(Z)-N,N-Dimethyl-2-[phenyl(pyridin-2- yl)methylidene]hydrazinecarbothioamide

The title compound, C15H16N4S, exists in the Z conformation with the thionyl S atom lying cis to the azomethine N atom. The shortening of the N—N distance [1.3697 (17) A ° ] is due to extensive delocalization with the pyridine ring. The hydrazine– carbothioamide unit is almost planar, with a maximum deviation of 0.013 (2) A ° for the amide N atom. The stability of this conformation is favoured by the formation of an intramolecular N—H N hydrogen bond. The packing of the molecules involves no classical intermolecular hydrogenbonding interactions; however, a C—H interaction occurs

1,3-Dipolar cycloadditions to unsymmetrical ketone-derived chiral stabilized azomethine ylides: strategies for the synthesis of highly substituted amino acids

We report herein, the first generation of unsymmetrical ketone-derived chiral stabilized azomethine ylides. Intrairiolecular and intermolecular cycloaddition strategies have been utilized to synthesize both an enantiornerically pure bicyclic proline derivative and an enantionierically pure beta-hydroxy-alpha-amino acid.

Zinc mediated azide-alkyne ligation to 1,5- and 1,4,5-substituted 1,2,3-triazoles

A mild method for regioselective formation of 1,5-substituted 1,2,3-triazoles is described. The zinc-mediated reaction works at room temperature and is successful across a wide range of azido/alkynyl substrates. Additionally, the triazole 4-position can be further functionalized through the intermediate aryl-zinc to accommodate a diverse three-component coupling strategy.

Fenchyl substituted 1,2-dioxetanes as an alternative to adamantyl derivatives for bioanalytical applications

The synthesis and study of the chemiluminescence parameters and thermal stability of 1,2-dioxetanes containing a spirofenchyl substituent are reported. Three fenchyl-substituted 1,2-dioxetanes were synthesized by photooxygenation of the corresponding alkenes, obtained by Barton-Kellogg olefination of the readily available (-)-fenchone. The fenchyl-substituted 1,2-dioxetanes showed thermal stabilities similar to those of the corresponding spiroadamantyl-substituted derivatives, although being slightly more labile with respect to unimolecular decomposition than the latter derivatives, which are widely utilized as labels in a great variety of chemiluminescent immunoassays. Fluoride induced decomposition of one triggerable fenchyl 1,2-dioxetane derivative showed kinetic parameters similar to those of the corresponding adamantyl-substituted derivative. The chemiluminescence quantum yields in the one percent range are also similar to that of other widely utilized chemiluminescence systems as the luminol reaction. These results indicate that fenchyl-substituted 1,2-dioxetanes can potentially be utilized as a cheaper alternative to substitute the corresponding spiroadamantyl derivatives in bioanalytical applications. (C) 2010 Elsevier B.V. All rights reserved.

Novel 1,4-substituted-1,2,3-triazoles as antitubercular agents

Tuberculosis (TB) remains a pressing unmet medical need, particularly with the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. Here, a series of 1,4-substituted-1,2,3-triazoles have been synthesized and evaluated as potential antitubercular agents. These compounds were assembled via click chemistry in high crude purity and in moderate to high yield. Of the compounds tested, 12 compounds showed promising antitubercular activity with six possessing minimum inhibitory concentration (MIC) values <10 μg mL^-1, and total selectivity for Mycobacterium tuberculosis (Mtb) growth inhibition. A second set of 21 compounds bearing variations on ring C were synthesized and evaluated. This second library gave an additional six compounds displaying MIC values ≤10 μg mL^-1 and total selectivity for Mtb growth inhibition. These compounds serve as an excellent starting point for further development of antitubercular therapies.

Design of 1,2-dioxines with anti-Candida activity: aromatic substituted 1,2-dioxines

In an ongoing effort to rationally design new antimicrobials, 47 new 1,2-dioxines have been synthesised. Broad antifungal structure-activity relationships governing aromatically substituted epoxy-1,2-dioxines 2 and 3 and their parent 1,2-dioxines 1 were assessed primarily against the pathogenic yeast, Candida albicans, with haemolytic activity of selected examples also reported.

