Insights into the N,N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: an alternative N-monoacylation reaction

Théodorou, Vassiliki; Gogou, Marina; Giannousi, Aimilia; Skobridis, Konstantinos

doi:10.3998/ark.5550190.p008.209

Cited by 3 publications

(1 citation statement)

References 27 publications

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“…Presented series of compounds were prepared by one step acylation of chosen aminopyridine derivative (2-aminopyridine, 3-aminopyridine, 5-chloropyridin-2-amine or 6-chloropyridin-2-amine) with substituted benzoyl chlorides in the presence of dry pyridine as a base. Pyridine was employed to prevent the formation of diacetylated products, which are the major products when a stronger base (such as triethylamine) is used (Theodorou et al, 2014). Since the reaction is exothermic, reaction mixture was cooled down in the fridge before the benzoyl chloride was added.…”

Section: Synthesismentioning

confidence: 99%

N‐pyridinylbenzamides: an isosteric approach towards new antimycobacterial compounds

et al. 2020

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A series of N-pyridinylbenzamides was designed and prepared to investigate the influence of isosterism and positional isomerism on antimycobacterial activity. Comparison to previously published isosteric N-pyrazinylbenzamides was made as an attempt to draw structure-activity relationships in such type of compounds. In total, we prepared 44 different compounds, out of which fourteen had minimum inhibitory concentration (MIC) values against Mycobacterium tuberculosis H37Ra below 31.25 µg/ml, most promising being N-(5-chloropyridin-2-yl)-3-(trifluoromethyl) benzamide (23) and N-(6-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (24) with MIC = 7.81 µg/ml (26 µm). Five compounds showed broad-spectrum antimycobacterial activity against M. tuberculosis H37Ra, M. smegmatis and M. aurum. N-(pyridin-2-yl)benzamides were generally more active than N-(pyridin-3-yl)benzamides, indicating that N-1 in the parental structure of N-pyrazinylbenzamides might be more important for antimycobacterial activity than N-4. Marginal antibacterial and antifungal activity was observed for title compounds. The hepatotoxicity of title compounds was assessed in vitro on hepatocellular carcinoma cell line HepG2, and they may be considered non-toxic (22 compounds with IC 50 over 200 µm).

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Section: Synthesismentioning

confidence: 99%

N‐pyridinylbenzamides: an isosteric approach towards new antimycobacterial compounds

et al. 2020

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Synthesis and characterization of new N-{4,6-bis[2-(het)arylvinyl]pyrimidin-2-yl}-substituted polycyclic aromatic imides

et al. 2019

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Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents

et al. 2018

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Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R2 = Me; 2i: R2 = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-yl)benzamides with hydroxy substitution (2b: R2 = 2-OH; 2d: R2 = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.

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Insights into the N,N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: an alternative N-monoacylation reaction

Cited by 3 publications

References 27 publications

N‐pyridinylbenzamides: an isosteric approach towards new antimycobacterial compounds

N‐pyridinylbenzamides: an isosteric approach towards new antimycobacterial compounds

Synthesis and characterization of new N-{4,6-bis[2-(het)arylvinyl]pyrimidin-2-yl}-substituted polycyclic aromatic imides

Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents

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