Dihydroazolopyrimidine crownophanes. Synthesis and tuberculostatic activity

Abstract

Azolo[1,5-a]pyrimidines are considered to be purine analogues and they form one of the most promising groups of biologically active compounds[1-16] in medicinal chemistry. One of the strategies enhancing biochemical activity of azolo[1,5-a]pyrimidines is introduction of functional groups responsible for solubility and transport into their pharmacophore nucleus.[1,16] In this study, we wish to report ultrasound- and microwave-assisted one-pot cascade synthesis of macroheterocyclic 1-phenyl-2-(21-phenyl-10,11,13,14,20,20a-hexahydro-4aH-dibenzo-[13,14: 8,9][1,4,7] trioxacyclotetradecino[11,10-e]azolo[1,5-a]pyrimidin-20-yl)-1-ethanones. US and MV irradiation of the reaction mixtures under alkaline catalysis was found to promote a significant reduction of the reaction times (from 35 to 2 hours) and shift of the equilibrium in favor of 6,7-dihydroazolo[1,5-a]pyrimidine crownophanes in excellent yields (from 18[24] to 75 %). The high regio and stereoselectivity of the (R,S,R)-macroheterocyclic diastereomer formation was established by means of X-ray crystallography, 1H NMR spectroscopy, as well as HPLC and preparative chromatography. The aq. DMF appeared to be an acceptable solvent for stabilization of the important template-assisted pseudo-cyclic complex of the chalcone podand in this synthesis. Introduction of the dibenzo-crown ether transport moiety into 6,7-dihydroazolo[1,5-a]pyrimidines proved to increase their tuberculostatic activity in order to MIC 3.15 mg/ml. © ISUCT Publishing.