Abstract
Three novel N-(α-bromoacyl)-α-amino esters: methyl 2-(2-bromo-3-methylbutanamido)pentanoate (1), methyl 2-(2-bromo-3-methylbutanamido)-2-phenylacetate (2) and methyl 2-(2-bromo-3-methylbutanamido)-3-phenylpropanoate (3) were synthesized. Single crystal X-ray diffraction data are reported for compounds 1 and 2. The cytotoxicity, antiinflammatory and antibacterial activity of compounds 1-3 were investigated. Additionally, the physico-chemical properties of studied compounds were calculated and an in silico toxicological study of compounds 1-3 was performed. The low level of cytotoxicity and absence of antibacterial and anti-inflammatory activity of 1-3 in tested concentrations might be a beneficial prerequisite for their incorporation in prodrugs.
Highlights
Searching for new potent drugs with enhanced physiological performance, many studies have been focused on the design of dipeptide-based prodrugs of known medications
(R,S)-2-bromo-3-methylbutanoyl chloride reacted with appropriate hydrochlorides of amino acid esters in dichloromethane at 0 °C
Methyl ester of D-norvaline was applied in order to obtain a dipeptide derivative with two aliphatic side chains, whereas the aromatic fragments were introduced by reacting with methyl esters of L-phenylglycine and L-phenylalanine
Summary
Searching for new potent drugs with enhanced physiological performance, many studies have been focused on the design of dipeptide-based prodrugs of known medications. The synthesis of dipeptide esters of acyclovir (2-amino-9-(2-hydroxyethoxymethyl)-3H-purin-6one) (Fig. 1) and structurally related antiherpetic drugs gancyclovir (2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)-3H-purin-6-one) and saquinavir ((2S)-N-[(2S, 3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide), lead to the discovery of new analogues with higher water-solubility at physiological pH and improved membrane permeability.[1,2,3,4,5] The same strategy was successfully applied in the development of new prodrugs of floxuridine (5-fluoro-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4dione) and azidothymidine (1-[(2R,4S,5S)-4-azido-5-. Valine (Val) was selected as the N-terminal amino acid for the preparation of N-(α-bromoacyl)-α-amino esters based on our previous studies on the biological activities of valine-containing cyclic didepsipeptides.[20,21,22,24,30] At the C-terminal end of the dipeptide, three amino esters with aliphatic (norvaline) and aromatic (phenylglycine and phenylalanine) side chains were positioned in order to exhibit different physico-chemical properties. The physico-chemical properties of studied compounds were calculated using Molinspiration tool[36] and an in silico toxicological study was performed using the OSIRIS Property Explorer.[37]
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