Enantiomeric separation of a melatonin agonist Ramelteon using amylose-based chiral stationary phase

A new simple isocratic chiral liquid chromatographic method was developed for the enantiomeric purity of Ramelteon[(S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl) ethyl]-propionamide], a melatonin agonist in bulk drugs. The chromatographic separation was achieved on Chiralpak AD-H, 250 mm × 4.6 mm, 5 μm column using a mobile phase system consisting of n-hexane, ethanol and methanesulfonic acid in the ratio of 900:100:0.1 (v/v/v). The mobile phase was pumped on the column at the flow rate of 1 mL min^?1. Addition of methane sulfonic acid in the mobile phase enhanced chromatographic efficiency and resolution between the enantiomers. The resolution between the enantiomers was found to be more than four. The developed method was subsequently validated and proved to be accurate and precise. The experimentally established limit of detection and quantification of (R)-enantiomer were found to be 25.5 and 77.2 ng ml^?1, respectively, for 20 μl injection volumes. The percentage recovery of (R)-enantiomer was ranged from 98.5 to 101.9 in bulk drug samples of Ramelteon. The stability of Ramelteon sample in analytical solution was checked for about 48 h at room temperature and was found to be stable for about 48 h. The proposed method was found to be suitable and accurate for the quantitative determination of (R)-enantiomer in drug substance.     

Rapid determination of rifaximin in rat serum and urine by direct injection on to a shielded hydrophobic stationary phase by HPLC

A simple and rapid reversed‐phase HPLC method for determination of rifaximin in rat serum and urine was developed. Separation of rifaximin from biological matrix was achieved by direct injection of rat serum and urine onto a restricted‐access medium, Supelco LC‐Hisep, a shielded hydrophobic stationary phase, using acetonitrile:water:acetic acid (18:82:0.1 v/v/v) as a mobile phase. The linear range was 0.10–20 µg/mL (r² > 0.999, n = 6), intraday and interday variation was <6.10%. The limits of detection and quantification were 0.03 (signal‐to‐noise ratio >3) and 0.10 µg/mL (signal‐to‐noise ratio >10), respectively. The method was successfully applied to pharmacokinetic studies of rifaximin after an oral administration to rats. Copyright © 2008 John Wiley & Sons, Ltd.     

A highly divergent Pictet-Spengler approach for pyrrolo[1,2-a]quinoxalines from aryl amine using 1,2-dinitrobenzene as an oxidant

A convenient Pictet-Splengler approach for the synthesis of substituted pyrrolo[1,2-a]quinoxalines from aryl amine and 1-(2-aminoaryl)-pyrrole has been developed. This is the first domino protocol involving formation of benzaldehyde as an intermediate from benzyl amines and benzyl alcohols using 1,2-DNB as an oxidant, followed by its endo cyclization with 1-(2-aminophenyl)-pyrrole to furnish the pyrrolo[1,2-a]quinoxalines. Notably, this procedure exhibits good functional group tolerance as well as good to moderate yield of pyrrolo[1,2-a]quinoxaline.     

Chugaev‐type bis(acyclic diaminocarbenes) as a new ligand class for the palladium‐catalyzed Mizoroki–Heck reaction

A series of differently substituted Chugaev‐type palladium bis(acyclic diaminocarbene) complexes was screened to identify the most active catalyst for Mizoroki–Heck coupling reactions of aryl bromides with styrene. The best catalyst, which contains three methyl groups on the bis(carbene) ligand, gives excellent coupling yields at 120 °C for both activated and deactivated aryl bromides. However, activity with aryl chlorides is limited to electron‐deficient examples. The optimized catalyst demonstrates limited air and moisture stability, giving reduced yields in couplings of activated aryl bromides in open‐flask conditions. The modular synthesis of this class of catalysts should allow further fine‐tuning of activity in Mizoroki–Heck and related coupling reactions. Copyright © 2012 John Wiley & Sons, Ltd.     

Metal-free intramolecular cyclopropanation of alkenes through iodonium ylide methodology

Intramolecular cyclopropanation of alkenes occurs thermally with iodonium ylides in the absence of conventional metal catalysts such as Rh(II) and Cu(II). In rigid molecular systems conversions are near quantitative. A mechanism is proposed involving formal 2+2 cycloaddition followed by reductive elimination of PhI to yield the cyclopropane.     

Quality profile of litchi (Litchi chinensis) cultivars from India and effect of radiation processing

Litchi (Litchi chinensis) is a non-climacteric tropical fruit. The fruit has a short shelf-life making its marketing difficult. Physical, biochemical, microbiological, and organoleptic properties of two major commercially grown Indian cultivars of litchi, ‘Shahi’ and ‘China’ were studied. The effect of gamma radiation processing and low temperature storage on the above parameters was evaluated to standardize the optimal process parameters for shelf-life extension of litchi. Physical and biochemical parameters analyzed included weight, moisture, pH, titratable acidity, texture, color, total and reducing sugar, total soluble solids, vitamin C, and flavonoid content. Weight, moisture content, and pH in the fresh fruit ranged between 21–26 g, 74–77%, and 3.7–4.4, respectively, whereas, total and reducing sugar ranged 10–15, and 10–13 g%, respectively. In ‘Shahi’ vitamin C content was found to be around 17–19 mg%, whereas, in ‘China’ it was 22–28 mg%. Flavonoid content was in the range of 26–34 μg catechin equivalents/g of fresh fruit. Total surface and internal bacterial load was around 4 and 3 log cfu/g, respectively. Surface yeast-mold count (YMC) was ～3 log cfu/g whereas internal YMC was ～2 log cfu/g. Radiation treatment reduced microbial load in a dose dependent manner. Treatment at 0.5 kGy did not significantly affect the quality parameters of the fruit. Treated fruits retained the “good” organoleptic rating during storage. Thus, radiation treatment (0.5 kGy) in combination with low temperature (4 °C) storage achieved a shelf-life of 28 days for litchi fruit.     

A Concise Total Synthesis of (+)‐(6S,9R,10R)‐Bovidic Acid

A straightforward strategy for the stereoselective synthesis of (+)‐bovidic acid has been developed in eleven steps with an overall yield of 8.85%. The synthesis started from commercially available nonanal, and the key reactions involved were Sharpless asymmetric dihydroxylation, Grignard reaction, and Corey? Bakshi? Shibata reduction.     

Single crystal structure of 3-(2-(3-acetylphenyl)hydrazono)pentane-2,4-dione and molecular docking study with CYP450 members for anticancer molecular screening

Coupling of acetyl acetone with diazotized 3-aminoacetophenone was carried out to give the compound 3. The compound was characterized by IR, ¹HNMR, MS and elemental analysis. The X-ray analysis of 3 revels its planar nature with torsion angles between phenyl ring and acetyl group C2–C3–C7–O1 and C2–C3–C7–C8 of 177.8(3)° and ?0.9(4)°, respectively. Small deviations from planarity are evident also by torsion angles N1–N2–C9–C10 and N2–C9–C12–O3 of 176.6(2)° and 2.9(4)°, while the N2–C9–C10–O2 torsion angle with the value of ?165.2(3)° deviates from planarity. Hydrogen-bonded chain formed through C5–H5?O2 is connected with the adjacent antiparallel chain through C11–H11B···π interaction between the methyl group of the acetyl substituent and phenyl ring forming a double-layered chain. N1–N2 shows presence of single bond, showing it to be a hydrazone. Molecular docking study of the title compound with six members from CYP450 family shows encouraging activity.     

Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.