Antifungal Activity of Isothiocyanates and Related Compounds: III. Derivatives of Diphenyl, Stilbene, Azobenzene, and Several Polycondensed Aromatic Hydrocarbons

This paper presents the results of a study on the antifungal activity of isothiocyanates-derivatives of biphenyl (group "A"), of stilbene ("B"), of azobenzene and benzeneazonaphthalene ("C"), of naphthalene ("D"), and of further polycondensed aromatic hydrocarbons ("E"). From a total of 48 investigated compounds, antifungal activity was observed only in A and D group compounds. B, C, and E group derivatives are extremely insoluble in water, and the molecules are very large; as a result, they probably cannot pass into spores or mycelium of fungi. Thus, the -NCS group cannot manifest its reactivity.     

Antifungal Activity of 2,4-Dihydroxyacylophenones and Related Compounds

The antifungal activity of 2,4-dihydroxyacylophenones and related compounds against Trichophyton spp and other fungi were investigated to determine their structure-activity relationships.

The activity of these compounds was found to be closely related to the length of the acyl and alkyl substituents attached to the 1,3-dihydroxybenzene moiety In addition, differences in activity were observed depending on the position of the alkyl substituents and on the number of substituents attached to the 1,3-dihydroxybenzene moiety. Some compounds tested showed potent antifungal activity against Trichophyton spp. and other fungi that was more active than amphotericin B.     

Simple synthesis of novel diphenylsulfapyrimidine acetates from chalcones and their antimicrobial activity

Given the significant low yield (19-43%) in reported results on the cyclocondensation of sulfaguanidine acetate with chalcones, a careful reinvestigation was carried out. A new series of chalcones, bearing electron-attracting groups in the aromatic moiety, have been used as precursors in the synthesis of diphenylsulfapyrimidine acetates with good yield. All synthesized compounds were active against G(+)- and G(-)-bacteria, and fungi. Combination of substituents (Cl, OMe, NO2, etc.) enhanced antimicrobial activity. Derivative with two NO2 groups exhibits an activity comparable with sulfadiazine.     

Metallocene-based antimalarials: an exploration into the influence of the ferrocenyl moiety on in vitro antimalarial activity in chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum

To establish the role of the ferrocenyl moiety in the antiplasmodial activity of ferroquine, compounds in which this moiety is replaced by the corresponding ruthenium-based moieties were synthesized and evaluated. In both the sensitive (D10) and resistant (K1) strains of Plasmodium falciparum, ruthenoquine analogues showed comparable potency to ferroquine. This suggests that a probable role of the ferrocenyl fragment is to serve simply as a hydrophobic spacer group. In addition, ferroquine analogues with different aromatic substituents were synthesized and evaluated. Unexpectedly high activity for quinoline compounds lacking the 7-chloro substituent suggests the ferrocenyl moiety may have an additive and/or synergistic effect.     

Design, synthesis, and biological evaluation of a series of simple and novel potential antimalarial compounds.

A series of compounds bearing an endocyclic -N-O- moiety with potential antimalarial activity based on simple derivatives of the tropolone purpurogallin was prepared by means of a hetero Diels-Alder reaction using nitrosobenzene as a dienophile. The rationale behind the design of these compounds is presented, together with the synthetic route to derivatives bearing aromatic and aliphatic esters of the C4'-position hydroxyl group of the purpurogallin framework, as well as biological data obtained from in vitro assays against Plasmodium falciparum and Trypanosoma cruzi. Several of the new compounds have activities in the 3-9 microM range, and provide leads for the development of a novel class of antiparasitic drugs with improved biological and pharmacological properties.     

Parallel synthesis and pharmacological screening of nonpeptide ligands of the neuropeptide Y receptor subtype Y5.

