Molecular characterization and antifungal activity of lipopeptides produced from Bacillus subtilis against plant fungal pathogen Alternaria alternata.

Over 380 host plant species have been known to develop leaf spots as a result of the fungus Alternaria alternata. It is an aspiring pathogen that affects a variety of hosts and causes rots, blights, and leaf spots on different plant sections. In this investigation, the lipopeptides from the B. subtilis strains T3, T4, T5, and T6 were evaluated for their antifungal activities. In the genomic DNA, iturin, surfactin, and fengycin genes were found recovered from B. subtilis bacterium by PCR amplification. From different B. subtilis strains, antifungal Lipopeptides were extracted, identified by HPLC, and quantified with values for T3 (24 g/ml), T4 (32 g/ml), T5 (28 g/ml), and T6 (18 g/ml). To test the antifungal activity, the isolated lipopeptides from the B. subtilis T3, T4, T5, and T6 strains were applied to Alternaria alternata at a concentration of 10 g/ml. Lipopeptides were found to suppress Alternaria alternata at rates of T3 (75.14%), T4 (75.93%), T5 (80.40%), and T6 (85.88%). The T6 strain outperformed the other three by having the highest antifungal activity against Alternaria alternata (85.88%).

Pd-catalyzed homo-coupling of benzofurans: one-pot synthesis of diverse 3,3'-bisbenzofurans.

An efficient and one-pot synthesis of 3,3'-bisbenzofuran derivatives has been developed. The protocol involved the use of a Pd catalyst and Cu(OAc)2 along with molecular oxygen as the oxidant to afford bisbenzofurans via a dehydrogenative homo-coupling reaction. The reaction exhibited good functional group/heterocycle tolerance and is amenable for gram scale synthesis.

Synthesis of fused bis-indazoles/indazoles via a one-pot sequential strategy.

We report here an efficient synthesis of fused bis-indazoles/indazoles via a one-pot sequential strategy starting from o-azido aldehydes and amines. This novel method involves the sequential formation of 2H-indazole followed by a Pd-catalyzed intramolecular cross-dehydrogenative coupling reaction. Overall, this one-pot sequential reaction involved the formation of new five bonds, resulting in the formation of three heterocyclic rings.

Catalyst and solvent switched divergent C-H functionalization: oxidative annulation of N-aryl substituted quinazolin-4-amine with alkynes.

The development of site-selective C-H functionalizations/annulations is one of the most challenging practices in synthetic organic chemistry particularly for substrates bearing several similarly reactive C-H bonds. Herein, we describe catalyst and solvent controlled ortho/peri site-selective oxidative annulation of C-H bonds of N-aryl substituted quinazolin-4-amines with internal alkynes. The ortho C-H selective annulation was observed using Pd-catalyst in DMF to give indole-quinazoline derivatives, while, Ru-catalyst in PEG-400 favoured the peri C-H bond annulation exclusively to furnish pyrido-quinazoline derivatives.

Bimetallic Cu/Pd-catalyzed three-component azide-alkyne cycloaddition/isocyanide insertion: synthesis of fully decorated tricyclic triazoles.

The construction of fully decorated 1,2,3-triazole-fused 5-, 6- and 7-membered rings has been disclosed via a bimetallic relay-catalyzed cascade process combining azide-alkyne cycloaddition, C(sp2)-H functionalization of intermediary 1,2,3-triazoles and isocyanide insertion. The salient features of this methodology include simple starting materials, reduced synthetic steps, good substrate scope and high efficiency.

FeCl3 catalysed 7-membered ring formation in a single pot: a new route to indole-fused oxepines/azepines and their cytotoxic activity.

Various oxepine and azepine fused N-heterocyclic derivatives were synthesized using a new and one-pot reaction of 2,3-dichloro quinoxaline/pyrazine with 2-(1H-indol-2-yl)phenol/aniline in the presence of 25 mol% FeCl3. The reaction proceeded via C-C bond followed by C-X (X = O or N) bond formation to construct the central 7-membered ring, affording the desired products in good yields. The structure assignment was confirmed by the single crystal X-ray analysis of a synthesized oxepine fused N-heterocycle derivative. Most of the synthesized compounds were found to be promising when tested for their anti-proliferative properties against cervical and breast cancer cell lines.

Use of AlCl3 in Friedel Crafts arylation type reactions and beyond: an overview on the development of unique methodologies leading to N-heteroarenes.

As a privileged class of heterocyclic compounds N-heteroarenes have found enormous applications in many areas including medicinal/pharmaceutical chemistry and drug discovery. Consequently, a wide variety of methods have been reported for their synthesis. While not free from their own limitations the AlCl3 mediated methods appeared to have some particular advantages in preparing a number of useful N-heteroarenes. Besides the famous Friedel-Crafts (FC) alkylation/acylation reactions one such example is AlCl3-induced heteroarylation of arenes and heteroarenes (FC arylation type reactions) that can be used to prepare a certain class of N-heteroarenes in an operationally simple, efficient and cost effective manner. Interestingly, pyridine is not a good substrate in FC alkylation/acylation reactions whereas 2-chloropyridines are indeed effective in heteroarylation reaction. However, no systematic and detailed study regarding the application potential of this method was performed until 2002. Some other examples that emerged in the recent past include AlCl3 induced heteroarylation-cyclization, hydroarylation-heteroarylation, sulfonyl group migration etc. All these innovative methodologies allowed the direct access to several unique and novel N-heteroarenes some of which showed interesting pharmacological properties including anti-inflammatory, anti-cancer and antibacterial activities when tested in vitro. While unlike FC reactions many of these AlCl3 mediated methodologies are still in their initial stage of developments, a continuing effort to uncover their further potential in organic synthesis/medicinal chemistry is necessary. The current article provides an overview of these unique methodologies that highlight the use of AlCl3 beyond FC reactions leading to new N-heteroarenes.

