46970-87-0Relevant academic research and scientific papers
Synthesis of Novel Quaternary Ammonium Salts and Their in Vitro Antileishmanial Activity and U-937 Cell Cytotoxicity
Duque-Benítez, Sandra M.,Ríos-Vásquez, Luz Amalia,Ocampo-Cardona, Rogelio,Cede?o, David L.,Jones, Marjorie A.,Vélez, Iván D.,Robledo, Sara M.
, (2016/05/24)
This work describes the synthesis of a series of quaternary ammonium salts and the assessment of their in vitro antileishmanial activity and cytotoxicity. A preliminary discussion on a structure-activity relationship of the compounds is also included. Three series of quaternary ammonium salts were prepared: (i) halomethylated quaternary ammonium salts (series I); (ii) non-halogenated quaternary ammonium salts (series II) and (iii) halomethylated choline analogs (series III). Assessments of their in vitro cytotoxicity in human promonocytic cells U-937 and antileishmanial activity in axenic amastigotes of L. (Viannia) panamensis (M/HOM/87/UA140-pIR-eGFP) were carried out using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) micromethod. Antileishmanial activity was also tested in intracellular amastigotes of L. (V) panamensis using flow cytometry. High toxicity for human U937 cells was found with most of the compounds, which exhibited Lethal Concentration 50 (LC50 ) values in the range of 9 to 46 μg/mL. Most of the compounds evidenced antileishmanial activity. In axenic amastigotes, the antileishmanial activity varied from 14 to 57 μg/mL, while in intracellular amastigotes their activity varied from 17 to 50 μg/mL. N-Chloromethyl-N,N-dimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (1a), N-iodomethyl-N,N-dimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (2a), N,N,N-trimethyl-N-(4,4-diphenylbut-3-en-1-yl)ammonium iodide (3a) and N,N,N-trimethyl-N-(5,5-diphenylpent-4-en-1-yl)ammonium iodide (3b) turned out to be the most active compounds against intracellular amastigotes of L. (V) panamensis, with EC50 values varying between 24.7 for compound 3b and 38.4 μg/mL for compound 1a. Thus, these compounds represents new "hits" in the development of leishmanicidal drugs.
Discovery of diphenyl amine based sodium channel blockers, effective against hNav1.2
Hudgens, Debjani P.,Taylor, Catherine,Batts, Timothy W.,Patel, Manoj K.,Brown, Milton L.
, p. 8366 - 8378 (2008/02/05)
The development of new therapies for chronic pain is an area of unmet medical need. Central to pathways of chronic pain is the upregulation of voltage-gated sodium channels. The use of tricyclic antidepressants, which also have sodium channel activity, in chronic pain therapy prompted us to develop novel compounds from this scaffold. Herein, we show that the tricyclic moiety is not needed for effective inhibition of the [3H]-BTX binding site and sodium currents of hNav1.2. Our lead compound 6, containing a diphenyl amine motif, demonstrated a 53% inhibitory block of Nav1.2 currents at 10 μM, which is greater than 50% increase in current block in comparison to the amitriptyline standard. Altogether our study establishes that the tricyclic motif is unnecessary for hNav1.2 activity and modification of the amine portion is detrimental to sodium channel block.
NOVEL TRICYCLIC, BICYCLIC, MONOCYCLIC, AND ACYCLIC AMINES AS POTENT SODIUM CHANNEL BLOCKING AGENTS
-
Page/Page column 37, (2008/06/13)
The present invention provides acyclic, bicyclic, monocyclic, and tricyclic analogs and derivatives of tricyclic antidepressants which have sodium channel inhibiting activity. The compounds of the invention are useful as analgesics and anesthetics for diseases, conditions, and disorders where regulation of sodium channel activity can alleviate pain.
