2-Substituted agelasine analogs : synthesis and biological activity, and structure and reactivity of synthetic intermediates

2-Substituted N-methoxy-9-methyl-9H-purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9H-purines or 2-chloro-N-methoxy-9-methyl- 9H-purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on 1H NMR. The tautomers were identified by 1D and 2D 1H, 13C, and 15N NMR techniques, and showed significant variation both in 13C and 15N shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino:imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N-methoxy-9-methyl-9H-purin-6- amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines

Asymmetric Synthesis of Enantiomerically Pure Milnacipran Analogs

There are currently no antidepressant drugs available with the desired efficacy, onset of action, or absence of side effects. Milnacipran is a commercially available antidepressant drug that shows affinity for the serotonin and norepinephrine transporters. During the present work it has been used as a lead compound in the development of a series of analogs. A three-step synthesis was employed in the preparation of eleven 2-(aminomethyl)-1-aryl-N,N-diethylcyclopropanecarboxamide hydrochlorides from the corresponding 1-aryl-3-oxa-bicyclo[3.1.0]hexane-2-ones. The bicyclic lactone building blocks were prepared by two different methods, these being an asymmetric synthesis in a reaction of arylacetonitrile with epichlorohydrin, and an intramolecular cyclopropanation reaction of a diazocompound. Yields range from moderate to excellent, and high enantiomeric excess is achieved in all cases. Sizty-nine new compounds were prepared and identified during the project. IC50-values show that (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-(naphthalen-2-yl)cyclopropanecarboxamide has a higher affinity for the serotonin and dopamine transporters than milnacipran, and an equivalent affinity for the norepinephrine transporter

2-Substituted agelasine analogs : synthesis and biological activity, and structure and reactivity of synthetic intermediates

2-Substituted N-methoxy-9-methyl-9H-purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9H-purines or 2-chloro-N-methoxy-9-methyl- 9H-purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on 1H NMR. The tautomers were identified by 1D and 2D 1H, 13C, and 15N NMR techniques, and showed significant variation both in 13C and 15N shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino:imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N-methoxy-9-methyl-9H-purin-6- amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines