EN3427: A Novel Cationic Aminoindane with Long-Acting Local Anesthetic Properties

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 120, Issue : 4, Pages : 941-949

DOI : 10.1213/ANE.0000000000000629

Author : Banerjee, Manish; Baranwal, Atul; Saha, Soumya; Saha, Ashis; Priestley, Tony

Abstract : Background: Currently approved local anesthetic drugs provide relatively brief local anesthesia that is appropriate and even desirable in some settings, but an extended duration of action beyond their capabilities would be a distinct benefit in other clin. situations. We implemented a drug discovery program that sought to identify novel local anesthetic mols. that specifically demonstrated a long-acting, preferential action on nociceptor sensory afferents that expressed transient receptor potential (TRP) channels. The hypothesis we tested was whether relatively membrane-impermeant local anesthetic mols. could confer long-lasting anesthesia if neuronal access was facilitated by TRP channel activation. The current work describes in vivo studies on a lead mol. that emerged from the discovery program, EN3427, in several rodent pain models. Methods: Studies were performed on male Sprague-Dawley rats using 2 models of acute mech. paw-pinch-evoked and pinprick-evoked nociceptive pain. Behavioral responses to noxious stimuli were assessed at baseline, i.e., before any pharmacol. intervention, and at various timepoints after a single perisciatic or s.c. administration of either EN3427 alone or in combination with lidocaine. Paw withdrawal thresholds or cutaneous trunci reflexes were quantified, and pre-post drug values were compared statistically with anal. of variance followed by post hoc Dunnett multiple range test. Results: A single perisciatic injection of lidocaine (2%) produced relief of paw-pinch-evoked pain that was significantly different from baseline through to the 1-h timepoint (Dunnett multiplicity-adjusted P = 0.0081), as assessed using paw withdrawal or vocalization end points. EN3427 (0.2%), in the same model, produced a long-lasting block, with pain thresholds being significantly above baseline through to the 18-h timepoint (Dunnett multiplicity-adjusted P = 0.0002); the combination of EN3427 (0.2%) plus lidocaine (2%) produced even longer lasting analgesia, with pain thresholds being significantly above baseline through to the 24-h timepoint (Dunnett multiplicity-adjusted P = 0.0073). Similar results were obtained with use of the pinprick approach. A single s.c. injection of lidocaine (2%) produced complete loss of sensation to cutaneous pinprick through 0.5 h, but sensitivity thresholds were no different to baseline by the 1-h timepoint, a similar injection of EN3427 alone (0.2%) produced a loss of sensation that was significantly different from baseline through the 8-h timepoint (Dunnett multiplicity-adjusted P = 0.0045), and the combination of lidocaine (2%) plus EN3427 (0.2%) appeared to further enhance duration of analgesia, although this was significantly different from baseline only through the 10-h timepoint (Dunnett multiplicity-adjusted P = 0.0048). Analgesic efficacy was dose related; using the combined injection approach, we found that increases in the dose of EN3427 with a fixed 2% lidocaine led to substantially extended analgesia and increasing doses of lidocaine combined with a fixed dose of EN3427 (0.2%) led to only modestly increased duration of action. Conclusions: The present studies demonstrate that a new mol. entity, EN3427, produces effective and long-lasting analgesia in 2 rodent pain models. The analgesic effects of EN3427 are significantly longer-lasting than lidocaine and are further extended when EN3427 is combined with lidocaine. The results are discussed with respect to a possible lidocaine-mediated TRP channel activation and facilitated neuronal access of EN3427, with subsequent entrapment conferring extended-duration efficacy.