Several series of low-molecular-mass ligands of the neuropeptide receptor subtype Y5 were prepared using a mixed strategy of synthesis on solid phase and in solution. Collections of single compounds were obtained by an automated parallel procedure which allowed quick variation and investigation of the central spacer moiety, as well as of the aromatic substituents on each side. The strategy of parallel synthesis and screening of partially purified analogs helped to select rapidly potent and selective leads which displayed comparable antagonistic potency against neuropeptide Y activity on the Y5 receptor and better receptor selectivity than the original reference compounds.     

Design,synthesis and antifungal activity of amide and imine derivatives containing a kakuol moiety

In continuation of our program to discover new potential antifungal agents, a series of amide and imine derivatives containing a kakuol moiety were synthesized and characterized by the spectroscopic analysis. By using the mycelium growth rate method, the target compounds were evaluated systematically for antifungal activities in vitro against four plant pathogenic fungi, and structure–activity relationships (SAR) were derived. Compounds 7d, 7e, 7h, 7i and 7r showed obvious inhibitory activity against the corresponding tested fungi at 50 μg/mL. Especially, compounds 7e and 7r displayed more potent antifungal activity against B. cinerea than that of thiabendazole (a positive control). Moreover, compound 7e also exhibited good activity against A. alternata with EC₅₀ values of 11.0 µg/mL, and the value was slightly superior to that of thiabendazole (EC₅₀ = 14.9 µg/mL). SAR analysis showed that the ether group was a highly sensitive structural moiety to the activity and the type as well as position of substituents on benzene ring could make some effects on the activity.     

Hydroxycoumarins as selective MAO-B inhibitors

A series of 3-aryl-4-hydroxycoumarin derivatives was synthesized with the aim to find out the structural features for the MAO inhibitory activity and selectivity. Methoxy and/or chloro substituents were introduced in the 3-phenyl ring, whereas the position 6 in the coumarin moiety was not substituted or substituted with a methyl group or a chloro atom due to their different electronic, steric and/or lipophilic properties. Most of the synthesized compounds presented MAO-B inhibitory activity. The presence of methoxy and chloro groups, respectively in the para and meta positions of the 3-phenyl ring, have an important influence on the inhibitory activity. Moreover, the presence of a chloro atom in the six position of the moiety (compound 7) improved the inhibitor activity as well as its selectivity against MAO-B compared with iproniazide, used as reference compound. Docking experiments were carried out to understand which are the most energetically preferred orientations adopted by compounds 5, 6 and 7 inside the MAO-B binding pocket.     

The synthesis and antibacterial activity of totarol derivatives. Part 2: Modifications at C-12 and O-13

Alterations of the C-12 and C-13 aromatic ring substituents of totarol (1) afforded the series of derivatives 2-14, and introduction of substituents at C-12 gave exclusively 2a-14a. The majority of these analogues were tested in vitro against the following organisms: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and multiresistant Klebsiella pneumoniae. The results were evaluated in terms of structure-activity relationship which reveals that: (a) the phenolic moiety at C-13, in general, is essential for antibacterial activity at < 32 microg/mL against gram-positive species, and (b) derivatization at C-12 has an undesirable effect on the antibacterial activity of this class of compounds, while (c) all compounds tested are ineffective against the gram-negative Klebsiella pneumoniae.     

Hydrazones of 2-aryl-quinoline-4-carboxylic acid hydrazides: synthesis and preliminary evaluation as antimicrobial agents

A new series of 2-arylquinoline-4-carboxylic acid hydrazide–hydrazones was synthesized using an appropriate synthetic route. All the target compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus as an example for Gram-positive bacteria, Escherichia coli as an example for Gram-negative bacteria, and Candida albicans as a representative of fungi. The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standards. Among the compounds tested, compounds having nitro substituents at the arylidene moiety showed the most potent antifungal as well as antibacterial activities against E. coli. Compound 23 displayed an antifungal activity comparable to that of nystatin. However, none of the compounds demonstrated any antibacterial activity against S. aureus. Hydrophobicity of the target compounds correlated weakly with their antibacterial and antifungal activities. The most potent compounds namely, 7, 18, 19, 22, and 23 were assessed for hemolytic toxicity and found to be non-hemolytic up to a concentration of 100 μg/mL. In addition, the most potent compound (23) was evaluated for in vitro cytotoxic activity against various cancer cell lines. This compound was found to display no cytotoxic activity but rather it induces the proliferation rate of Hep-G2 cells.     

