Naphtho[2,3-b][1,4]-thiazine-5,10-diones and 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thioalkanoate derivatives: synthesis and biological evaluation as potential antibacterial and antifungal agents

A series of 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thio-alkanoate derivatives 3-21 and naphtho[2,3-b][1,4]-thiazine-5,10-diones 24 were synthesized and evaluated for their antibacterial and antifungal activities. The structure-activity relationships of these compounds were studied and the results show that the compound 24a exhibited better antibacterial activity than Gentamycin in vitro against Staphylococcus aureus. In addition 24a also imparted marked antifungal activity in vitro against Cryptococcus neoformans, Sporothrix schenckii, and Trichophyton mentagraphytes when compared with Fluconazole. Compounds 15, 18, 19, and 21 also exhibited significant antibacterial activity in vitro against S. aureus.     

Osteogenic activity of constituents from Butea monosperma

Phytochemical investigation from the stem bark of Butea monosperma, led to the isolation and identification of three new compounds named buteaspermin A (1), buteaspermin B (2) and buteaspermanol (3), along with 19 known compounds. The structure of compounds 1–22 were established on the basis of their spectroscopic data. The isolated compounds 2–17 were evaluated using neonatal (1–3 day old) rat calvaria derived primary osteoblast cultures. Five of these compounds 7, 10–13 showed promising osteogenic activity, attributed to increased osteoblast proliferation, differentiation and mineralization as evidenced by marked increase in expression of alkaline phosphatase, an early phase differentiation marker, and alizarin Red S staining of osteoblasts cultured for 48 h and von Kossa silver staining of nodules formed 15 days after culture with these compounds. Quantification of mineralization by optical density measurement of Alizarin Red S extracted from stained osteoblasts cultured for 7 days in presence of these compounds showed significant (P < 0.05, vs corresponding vehicle control group) increase in mineralization. On the basis of biological results, structure–activity relationships are discussed.     

Methoxylated isoflavones,cajanin and isoformononetin,have non‐estrogenic bone forming effect via differential mitogen activated protein kinase (MAPK) signaling

Following a lead obtained from stem‐bark extract of Butea monosperma, two structurally related methoxyisoflavones; cajanin and isoformononetin were studied for their effects in osteoblasts. Cajanin had strong mitogenic as well as differentiation‐promoting effects on osteoblasts that involved subsequent activation of MEK‐Erk and Akt pathways. On the other hand, isoformononetin exhibited potent anti‐apoptotic effect in addition to promoting osteoblast differentiation that involved parallel activation of MEK‐Erk and Akt pathways. Unlike genistein or daidzein, none of these two compounds appear to act via estrogen receptors in osteoblast. Once daily oral (by gavage) treatment for 30 consecutive days was given to recently weaned female Sprague–Dawley rats with each of these compounds at 10.0 mg kg^?1 day^?1 dose. Cajanin increased bone mineral density (BMD) at all skeletal sites studied, bone biomechanical strength, mineral apposition rate (MAR) and bone formation rate (BFR), compared with control. BMD levels at various anatomic positions were also increased with isoformononetin compared with control however, its effect was less potent than cajanin. Isoformononetin had no effect on the parameters of bone biomechanical strength although it enhanced MAR and BFR compared with control. Isoformononetin had very mild uterotrophic effect, whereas cajanin was devoid of any such effect. Our data suggest that cajanin is more potent than isoformononetin in accelerating peak bone mass achievement. To the best of our knowledge, this work represents the first attempt to elucidate structure‐activity relationship between the two methoxylated isoflavones regarding their effects in osteoblasts and bone formation. J. Cell. Biochem. 108: 388–399, 2009. © 2009 Wiley‐Liss, Inc.     

