Furthermore, while the classical neuroleptic drugs block the striatal 3H-spiperone and 3H-NPA binding sites to about the same degree, the substituted benzamides appear to have a higher affinity for the DA receptors labelled by 3H-NPA than those labelled by 3H-spiperone. Z‐Arg‐Leu‐Arg‐Gly‐Gly‐AMC acetate was used as substrate at a final concentration of 50 μM, cleaved AMC was exited at 360 nm and detected at 460 nm. Scheme 1 gives an overview of synthetic routes for the synthesis of inhibitors used for our SAR studies. The 4OW0‐model included 37 binders and 6 non‐binders from the reported isoindoline‐series (14 h–l) and piperidine‐scaffolds reported by Baez‐Santos et al..21 Additional 200 decoys were generated for 14 h, 20 and the ligands from PLpro‐inhibitor complexes with PDB‐IDs 3MJ522 and 4OVZ.21 All molecules were protonated and energy‐minimized using the Merck Molecular Forcefied (MMFF94x)30 within MOE2019.0131 before docking. ESI (MS) m/z: calcd for C20H19NO2 [M+H]+306.15, found 306.1. mp: 161 °C. Percentage inhibition was measured at 100 μM inhibitor concentration [b]. The solvent was evaporated, and the product kept under argon atmosphere. Subscription will auto renew annually. Some compounds that showed acceptable inhibition against SARS‐CoV PLpro (i. e. 2 c, 2 e–h, 2 t, 14 a, 14 d) were less active against SARS‐CoV‐2 PLpro. (A): Synthesis of benzamides 2 a–t. 2‐Methyl‐N‐[(1S)‐1‐naphth‐1‐ylethyl]benzamide (4 d): To a solution of (1S)‐1‐Naphth‐1‐ylethylamine (50 μL, 53.4 mg, 0.312 mmol, 1 eq.) Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2. Cells and viruses. The methyl substituent is further oriented toward a small hydrophobic pocket shaped by Leu163, Tyr 265 and Tyr274. The organic phase was evaporated under reduced pressure and the crude product was recrystallized twice from ethyl acetate to yield 4d (61 mg, 0.21 mmol, yield: 68 %). MS (ESI): m/z calcd for C19H16INO [M+H]+402.04, found 402.0. 303, 189–191 (1978). Rf=0.21 (CH/EtOAc 3 : 1). 2‐Methyl‐N‐[(1R)‐naphth‐1‐ylethyl]benzamide (2 a): This compound was synthesized according to the general procedure Ac. The crude product was recrystallized from methanol and water to yield 4 a (480 mg, 2.0 mmol, yield: 36 %). In contrast to what was expected from the comparison of the compounds 18 and 19, in which the larger ethyl substituent resulted in a loss of activity,20 the IC50 values obtained for compounds 2 e–i revealed no direct correlation to the substituent's atomic radius: Interestingly, the activities of fluoro‐ and bromo‐substituted compounds were similar, while chloro‐substitution slightly improved the inhibition capacity, and iodo‐substitution reduced the affinity. mp: decomp.>150 °C. Chemical shifts are reported in parts per million (ppm). (R)‐2‐Cyano‐N‐(1‐(naphth‐1‐yl)ethyl)benzamide (2 e): This compound was synthesized according to the general procedure C. 90 mg, 0.30 mmol, yield: 48 %. MS (ESI): m/z calcd for C19H16ClNO [M+H]+310.1, found 310.2. 2‐Fluor‐N‐[(1R)‐1‐naphth‐1‐ylethyl]benzamide (2 f): This compound was synthesized according to the general procedure C. 115 mg, 0.39 mmol, yield: 63 %. 13C NMR (100 MHz, CDCl3) δ=20.6, 45.2, 122.7, 123.4, 125.2, 125.9, 126.7, 126.9, 128.5, 128.8, 131.2, 131.4, 134.0, 134.5, 138.1, 166.4 ppm. Copyright © 2020 Elsevier B.V. or its licensors or contributors. For a clear view, only residues with direct contacts to the ligands are labeled. Polar interactions are indicated as yellow dashed lines. C General procedure for the synthesis of amides catalyzed by DIC. 13C NMR (100 MHz, CDCl3) δ=19.9, 57.2, 125.8, 126.6, 127.4, 127.6, 128.7, 130.0, 131.1, 136.1, 136.4, 141.5, 169.0 ppm. 114 mg, 0.28 mmol, yield: 70 %. Naunyn-Schmiedeberg's Arch. In this set of substituents, chlorine seems to have the best and iodine the worst combination of both. Biochem. 