Antimicrobial properties of Kalanchoe blossfeldiana: a focus on drug resistance with particular reference to quorum sensing-mediated bacterial biofilm formation

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 67, Issue : 7, Pages : 951-962

DOI : 10.1111/jphp.12397

Author : Sarkar, Ratul; Mondal, Chaitali; Bera, Rammohan; Chakraborty, Sumon; Barik, Rajib; Roy, Paramita; Kumar, Alekh; Yadav, Kirendra K.; Choudhury, Jayanta; Chaudhary, Sushil K.; Samanta, Samir K.; Karmakar, Sanmoy; Das, Satadal; Mukherjee, Pulok K.; Mukherjee, Joydeep; Sen, Tuhinadri

Abstract : This study investigates the antimicrobial properties of Kalanchoe blossfeldiana with a particular reference to quorum sensing (QS)-mediated biofilm formation. A methanol extract of K. blossfeldiana leaves (MEKB) was evaluated for antimicrobial properties including QS-controlled production of biofilm (including virulence factor, motility and lactone formation) in Pseudomonas aeruginosa. The methanol extract of K. blossfeldiana was also evaluated for anti-cytokine (tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta) properties in peripheral blood mononuclear cells (PBMC). The methanol extract of K. blossfeldiana exhibited an antimicrobial effect on clin. isolates, as well as standard reference strains. Pseudomonas aeruginosa exposed to MEKB [subminimum inhibitory concentration (MIC)] displayed reduced biofilm formation, whereas supra-MIC produced destruction of preformed biofilms. The methanol extract of K. blossfeldiana reduced the secretion of virulence factors (protease and pyoverdin) along with generation of acyl homoserine lactone (AHL). Confocal laser scanning microscopy images indicate reduction of biofilm thickness. The extract also reduced cytokine formation in lipopolysaccharide-stimulated PBMC. Thus, Kalanchoe blossfeldiana was found to interfere with AHL production, which in turn may be responsible for downregulating QS-mediated production of biofilm and virulence.

Enantiopure synthesis of dihydrobenzo[1,4]-oxazine-3-carboxylic acids and a route to benzoxazinyl oxazolidinones

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 13, Issue : 11, Pages : 3211-3219

DOI : 10.1039/c4ob02475c

Author : Malhotra, Rajesh; Dey, Tushar K.; Basu, Sourav; Hajra, Saumen

Abstract : A two step protocol is developed for the efficient synthesis of enantiopure N-Boc-dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids from serine derived cyclic sulfamidate via intramol. arylamination. The RuPhos Palladacycle along with addnl. RuPhos ligand is an efficient catalyst for the arylamination of β-(2-bromoaryloxy)amino acids 3 to provide easy and direct access to a variety of dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4 with complete retention of enantiopurity in moderate to high yields. Dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids are not only important unnatural amino acids, but are key precursors for the synthesis of important compounds such as benzoxazinyl oxazolidinones. A general approach for the synthesis of benzoxazinyl oxazolidinone is presented.

A Palladium on Carbon Catalyzed One-Pot Synthesis of Substituted Benzimidazoles

Published in: Journal, Volume : 46, Issue : 22, Pages : 3121-3132

DOI : 10.1055/s-0034-1378454

Author : Joardar, Soumen; Bhattacharyya, Anjan; Das, Saktipada

Abstract : A new and efficient palladium on carbon catalyzed one-pot intramol. nitro reduction/cyclization reaction has been developed for the preparation of a series of substituted benzimidazoles, including some novel ring-fused [1,2-a]-tricyclic, [1,2-a]-tetracyclic, and chiral benzimidazoles. The main advantages of this method are the mild and simple reaction conditions, the easy isolation of the products, and the excellent yields. The reaction has the potential to be used as a general procedure for the preparation of 7-aminobenzimidazoles in good yields. A plausible mechanism for the reaction is proposed.

A water compatible turn ‘on’ optical probe for Cu2+ based on a fluorescein-sugar conjugate

Published in: Journal, Volume : 196, Pages : 345-351

DOI : 10.1016/j.snb.2014.02.031

Author : Diwan, Uzra; Kumar, Ajit; Kumar, Virendra; Upadhyay, K. K.; Roychowdhury, P. K.