Pyranocoumarins: A new class of anti-hyperglycemic and anti-dyslipidemic agents

A series of pyranocoumarin derivatives were synthesized and evaluated in vivo for their anti-hyperglycemic as well as anti-dyslipidemic activities. Compounds 7a, 7c, 8a, 8b, 8c, 8e and 8f have shown promising anti-hyperglycemic activities in sucrose loaded model (SLM) as well as sucrose challenged streptozotocin induced diabetic rat model (STZ). Compounds 8a and 8b were showing 38.0% and 42.0% blood glucose lowering activity in db/db mice model. In vitro anti-hyperglycemic activity evaluation exhibited that compounds 8a (IC₅₀ = 24.5 μM) and 8b (IC₅₀ = 36.2 μM) are potential PTP-1B inhibitors thereby revealing their possible mechanism of anti-diabetic action. Compounds 7a, 7b, 8a, 8b, 8d, 8e and 8f have shown significant anti-dyslipidemic activity in triton induced dyslipidemia in rats.     

Large-scale separation of clavine alkaloids from Ipomoea muricata by pH-zone-refining centrifugal partition chromatography

Centrifugal partition chromatography in the pH-zone-refining mode was successfully applied to the separation of alkaloids, directly from a crude extract of Ipomoea muricata. The experiment was performed with a two-phase solvent system composed of methyl tert-butyl ether (MtBE)–acetonitrile–water (4:1:5, v/v) where triethylamine (10 mM) was added to the upper organic stationary phase as a retainer and trifluoroacetic acid (10 mM) to the aqueous mobile phase as an eluter. From 4 g of crude extract, 210 mg lysergol and 182 mg chanoclavine were obtained in 97% and 79.6% purities. Total yield recovery was >95%. Isolated alkaloids were characterized on the basis of their ¹H, ¹³C NMR and ESI-MS data.     

Design, synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents

A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-alpha-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6-23 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli.     

Isolation of an unusual metabolite 2-allyloxyphenol from a marine actinobacterium, its biological activities and applications

A marine actinobacterium isolated from the Bay of Bengal, India and previously found to be producing an antimicrobial and cytotoxic terpenoid was further investigated for antimicrobial metabolites. The bacterium was preliminarily identified as a new species of the genus Streptomyces (strain MS1/7). The cell-free culture broth was extracted with n-butanol and purified using silica gel column chromatography and high-performance liquid chromatography. Molecular characterization was done using ESI mass, IR and ¹H and ¹³C NMR spectrometry. 2-Allyloxyphenol (MW 150; C₉H₁₀O₂), a synthetic drug and chemical intermediate, was obtained as a natural product for the first time. Serendipitous natural occurrence provided new insights into the synthetic molecule. 2-Allyloxyphenol was found to be inhibitory to 21 bacteria and three fungi in the minimum range 0.2–1.75 mg mL⁻¹ determined by agar dilution method. 2-Allyoxyphenol possesses strong antioxidant property (IC₅₀ 22 μg mL⁻¹, measured by 1, 1-diphenyl-2-picryl hydrazyl scavenging activity). Hydroxyl and allyloxy groups in 2-allyloxyphenol were responsible for antimicrobial and antioxidant activities. 2-Allyloxyphenol has marked resemblance to smoky aroma and is two to three times more active as an antimicrobial than some commercial smoke-flavour compounds. Absence of hemolytic toxicity, potential carcinogenicity, cytotoxicity and reports of toxic reactions in literature suggest possible application of 2-allyloxyphenol as a food preservative and an oral disinfectant.     

Functional profiling of p53-binding sites in Hdm2 and Hdmx using a genetic selection system

Upregulation of structurally homologous oncoproteins Hdm2 and Hdmx has been linked to the depletion or inactivation of their common regulation target the tumor suppressor p53 protein leading to the progression of cancer. The restoration of the p53 function, rendered suppressed or dormant by these negative regulators, establishes, therefore, a unique opportunity for a targeted induction of apoptosis in cancers that retain wild-type p53. While several small molecules have been reported to rescue the tumor suppressor by antagonizing the Hdm2–p53 interaction, these agents displayed limited application scope by being ineffective in tumors enriched with active Hdmx. Here, we describe the use of a genetic selection system and encoded library of conformationally pre-organized peptides to perform functional profiling of each regulator revealing specific recognition features that guide the antagonism of Hdm2–p53 and Hdmx–p53 interactions. Structure–activity relationship analysis of the most effective leads identified functional and structural elements mediating selective recognition of the two structurally related regulators, while providing convenient starting points for further activity optimization.