Crystal structures of four indole derivatives as possible cannabinoid allosteric antagonists

Abstract

The crystal structures of four indole derivatives with various substituents at the 2-, 3- and 5-positions of the ring system are described. The dominant inter­molecular inter­action in each case is an N—H⋯O hydrogen bond, which generates either chains or inversion dimers. Weak C—H⋯O, C—H⋯π and π–π inter­actions occur in these structures but there is no consistent pattern amongst them. Two of these compounds act as modest enhancers of CB1 cannabanoid signalling and two are inactive.

Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor

“…(Fig. ) . Of these four indoles, compounds III and IV had moderate CB1 agonism effect while compounds I and II were inactive.…”

Different N—H...π interactions in two indole derivatives

“…There are over 7000 crystal structures of indole derivatives in the Cambridge Structural Database (CSD; Groom et al, 2016), but none of them have an iso-propyl group at the 6-position. Six structures contain a p-methoxybenzene grouping at the 2position and four contain a 2-nitro-1-phenylethyl grouping at the 3-position; these latter structures are the ones recently described by us (Kerr et al, 2015).…”

“…As part of our ongoing synthetic, biological (Kerr, 2013) and structural studies (Kerr et al, 2015(Kerr et al, , 2016 of variously substituted indole derivatives, we now report the syntheses and crystal structures of 6-isopropyl-3-(2-nitro-1-phenylethyl)-1H-indole, C 19 H 20 N 2 O 2 , (I), and 2-(4-methoxyphenyl)-3-(2-nitro-1-phenylethyl)-1H-indole, C 23 H 20 N 2 O 3 , (II), in which N-HÁ Á Á bonds are the most important intermolecular interactions, but result in quite different structures.…”

“…The orange circles indicate ring centroids. To prepare (II), 2-bromo-3-(2-nitro-1-phenylethyl)-1Hindole (Kerr et al, 2015) (90 mg, 0.26 mmol), 4-methoxyphenylboronic acid (53 mg, 0.35 mmol), Na 2 CO 3 (29 mg, 0.27 mmol), LiCl (22 mg, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) were placed in a microwave reactor vessel under argon. Degassed water (4 ml), toluene (6 ml) and ethanol (6 ml) were added and the reaction was heated to 373 K (high absorbance mode, 30 W, 8 bar) for 2 h. The mixture was acidified to pH 2 with 10% HCl(aq) then extracted into EtOAc (10 ml  3).…”

Crystal structures of four indole derivatives with a phenyl substituent at the 2-position and a carbonyl group at the 3-position: theC(6) N—H...O chain remains the same, but the weak reinforcing interactions are different

“…(França et al, 2014;Kaushik et al, 2013;Biswal et al, 2012;Sharma et al, 2010). ISSN 2056-9890 As part of our ongoing synthetic and biological (Kerr, 2013) and structural studies in this area (Kerr et al, 2015) we report herein the crystal structures of four indole derivatives, namely: 1-(2-phenyl-1H-indol-3-yl)ethanone, C 16 H 13 NO, (I), 2-cyclohexyl-1-(2-phenyl-1H-indol-3-yl)ethanone, C 22 H 23 NO, (II), 3,3-dimethyl-1-(2-phenyl-1H-indol-3-yl)butan-1-one, C 20 H 21 NO, (III), and 3-benzoyl-2-phenyl-1H-indole, C 21 H 15 NO, (IV).…”