Abstract : A fluorescein-sugar conjugated chromo-fluorogenic turn ‘on’ probe (FG) has been synthesized for detection of Cu2+. The FG comprises of fluorescein as an efficient fluorophore and a sugar moiety, viz., galactose as the binding unit. The inclusion of galactose into FG led towards its good water compatibility. When Cu2+ was added in 70% aqueous HEPES buffered solution (pH 7.4) of FG, the absorbance and the fluorescence spectral pattern of the same were modulated dramatically with observation of absorption and emission bands at 632 and 515 nm, resp. The detection limit from fluorescence titration was calculated as 6.32 nM which further establishes high sensitivity of FG towards Cu2+. The spectral studies for the interaction of FG with Cu2+ indicated towards metal ion triggered spirolactam ring opening of FG as the mechanistic pathway of the sensing phenomenon.

Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists

Published in: Journal, Article, Volume : 24, Issue : 3, Pages : 949-953

DOI : 10.1016/j.bmcl.2013.12.063

Author : Gillespie, Paul; Goodnow, Robert A.; Saha, Goutam; Bose, Gopal; Moulik, Kakali; Zwingelstein, Catherine; Myers, Michael; Conde-Knape, Karin; Pietranico-Cole, Sherrie; So, Sung-Sau

Abstract : We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the Ph ring are important for potency and full efficacy. Compound I combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 460, Issue : 1-2, Pages : 949-953

DOI : 10.1016/j.ijpharm.2013.10.055

Author : Choudhury, Hira; Gorain, Bapi; Karmakar, Sanmoy; Biswas, Easha; Dey, Goutam; Barik, Rajib; Mandal, Mahitosh; Pal, Tapan Kumar

Abstract : Paclitaxel, a potential anticancer agent against solid tumors has been restricted from its oral use due to poor water solubility as well as Pgp efflux property. The present study was aimed to improve the oral bioavailability of paclitaxel through development of (o/w) nanoemulsion consisting of Capryol 90 as internal phase with Tween 20 as emulsifier with water as an external phase. Formulations were selected from the nanoemulsion region of pseudo-ternary phase diagrams, formulated by aqueous titration method. The developed nanoemulsion has been characterized by its thermodn. stability, morphol., droplet size, zeta potential, viscosity where in vitro release was evaluated through dialysis. Paclitaxel nanoemulsion exhibited thermodynamical stability with low viscosity, nano-sized oil droplets in water with low poly-dispersity index. The shelf life of the paclitaxel nanoemulsion was found to be approx. 2.38 years. Increased permeability through the Caco-2 cell monolayer and decreased efflux is great advantageous for nanoemulsion formulation. The effects of paclitaxel nanoemulsion on breast cancer cell proliferation, morphol. and DNA fragmentation were analyzed in vitro which showed significant anti-proliferation and decreased IC50 values in nanoemulsion group which may be due to enhanced uptake of paclitaxel through the oil core. Moreover, the absolute oral bioavailability and sustained release profile of the paclitaxel nanoemulsion evaluated in mouse model was found to improve up to 55.9%. The concentration of paclitaxel in mice plasma was determined by our validated LC-MS/MS method. By reviewing the significant outcome of the present investigation based on stability study, Caco-2 permeability, cell proliferative assay and pharmacokinetic profile it may be concluded that the oral nanoemulsion has got encouraging advantages over the presently available formulations of this injectable chemotherapeutic drug.

Protecting group directed cyclization: asymmetric synthesis of both cis- and trans-dihydrexidine from a common precursor

Published in: Journal, Volume : 69, Issue : 43, Pages : 8994-9000

DOI : 10.1016/j.tet.2013.08.042

Author : Malhotra, Rajesh; Chakrabarti, Sagar; Dey, Tushar K.; Dutta, Swarup; Alapati, Krishna Babu; Dutta, Shantanu; Roy, Subho; Basu, Sourav; Hajra, Saumen

Abstract : Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from l-serine dictates the cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alc. undergo cascade cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel-Crafts cyclization control the cis-stereochem. of the B-ring. N-Cbz and O-benzyl protection direct first F-C cyclization yielding the trans-1-aryl-2-aminotetralin and subsequent deprotection-cyclization forming the C-ring afforded dihydrexidine.