Antioxidant capacity and environmentally friendly synthesis of dihydropyrimidin-(2H)-ones promoted by naturally occurring organic acids

The Biginelli reaction is a multicomponent reaction involving the condensation between an aldehyde, a beta-ketoester, and urea or thiourea, in the presence of an acid catalyst, producing dihydropyrimidinones (DHPMs). Owing to their important pharmacological properties, the DHPMs have been studied by many authors. However, most of the methodologies used for the synthesis of these compounds require drastic reaction conditions. In the current study, we report an efficient and clean procedure for preparing DHPMs by the use of citric acid or tartaric acid as a promoter of the Biginelli synthesis in ethanol as solvent. In addition, we have evaluated the antioxidant capacity of the compounds synthesized by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and the thiobarbituric acid-reactive species test. Two compounds presented antioxidant activity and also reduced lipid peroxidation at concentrations of 200 and 300 mu M. In summary, we report an environmentally friendly procedure for the preparation of DHPMs and demonstrate the antioxidant capacity of some of the compounds. (C) 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:155161, 2012; View this article online at . DOI 10.1002/jbt.20424

Highly Substituted Isoxazoles: The Baylis-Hillman reaction of substituted 4-isoxazolecarbaldehydes and attempted cyclization to isoxazole-annulated derivatives

In an attempt to understand the effect of position of the formyl group on the efficiency of Baylis-Hillman reaction within isoxazolecarboxaldehydes, the reactions of substituted 4-isoxazolecarboxaldehydes to obtain highly substituted isoxazoles are described. Attempts to obtain isoxazole-annealed derivatives from these Baylis-Hillman adducts involving SNR’-SNAr substitu-tion strategy are also described.

Interesting results of catalytic hydrogenation of 3-(2-nitrophenyl)-isoxazoles and 3-(nitro-substituted-phenyl)-2-isoxazolines

The Pd-C-assisted hydrogenolysis of substituted 3-(2-nitrophenyl)-isoxazoles, irrespective of substitution on the isoxa-zole ring, invariably leads to reduction of nitro to amino group with concomitant regiospecific ring closure to yield substituted 4-quinolinamines. In contrast similar hydrogenation of 3-(nitro substituted phenyl)-2-isoxazolines results in reduction of the nitro group only with conservation of isoxazoline ring to yield 3-(amino substituted phenyl)-2-isoxazolines.

A σ32 mutant with a single amino acid change in the highly conserved region 2.2 exhibits reduced core RNA polymerase affinity

σ32, the product of the rpoH gene in Escherichia coli, provides promoter specificity by interacting with core RNAP. Amino acid sequence alignment of σ32 with other sigma factors in the σ70 family has revealed regions of sequence homology. We have investigated the function of the most highly conserved region, 2.2, using purified products of various rpoH alleles. Core RNAP binding analysis by glycerol gradient sedimentation has revealed reduced core RNAP affinity for one of the mutant σ32 proteins, Q80R. This reduced core interaction is exacerbated in the presence of σ70, which competes with σ32 for binding of core RNAP. When a different but more conserved amino acid was introduced at this position by site-directed mutagenesis (Q80N), this mutant sigma factor still displayed a significant reduction in its core RNAP affinity. Based on these results, we conclude that at least one specific amino acid in region 2.2 is involved in core RNAP interaction.

A combinatorial approach to the chemical synthesis and biological evaluation of 3,4,5-trisubstiituted furan-2(5H)-ones

Many important natural products contain the furan-2(5H)-one structure. The structure of this molecule lends itself to manipulation using combinatorial techniques due to the presence of more than one site for the attachment of different suhstituents. By developing different reaction schemes at the three sites available for attachment on the furan-2(5H)-one scaffold, combinatorial chemistry techniques can be employed to assemble libraries of novel furan 2(5H)-ones. These libraries can then be entered into various biological screening programmes. This approach will enable a vast diversity or compounds to be examined, in the hope or finding new biologically active Iead structures. The work in this thesis has investigated the potential that combinatorial chemistry has in the quest for new biologically active lead structures based on the furan-2(5H)-one structure. Different reactions were investigated with respect to their suitability for inclusion in a library. Once sets of reactions at the various sites had been established, the viability of these reactions in the assembly of combinatorial libraries was investigated. Purification methods were developed, and the purified products entered into suitable biological screening tests. Results from some of these tests were optimised using structure activity relationships, and the resulting products re-screened. The screening tests performed were for anticancer and antimicrobial activity, cholecystokinin (CCK-B) antagonism and anti-inflammatory activity (in the quest for novel cyclo-oxygenase (COX-2) selective non-steroidal anti-inflammatory drugs). It has been shown that many reactions undergone by the furan-2(5H)-one structure are suitable for the assembly of a combinatorial library. Investigation into the assembly of different libraries has been carried out with initial screening results included. From this work, further investigation into combinatorial library assembly and structure activity relationships of screened reaction products can be undertaken.