Synthesis and SAR studies on azetidine-containing dipeptides as HCMV inhibitors

SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti-HCMV activity. The conformational restriction induced by the 2-azetidine residue into the dipeptide derivatives, identified by (1)H NMR as a γ-type reverse turn, seems to have influence on the activity of these molecules.     

Antifungal activity of isothiocyanates and related compounds. I. Naturally occurring isothiocyanates and their analogues

Data are presented concerning the antifungal activity of 11 natural isothiocyanates and 27 synthetized analogues in Aspergillus niger, Penicillium cyclopium, and Rhizopus oryzae, as well as in 13 additional saprophytic and parasitic fungi. A remarkable antifungal activity was observed in some analogues of benzylisothiocyanate and beta-phenylethylisothiocyanate. The latter-mentioned compounds have not been described previously. In the group of benzylisothiocyanates, a correlation, which was inversely proportional, was detected between ed(100) values for A. niger and R. oryzae and the corresponding molar solubilities of compounds in water. In contradistinction, no relationship was observed between antifungal activity and chemical reactivity of investigated derivatives.     

Thioether-bridged arylalkyl-linked N-phenylpyrazole derivatives: Design,synthesis, insecticidal activities,structure-activity relationship and molecular-modeling studies

Owing to thioether diverse physicochemical properties by non-covalent interactions with bio-macromolecules, thioether derivatives containing heterocyclic moiety are known for their interesting insecticidal bioactivities and attracting considerable attention as neuroactive insecticides. Here we synthesis a series of novel thioether bridged N-phenylpyrazole derivatives incorporating various (hetero)aromatic substituents into 4-position of the pyrazole ring. Structure-activity relationship (SAR) studies resulted in compounds 6d and 7d with the most potent insecticidal activity among the series containing various substituted benzene substituents (LC₅₀?=?13.70–25.47?μg/g). Further optimization to increase the lipophilicity and charge density of aromatic substituents of compounds 6d and 7d resulted in compounds 12d, 14d and 16d with sulfur-containing heterocycle substituents possessing good insecticidal activity against Musca domestica L. among the series (LC₅₀?=?0.67–1.30?μg/g). The thioether bridge N-phenylpyrazole derivatives, which exhibit different length of the spacer arm introduced between N-phenylpyrazole moiety and the (hetero)aromatic substituents, were also prepared and evaluated. By contrast, the insecticidal activities of compounds containing the short thioether bridge, 1,2-bis((hetero)aromatic thio) ethane, are higher than that containing the long thioether bridge, 1,3-bis((hetero)aromatic thio) propane. The results of molecular docking and pharmacophore analyses indicated A299, T303, and L306 of a subunit were essential to form non-covalent interactions contacts with the ligands. Specially, the sulfur-containing heterocycle substituent derivatives 12d and 14d as the sterically favored areas could form the important hydrophobic interactions with the deeper residue P295.     

Synthesis, structural investigations and biological evaluation of novel hexahydropyridazine-1-carboximidamides, -carbothioamides and -carbothioimidic acid esters as inducible nitric oxide synthase inhibitors

