirteen new polyamine derivatives coupled to hydroxybenzotriazole have been synthesized and evaluated for their in vitro antikinetoplastid activity. Trypanosoma Trypanothione reductase (TryR) was envisioned as a potential target. Among all tested molecules, only one compound, a N³-spermidine–benzotriazole derivative, displayed relevant inhibitory activity on this enzyme but was not active on parasites. The corresponding Boc-protected spermidine–benzotriazole was however trypanocidal against Trypanosoma brucei gambiense with an IC₅₀ value of 1 μM and was completely devoid of cytotoxicity. On the intramacrophage amastigotes of Leishmania donovani, a N²-spermidine conjugate of this series, exhibited an interesting IC₅₀ value of 3 μM associated with both low cytotoxicity against axenic Leishmania donovani. These new compounds are promising leads for the development of antikinetoplastid agents and their targets have to be deciphered.     

Synthesis of Sordaricin analogues as potent antifungal agents against Candida albicans

Sordaricin derivatives possessing a cyclohexane ring appendage attached via an ether, thioether, amine, oxime, ester or amide linkage were synthesized and their antifungal activity was evaluated in vitro. Compounds containing a thioether bond or an oxime bond as a linkage exhibited potent MICs (< or = 0.125 microg/mL) against four Candida albicans strains including azole-low-susceptible strains. They were also active (MIC < or = 0.125 microg/mL) against Candida glabrata. Their in vivo efficacy was confirmed in a murine intravenous infection model with Candida albicans.     

Synthesis, SAR, and antibacterial activity of novel oxazolidinone analogues possessing urea functionality

The syntheses of a number of novel oxazolidinone analogues possessing an urea functionality are reported. While the urea derivatives possessing aliphatic and aromatic groups were prepared by the more conventional isocyanate method, the derivatives possessing heterocyclic rings were synthesized by a relatively uncommon but otherwise efficient carbamate chemistry. Though the SAR resulted in novel compounds possessing in vitro activity equivalent to Linezolid, the compounds possess a range of substituents that are amenable for altering physicochemical properties of the resultant drug. The antibacterial activity was found to be not sensitive to the functional groups attached to the urea site regardless of the size and electronic characteristics. Based on in vivo results, one molecule has been identified as a candidate and additional work such as salt selection, scale-up, etc., are currently underway to take the molecule further through development.     

Benzotriazole stabilized lithium intermediates as a route to the elaboration of N-substituents in amides

Lithiation of N-(benzotriazol-1-ylmethyl)benzamide or N-(benzotriazol-1-ylmethyl)-2,2-dimethylbutyramide, readily prepared from the corresponding amides, formaldehyde and benzotriazole, followed by quenching with various electrophiles, such as alkyl halides, ketones or ester, gives the corresponding N-substituted derivatives. Subsequent displacement of the benzotriazole group with Grignard reagents, thiols or alcohols provides access to a wide variety of N-substituted amides in good yields. Treatment of the N-(benzotriazol-1-ylalkyl)benzamides with n- BuLi afforded the 1,1-dibenzamidoalkanes.     

Synthesis,cytotoxic activity,DNA topoisomerase-II inhibition,molecular modeling and structure–activity relationship of 9-anilinothiazolo[5,4-b]quinoline derivatives

Some novel 9-anilinothiazolo[5,4-b]quinoline derivatives were synthesized and their cytotoxic activities were examined. The inhibition of some of the most active compounds over human topoisomerase II (Topo II) activity was assessed with the kDNA decatenation assay. The novel compounds differ in the substituents attached to the anilino ring, a dialkylamino alkylamino group, a saturated heterocyclic moiety, a methylthio group at position 2 and a fluorine atom present or absent at 7-position. According to the data, compounds with a diethylaminopropylamino group and a chlorine atom at 4′-position of the anilino ring were the most cytotoxic. The molecular models of all compounds indicated a correlation between hydrophobicity and cytotoxic activity although the direction and magnitude of the dipole moment also had a significant influence on its cytotoxicity. The 2-dialkylaminoalkylamino substituent is flexible and is known to facilitate the crossing of cell membranes; thus, this last barrier may be a limiting step in the mechanisms mediating the cytotoxicity. On the other hand, the activity of 2-methylthio derivatives seems to rely more on the electronic effects brought about by the substitution of the aniline ring. The synthesis, cytotoxicity against cancer cell lines, in vitro inhibition of human topoisomerase II, molecular modeling and the preliminary analysis of structure–activity relationships are presented.     

Antibacterial Activity and Structure−Activity Relationship of a Series of Newly Synthesized Pleuromutilin Derivatives

A series of novel thioether or sulfoxide‐type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram‐positive pathogens. In this work, a five‐membered heterocyclic moiety, a pyrimidine‐heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether‐containing pleuromutilin derivatives exert a more potency activity than the sulfoxide‐type derivatives against Gram‐positive pathogens. The structure?activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives.     

Synthesis and antimalarial evaluation of a series of piperazinyl flavones

A series of 27 flavonoid derivatives containing a piperazinyl chain have been synthesized and tested for their antiplasmodial activity. Diverse substitution patterns on piperazinyl and flavone moieties were examined and found to affect the activity differently. The most active compounds, which have a 2,3,4-trimethoxybenzylpiperazinyl chain attached to the flavone at the 7-phenol group, showed in vitro activity against chloroquine-sensitive (Thai) and -resistant (FcB1,K1) Plasmodium falciparum strains in the micromolar to submicromolar range. One of them was active when given orally in a Plasmodium yoelii nigeriensis infected mouse model.