The synthesis and evaluation of small organic molecules as cholecystokinin antagonists

Cholecystokinin (CCK) is a peptide hormone, present in the alimentary and the CNS. It is the most abundant peptide in the brain. CCK has been implicated in a number of disorders. The link between CCK and anxiety was the basis for this research. A comprehensive discussion on the many types of CCK receptor antagonists is included. For the drug discovery process, a number of synthetic approaches have been investigated and alternative chemical approaches developed. 1,4-Benzodiazepine analogues were prepared, with substitutents In the 1,2 & 3- position of the benzodiazepine scaffold varied, and substituted 3-anilino benzodiazepines exhibited the greatest in vitro activity towards the CCKA receptor subtype. Through extensive screening, pyrazolinone-ureido derivatives were identified, optimised, SAR studied and re-screened. A comprehensive in vivo study on the most active analogue is included, which has a number of common structural features with L-36S, 260 including activity. Pyrazolinone-amide derivatives, bearing the tryptophan moiety were equally active. A number of existing and novel furan- 2(SH)-one building blocks were prepared, from which a selected mini-library of 4- amino-substituted furan-2(SH)-ones were prepared and evaluated. All synthesised compounds were evaluated in a CCK radiolabelled binding assay (CCKA & CCKB), with compounds demonstrating receptor selectivity and lead structures being discovered. The work in this thesis has identified a number of highly active prime structures, from which further investigations are essential in providing more in vitro & in vivo data and the need to prepare more analogues.

Antibacterial activity of 3-substituted pyrrole-2,5-diones against Pseudomonas aeruginosa

3-Substituted pyrrole-2,5-diones were synthesised from mucohalogen acids and the antibacterial activity was subsequently determined in biological assays. The minimum inhibitory concentration and the minimum bactericidal concentration of 2a were determined for a wide range of microorganisms in the low micromolar range. Protein identification using SDS-PAGE and LC/MS/MS demonstrated a partly degradation of OprF-related proteins giving an insight into the underlying mechanism of these novel antibacterial agents. © 2007 Bentham Science Publishers Ltd.

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5-thiol derivatives. 1. Synthesis and characterization

Purpose: To synthesize and characterize S-alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4- oxadiazole-5-thiol derivatives. Methods: 2-(1H-indol-3-yl)acetic acid (1) was reacted with absolute ethanol and catalytic amount of sulfuric acid to form ethyl 2-(1H-indol-3-yl)acetate (2) which was transformed to 2-(1H-indol-3- yl)acetohydrazide (3) by refluxing with hydrazine hydrate in methanol. Ring closure reaction of 3 with carbon disulfide and ethanolic potassium hydroxide yielded 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5- thiol (4) which was finally treated with alkyl/aralkyl halides (5a-u) in DMF and NaH to yield Salkylated/ aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiols (6a-u). Structural elucidation was done by IR, 1H-NMR and EI-MS techniques Results: 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol (4) was synthesized as the parent molecule and was characterized by IR and the spectrum showed peaks resonating at (cm-1) 2925 (Ar-H), 2250 (S-H ), 1593 (C=N ) and 1527 (Ar C=C ); 1H-NMR spectrum showed signals at δ 11.00 (s, 1H, NH-1ʹ), 7.49 ( br.d, J = 7.6 Hz, 1H, H-4\'), 7.37 (br.d, J = 8.0 Hz, 1H, H-7\'), 7.34 (br.s, 1H, H-2\'), 7.09 (t, J = 7.6 Hz, 1H, H-5\'), 7.00 (t, J = 7.6 Hz, 1H, H-6\') and 4.20 (s, 2H, CH2-10ʹ). EI-MS presented different fragments peaks at m/z 233 (C11H9N3OS)˙+ [M+2]+, 231 (C11H9N3OS)˙+ [M]+, 158 (C10H8NO)+, 156 (C10H8N2)˙+, 130 (C9H8N)+. The derivatives (6a-6u) were prepared and characterized accordingly. Conclusion: S-alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiols (6a-u) were successfully synthesized.

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5-thiol derivatives. 2. Anti-bacterial, enzymeinhibitory and hemolytic activities

Purpose: To evaluate the antibacterial, enzyme-inhibitory and hemolytic activities of Salkylated/ aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol derivatives. Methods: Antibacterial activities of the compounds were evaluated using broth dilution method in 96 well plates. Enzyme inhibitory activities assays were investigated against α-glucosidase, butyrylcholinesterase (BchE) and lipoxygenase (LOX) using acarbose, eserine and baicalien as reference standards, respectively. A mixture of enzyme, test compound and the substrate was incubated and variation in absorbance noted before and after incubation. In tests for hemolytic activities, the compounds were incubated with red blood cells and variations in absorbance were used as indices their hemolytic activities. Results: The compounds were potent antibacterial agents. Five of them exhibited very good antibacterial potential similar to ciprofloxacin, and had minimum inhibitory concentrations (MIC) of at least 9.00 ± 4.12 μM against S. aureus, E.coli, and B. subtilis. One of the compounds had strong enzyme inhibitory potential against α-glucosidase, with IC50 of 17.11 ± 0.02 μg/mL which was better than that of standard acarbose (IC50 38.25 ± 0.12 μg/mL). Another compound had 1.5 % hemolytic activity. Conclusion: S-Alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol deviratives with valuable antibacterial, anti-enzymatic and hemolytic activities have been successfully synthesized. These compounds may be useful in the development of pharmaceutical products.