Local excess of nitric oxide (NO) has been implicated in beta-cell damage, thus, a possible approach to the treatment of autoimmune IDDM is the selective inhibition of inducible nitric oxide synthase (iNOS). A series of variously substituted hexahydropyridazine-1-carbothioamides, -carbothioimidic acid esters and -carboximidamides was synthesized and dose-dependently evaluated as potential inhibitors of iNOS. The screening of the title compounds was performed with insulin-producing RIN-5AH cells and a combination of IL1-1 beta and IFN-gamma as inducers of cellular NO production. The structure-activity analysis revealed that the variation of substituents in the position 1 of the hexahydropyridazine strongly influences the inhibitory activity to iNOS as well as being critical for RIN cell survival. Among the compounds tested, the hexahydropyridazine-1-carbothioamides showed particularly significant inhibitory effects. However, for an efficient iNOS inhibition substitution at the nitrogen of the 1-carbothioamide group is important. Thus, the introduction of aliphatic chains such as propyl or butyl and of cyclic moieties such as cyclohexyl, 3-methoxyphenyl, and 4-methoxyphenyl (IC(50): 0.5-2.1 mM), respectively, provided compounds with similar inhibitory activity to aminoguanidine (IC(50): 0.3 mM), a common standard substance used for the selective inhibition of iNOS. However, the 1-carboximidamides, which represent more structurally related semicyclic derivatives of aminoguanidine, caused only incomplete iNOS inhibition. The hexahydropyridazine-1-carbothioimidic acid esters caused dose- and substituent-dependent damage of RIN-5AH cells. The toxicity of the synthesized compounds increased markedly if aliphatic substituents at the exocyclic N atom(s) were replaced by variously substituted aromatic rings.     

Exopolysaccharides of Xanthomonas pathovar strains that infect rice and wheat crops

In order to understand the mode of action of the taxonomically related pathogens Xanthomonas campestris pv. translucens, Xanthomonas oryzae pv. oryzae, and Xanthomonas oryzae pv. oryzicola, which attack wheat and rice crops, we examined the compositional differences of their exopolysaccharides (EPSs). Maximum production of polysaccharide in shake cultures of these pathogens was observed between 24 and 72 h. X. campestris pv. translucens, the leaf streak pathogen of wheat, produced a higher amount of polysaccharide (46.97 microg/ml) at 72 h compared to X. oryzae pv. oryzae (42.02 microg/ml), the bacterial blight pathogen of rice, and X. oryzae pv. oryzicola (41.91 microg/ml), the bacterial leaf streak pathogen of rice. Infrared (FTIR) spectra suggested that the polysaccharides of all three Xanthomonas pathovar strains have an -OH group with intermolecular hydrogen bonding, a C-H group of methyl alkanes, an aldehyde (RCHO) group, a C=C or C=O group, and a C-O group. FTIR spectra also revealed the presence of an acid anhydride group in X. oryzae pv. oryzae, a secondary aromatic or aliphatic amine group in X. campestris pv. translucens, and a primary aromatic or aliphatic amine group in X. oryzae pv. oryzae and X. oryzae pv. oryzicola. Nuclear magnetic resonance (NMR) spectra revealed the presence of unsubstituted sugars, an acetyl amine of hexose or pentose, and a beta-anomeric carbon of hexose or pentose in the polysaccharides of all bacteria. NMR spectra also identified the alpha-anomeric carbon of hexose or pentose in all strains, and a branching at the fourth carbon of the sugar only in X. campestris pv. translucens; the presence of an uronic acid molecule (acid anhydride group) in X. oryzae pv. oryzae; and a deoxy sugar, rhamnose, in X. oryzae pv. oryzicola.     

A series of crystal structures of a meta-cleavage product hydrolase from Pseudomonas fluorescens IP01 (CumD) complexed with various cleavage products

Meta-cleavage product hydrolase (MCP-hydrolase) is one of the key enzymes in the microbial degradation of aromatic compounds. MCP-hydrolase produces 2-hydroxypenta-2,4-dienoate and various organic acids, according to the C6 substituent of the substrate. Comprehensive analysis of the substrate specificity of the MCP-hydrolase from Pseudomonas fluorescens IP01 (CumD) was carried out by determining the kinetic parameters for nine substrates and crystal structures complexed with eight cleavage products. CumD preferred substrates with long non-branched C6 substituents, but did not effectively hydrolyze a substrate with a phenyl group. Superimposition of the complex structures indicated that benzoate was bound in a significantly different direction than other aliphatic cleavage products. The directions of the bound organic acids appeared to be related with the k(cat) values of the corresponding substrates. The Ile139 and Trp143 residues on helix alpha4 appeared to cause steric hindrance with the aromatic ring of the substrate, which hampers base-catalyzed attack by water.     