1H NMR (400 MHz, acetone‐d6) δ=1.62 (d, J=7.07 Hz, 3H), 4.68 (q, J=6.82 Hz, 1H), 6.43 (s., 2H), 7.42–7.64 (m, 4H), 7.79 (s, 4H), 7.83 (d, J=8.08 Hz, 1H), 7.93–7.97 (m, 1H), 8.22 (d, J=8.59 Hz, 1H), 9.59 (s., 1H) ppm. 135, 374–377 (1977), Schorderet, M.: The effects of dopamine piribedil (ET-495) and its metabolite S-584 on retinal adenylate cyclase. Learn more. 1H NMR (400 MHz, MeOD) δ=1.94 (d, J=6.65 Hz, 3H 46 %), 1.97 (d, J=6.65 Hz, 3H 54 %), 2.03 (s, 3H 46 %), 2.39 (s, 3H 54 %), 4.24–4.42 (m, 2H), 4.90–5.26 (m, 2H), 5.82 (q, J=6.65 Hz, 1H), 6.91–7.37 (m, 3H), 7.56–7.74 (m, 3H), 7.96–8.10 (m, 3H), 8.32 (t, J=8.03 Hz, 1H) ppm. MS (ESI): m/z calcd for C22H24N2O [M+H]+3.20, found 333.2. This data suggests that substituted benzamides form a pharmacologically-distinct group of dopamine antagonists, whose mechanism of action differs from that of classical neuroleptics. (ESI): m/z calcd for C18H17NOS [M+H]+296.11, found 296.1 Purity (LC, 254 nm):>99 %. MS (ESI): m/z calcd for C19H18N2O3S [M−H]− 353.09, found 353.2. mp: decomp.>240 °C. MS (ESI): m/z calcd for C20H16F3NO [M+H]+344.13, found 344.2. 13C NMR (100 MHz, CDCl3) δ=20.6 (CH3), 45.9 (CH), 110.4, 117.5, 122.9, 123.3, 125.3, 126.0, 126.8, 128.6, 128.7, 128.8, 130.9, 131.0, 132.8, 133.9, 133.9, 137.6, 138.5, 164.2 ppm. 1H NMR (400 MHz, CDCl3) δ=1.80 (d, J=6.82 Hz, 3H), 6.16–6.25 (m, 1H), 7.00–7.09 (m, 1H), 7.09–7.18 (m, 1H), 7.24 (td, J=7.58, 1.01 Hz, 1H), 7.42 (dddd, J=8.27, 7.33, 5.24, 1.89 Hz, 1H), 7.46–7.65 (m, 4H), 7.82 (d, J=8.08 Hz, 1H), 7.86–7.93 (m, 1H), 8.12 (td, J=7.83, 1.77 Hz, 1H), 8.23 (d, J=8.34 Hz, 1H) ppm. 2‐Iodo‐N‐[(1R)‐1‐naphth‐1‐ylethyl]benzamide (2 h): This compound was synthesized according to the general procedure C. 76 mg, 0.19 mmol, yield: 31 %. The benzamides also produced considerably less displacement of 3H-spiperone in the striatum than did classical neuroleptics. mp: 160 °C. The organic phase was washed with sodium hydrogen carbonate solution followed by saturated sodium chloride solution and dried over sodium sulfate. The same holds true for sterically more demanding substituents: While benzyl (2 l) still showed some inhibition comparable to phenyl (2 c) in the screening, a branched diphenylmethane derivative (2 m) showed no inhibition, probably due to spatial limitations at the binding site. 193, 265–275 (1951), Miller, R., Horn, A. S., Iversen, L. L.: The action of neuroleptic drugs on dopamine-stimulated adenosine cyclic 3′,5′-monophosphate production in rat neostriatum and limbic forebrain. 2‐Bromo‐N‐[(1R)‐1‐naphth‐1‐ylethyl]benzamide (2 g): This compound was synthesized according to the general procedure C. 120 mg, 0.34 mmol, yield: 55 %. Non‐aromatic residues as alternatives for the benzamide were not tolerated. The moderate +I‐effect of the methyl substituent is contrasted by the impactful −I‐effect of the trifluoromethyl group resulting in a loss of binding affinity. The isoindolines have a positively charged amine function in close proximity to the (naphthalen‐1‐yl)ethyl moiety. For assignments DEPT, HHCOSY, HMQC and HMBC experiments were performed. Ac General procedure for the synthesis of amides from carboxylic acid chlorides in a single phase system. N‐(2‐Fluorphenyl)‐2‐naphth‐1‐ylpropanamide (11 b): This compound was synthesized according to the general procedure B. Molecular docking. Purity (LC, 300 nm): 95.5 %. The amine (1.0 eq.) The filtrate was reduced in vacuo and the residue was dissolved in ethyl acetate. All reactions were monitored by thin‐layer chromatography using Macherey‐Nagel ALUGRAM Xtra SIL G/UV254 silica gel 60 plates for detection at 254 nm. (R)‐tert‐Butyl (4‐Methyl‐3‐((1‐(naphth‐1‐yl)ethyl)carbamoyl)phenyl) carbamate (2 q): This compound was synthesized according to the general procedure B.