Synthesis and antimicrobial activity of pyrimidinophanes with two uracil units and bridging nitrogen atoms

Abstract

A series of pyrimidinophanes containing two uracil units and nitrogen atoms in bridging polymethylene chains -(CH 2 ) n N(Et)(CH 2 ) m -(n, m = 5, 6) have been synthesized. The uracil moieties are represented by 6-methyl-, 5-decyl-6-methyl-, and 5-fluorouracils. Quaternization of the bridging N atom with ethylbromide or n-decylbromide yielded amphiphilic pyrimidinophanes, which were evaluated for their antibacterial and antifungal activity in terms of minimal inhibiting concentration (MIC) against Gram-positive and Gram-negative bacteria and fungi. It has been found that MICs of the amphiphilic pyrimidinophanes decrease with increasing lipophilicity of the alkyl substituents at the bridging N atoms and with increasing polymethylene N(pyr)-N chain length (in some cases MIC against Staphylococcus aureus is below 1 ìg/mL). The MICs increase dramatically upon introduction of lipophilic n-decyl substituents at C(5) atoms of the uracil moiety. The results can be used in the search for new highly effective antimicrobial agents.Amphiphilic compounds that contain natural peptide structural moieties with antimicrobial activity have recently attracted interest as antimicrobial agents. In most instances these compounds are oligomers, for example, amphiphilic polymethacrylates [1], polynorbornenes [2], and polyvinylalcohols [3] with ammonium groups.We synthesized for the first time macrocyclic amphiphilic compounds that were isomeric pyrimidinophanes consisting of 2,6-methyluracil moieties linked to each other through the N(1) and N(3) atoms of the pyrimidine rings by bridging -(CH 2 ) n N + (Et)(R)(CH 2 ) m -[n = 5, 6; R = Bn, CH 3 (CH 2 ) 9 ] [4]. These macrocycles can be viewed as low-molecular-weight cyclic oligomers. Herein we explain the effect of the lipophilic substituent in either the onium groups in the bridges or the uracil moiety on the antimicrobial and antifungal activity.We synthesized a series of isomeric pyrimidinophanes (IIIa -b -VIIIa -b) in which the length of the methylene chains and the lipophilicity of the uracyl moieties and onium groups in the bridge were varied by introducing into them n-decyl substituents. Macrocycles with other substituents on the pyrimidine rings, in particular with 5-fluorouracil moieties (pyrimidinophanes VIIa and -b), were also examined. 5-Decyluracil (XI) was synthesized using the following reaction sequence. Condensation of the ethyl ester of 3-decylacetoacetic acid (IX) with thiourea produced 2-thio-4-oxo-1,2,3,4-tetrahydro-5-decyl-6-methylpyrimidine (X) that was hydrolyzed in the presence of chloroacetic acid to XI (Scheme 1). Next, 1,3-bis(w-bromopentyl-or -hexyl-)-5-decyl-6-methyl-or 6-methyl-or 5-fluorouracils (XIIIa -e) were synthesized from the disodium salt of the corresponding uracil (XIIa -c) and the a,w-dibromoalkane in DMF according to the known procedure. Some of these were reacted with an excess of ethylamine to give 1,3-bis(wethylaminopentyl-or -hexyl-)-5-decyl-6-methyl-or 6-methyluracils (XIVa -c) (Scheme 2) [4,5].Reaction of the resulting dibromides (XIIIa -e...

Novel Bolaamphiphilic Pyrimidinophane As Building Block for Design of Nanosized Supramolecular Systems with Concentration-Dependent Structural Behavior

“…Therefore, the pH variable nanoreactors based on pyrimidinic surfactants analogous to those proposed in our work are of importance from the viewpoint of development of biomimetic catalysts showing high substrate specificity towards the substrates of different hydrophobicity. Pyrimidinic macrocyclic amphiphiles especially B1 are documented to exhibit high antimicrobial activity. − This property together with surface activity and controllable gel behavior is important for preparation of cosmetics, antibacterial liniments, etc.…”

“…Pyrimidinic macrocyclic amphiphiles especially B1 are documented to exhibit high antimicrobial activity. [61][62][63] This property together with surface activity and controllable gel behavior is important for preparation of cosmetics, antibacterial liniments, etc.…”

“…Pyrimidinophane (1). A mixture of disodium salt of N,N 0 -(hexane-1,6-diyl)-bis(4-amino-6-methylpyrimidine-2-thione) 2 43 (4.10 g, 10 mmol) and 1,3-bis(bromopentyl)-5-n-decyl-6-methyluracil 3 44 (5.0 g, 10 mmol) was stirred in DMF (400 mL) at room temperature for 30 h. The solvent was evaporated in vacuo. The residue was subjected to column chromatography using successive elution with hexane, diethyl ether, and 1:1 ethyl acetate-diethyl ether mixture.…”

Synthesis and antimicrobial activity of pyrimidinophanes containing a uracil moiety and a bridging sulfur atom

“…The methods used for preparing 1,3-bis(5-bromopentyl-1)-6-methyluracil (IIa) [11], 1,3-bis(6-bromohexyl-1)-6-methyluracil (IIb) [7], and 1,3-bis(6-bromohexyl-1)-5-decyl-6-methyluracil (IIc) [8] have been described previously.…”