Synthesis and biological evaluation of histamine Schiff bases as carbonic anhydrase I,II, IV,VII, and IX activators

A series of 20 histamine Schiff base was synthesised by reaction of histamine, a well known carbonic anhydrase (CA, E.C 4.2.2.1.) activator pharmacophore, with substituted aldehydes. The obtained histamine Schiff bases were assayed as activators of five selected human (h) CA isozymes, the cytosolic hCA I, hCA II, and hCA VII, the membrane-anchored hCA IV and transmembrane hCA IX. Some of these compounds showed efficient activity (in the nanomolar range) against the cytosolic isoform hCA VII, which is a key CA enzyme involved in brain metabolism. Moderate activity was observed against hCA I and hCA IV (in the nanomolar to low micromolar range). The structure–activity relationship for activation of these isoforms with the new histamine Schiff bases is discussed in detail based on the nature of the aliphatic, aromatic, or heterocyclic moiety present in the aldehyde fragment of the molecule, which may participate in diverse interactions with amino acid residues at the entrance of the active site, where activators bind, and which is the most variable part among the different CA isoforms.     

Evaluation of HIV-1 inhibition by stereoisomers and analogues of the sesquiterpenoid hydroquinone peyssonol A

Peyssonol A, a brominated natural product with documented anti-HIV-1 activity, was synthesized racemically along with 6 isomers and 15 truncated analogues and synthetic precursors. These compounds were screened in a cell-based assay against a recombinant HIV-1 strain to investigate structure–activity relationships. The results obtained suggest that both the aliphatic and aromatic domains of peyssonol A are responsible for its potency, while the stereochemical configuration of the substituents on the aliphatic domain, including their bromine atom, are largely irrelevant. Although none of the analogues tested were as potent as the parent natural product, several exhibited greater therapeutic indices due to reduced cytotoxicity, noting that nearly all compounds tested were measurably cytotoxic.     

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.     

Antimicrobial properties of substituted salicylaldehydes and related compounds

A systematic survey of the antimicrobial properties of substituted salicylaldehydes and some related aromatic aldehydes is reported. A total of 23 different compounds, each at four different concentrations, were studied using a panel of seven microbes (Aspergillus niger, Bacillus cereus, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Saccharomyces cerevisiae and Staphylococcus epidermidis) and employing the paper disc agar diffusion method. Several aldehydes, most notably halogenated, nitro-substituted and hydroxylated salicylaldehydes, displayed highly potent activity against the microbes studied, giving inhibitory zones up to 49 mm in diameter (paper disc diameter 6 mm), while unsubstituted benzaldehyde and salicylaldehyde had minimal activity. Further, 4,6-dimethoxysalicylaldehyde had considerable activity against C albicans and slight activity against S. cerevisiae, while displaying minimal activity against bacteria. Also two aromatic dialdehydes had interesting activity. In general, P. aeruginosa was the least sensitive microbe, a result that is in line with observations from a large screening project, in which this microbe was the one against which the least number of active substances was found. Interestingly, the structure-activity relationships of the aldehydes studied were clearly different for different microbes. Many of the aldehydes tested had such high antimicrobial activity that they are noteworthy candidates for practical applications as well as interesting lead compounds for the development of novel antimicrobial drugs and disinfectants. The structure-activity relationships are discussed in detail. For high activity, substituents are required in benzaldehyde as well as in its 2-hydroxy derivative salicylaldehyde. One hydroxy group alone (at the 2-position) is not enough, but further hydroxylation may produce high activity. The effects of substituents are in some cases dramatic. Halogenation, hydroxylation and nitro substitution may produce highly active compounds, but the effects are not easily predicted nor can they be extrapolated from one microbe to another.