Mycobacterium tuberculosis chorismate mutase: A potential target for TB.

Mycobacterium tuberculosis chorismate mutase (MtbCM) catalyzes the rearrangement of chorismate to prephenate in the shikimate biosynthetic pathway to form the essential amino acids, phenylalanine and tyrosine. Two genes encoding chorismate mutase have been identified in Mtb. The secretory form,∗MtbCM (encoded by Rv1885c) is assumed to play a key role in pathogenesis of tuberculosis. Also, the inhibition of MtbCM may hinder the supply of nutrients to the organism. Indeed, the existence of chorismate mutase (CM) in bacteria, fungi and higher plants but not in human and low sequence homology among known CM makes it an interesting target for the discovery of anti-tubercular agents. The present article mainly focuses on the recent developments in the structure, function and inhibition of MtbCM. The understanding of various aspects of MtbCM as presented in the current article may facilitate the design and subsequent chemical synthesis of new inhibitors against ∗MtbCM, that could lead to the discovery and development of novel and potent anti-tubercular agents in future.

Pd-mediated functionalization of polysubstituted pyrroles: their evaluation as potential inhibitors of PDE4.

Novel polysubstituted pyrroles have been designed and accessed via a one-pot multicomponent reaction followed by Pd-mediated C-C bond forming reactions. All the compounds synthesized were tested for their PDE4B inhibitory properties in vitro and two of them obtained via Heck reaction showed significant inhibition. The docking results suggested that these alkenyl derivatives containing ester moiety interact well with the PDE4B protein in silico where the ester carbonyl oxygen played a key role. The pyrrole framework presented here could be a new template for the identification of small molecule based novel inhibitors of PDE4. The single crystal X-ray data of a representative compound is presented.

C-N bond formation under Cu-catalysis: synthesis and in vitro evaluation of N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones against chorismate mutase.

A series of novel N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones were designed and synthesized as potential inhibitors of chorismate mutase. Synthesis of this class of compounds was carried out by using Cu-mediated C-N bond forming reaction between thieno[2,3-d]pyrimidin-4(3H)-ones and aryl boronic acids. The reaction can be performed in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric moisture. A range of compounds were prepared by using this method and single crystal X-ray diffraction study was performed using a representative compound. In vitro pharmacological data of some of the compounds synthesized along with dose response studies using active molecules are presented. In silico interactions of these molecules with chorismate mutase are also presented.

Design and synthesis of 4-alkynyl pyrazoles as inhibitors of PDE4: a practical access via Pd/C-Cu catalysis.

The design and synthesis of 4-alkynyl pyrazole derivatives has led to the identification of new class of PDE4 inhibitors. All these compounds were accessed for the first time via a facile Pd/C-CuI-PPh(3) mediated C-C bond forming reaction between an appropriate pyrazole iodide and various terminal alkynes. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized indicated that 4-alkynyl pyrazole could be a promising template for the discovery of novel PDE4 inhibitors.

Cu-mediated N-arylation of 1,2,3-triazin-4-ones: synthesis of fused triazinone derivatives as potential inhibitors of chorismate mutase.

A rapid and direct access to N-aryl substituted fused triazinone derivatives has been accomplished via N-arylation of 1,2,3-triazin-4-one ring involving a Cu-mediated coupling between triazinone derivatives and aryl boronic acids. A combination of Cu(OAc)(2)-Et(3)N in 1,2-dichloroethane was found to be effective and various fused triazinone derivatives have been prepared by using this methodology. Molecular structure of a representative compound was confirmed by single crystal X-ray diffraction study. The scope and limitations of this reaction is discussed. Some of the compounds synthesized were tested for chorismate mutase inhibitory properties in vitro. The in vitro dose response study of an active compound is presented.

Structure-activity relationship studies of novel pyrazole and imidazole carboxamides as cannabinoid-1 (CB1) antagonists.

The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.

Mortality from hepatocellular and biliary cancers: changing epidemiological trends.

OBJECTIVES: The incidence of hepatocellular carcinoma may be rising in the United States. The aim of this study was to determine the epidemiological trends in mortality from hepatocellular carcinoma (HCC) and biliary cancers (BCs) in Maryland during the last 3 decades. METHODS: The number of deaths due to HCC and BCs from 1970 to 1997 were obtained from the Maryland State Department of Health & Hygiene vital statistics database. Malignant neoplasms of the gallbladder and intrahepatic and extrahepatic bile ducts were grouped together as biliary cancers. To determine the trend in mortality, the total time period was divided into seven 4-yr periods. RESULTS: Mortality from HCC increased from 0.94 to 1.84 per 100,000 population (rate ratio = 1.94, CI = 1.87-2.03) and that from BCs increased from 1.28 to 1.7 per 100,000 population (rate ratio = 1.31, CI = 1.26-1.36) over the study period. Although mortality due to HCC doubled in men (1.34 to 2.7 per 100,000) during this period, only a modest increase was observed among women (0.59 to 1.06 per 100,000). Because of a marked increase in the number of deaths among white Americans, the difference in HCC-related mortality between white Americans and African Americans decreased considerably during this period. Mean age at death increased steadily for BCs from 67 to 73 yr, whereas there was no real trend for HCC. Among African Americans, the death from HCC remained stable, but there was a 2-fold increase in BC-related death. CONCLUSIONS: There was a marked increase in deaths from HCC over the past 3 decades in Maryland. This increase was more evident among men and white Americans. Deaths due to BCs increased modestly during the same period of observation. The marked rise in BC-related deaths among African Americans remains unexplained.