Synthesis of annelated analogues of 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442) using 1,3-oxazine-2,4(3H )-diones as key intermediates

Synthesis of Furoannelated Analogues of Emivirine (MKC‐442)

“…As shown in Table 1, the biologic activity of the oxaanalogues 3 a ,b were only slightly improved in comparison to 1-ethoxymethyl-7-phenyl-1,5,6,7-tetrahydro-cyclopenta[d]pyrimidine-2,4-dione 2 synthesized by Larsen et al [10]. However, it is still not within the range of Emivirine (IC 50 = 0.02 µM).…”

“…Modelling studies within our group have revealed [10] that the analogue 2 of Emivirine, containing an annelated ring at the C-5 and C-6 of the uracil ring, has approximately the same torsion angle as in the Emivirine-RT complex revealed by xray crystallography. In continuation of the previously reported synthesis of the annelated Emivirine analogue 2, this paper presents the synthesis of furoannelated analogues 3.…”

Design and synthesis of novel 5,6-bisindolylpyrimidin-4-ones structurally related to ruboxistaurin (LY333531)

“…18 The primary method for converting simple alkyl b-ketoesters to the corresponding pyrimidin-4-one moiety involves exposure of the substrate to either urea or thiourea, in the presence of sodium alkoxide in alcohol, and heating of this mixture for an extended period. 19 In 2002, it was first reported that simple b-ketoester precursors could be converted directly to corresponding 5,6-alkyl substituted uracils by conventional microwave irradiation in the presence of urea, under solvent-free conditions. 20 This report includes work carried out on the first reported conversion of a 2,3-bis(heteroaryl) methyl-3-oxopropionate to heterocyclic 5,6-disubstituted pyrimidin-4-ones.…”

“…Reaction of 5 equiv of this salt under standard methoxide conditions did not result in formation of any product 18, even following extended reflux for 72 h. Similarly, when reaction of 5 equiv of the salt was carried out, along with 10, in 10% aqueous KOH, the absence of either 19 or 2-amino oxazin-4(5H)-one was observed (method C; Table 1). 19 Due to concerns over these heterogeneous reaction conditions, a modified reaction was attempted involving mixing of 20 equiv of pulverised KOH along with 5 equiv of this salt along with 10, in THF, heated for 16 h (method D; Table 1), but without any success.…”

Synthesis of Novel MKC-442 Analogues with Potent Activities against HIV-1

“…The analogue 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, also known as Emivirine or Coactinone) [13], showed high activity against HIV-1 but unfortunately in phase III clinical trials it was also found to activate a liver enzyme in the 450 family which metabolizes protease inhibitors [14]. For this reason, and as a part of our continuing interest in the chemistry of NNRTIs [15][16][17], we are interested in whether alternative drug candidates can be found among the HEPT analogues. Recently, we reported that MKC-442 analogues with a 1-allyloxymethyl substituent showed activity against HIV-1 in the picomolar range [18].…”