6-Amino-1,3-dimethyluracil

Synthesis of aminouracil-tethered tri-substituted methanes in water by iodine-catalyzed multicomponent reactions.[Pubmed:30109557]

Mol Divers. 2019 Feb;23(1):205-213.

An efficient, mild and environmentally benign protocol has been developed for the synthesis of aminouracil-tethered tri-substituted methane derivatives. The three-component reaction of 2-hydroxy-1,4-naphthaquinone, 6-Amino-1,3-dimethyluracil and aldehydes in the presence of molecular iodine as catalyst under reflux conditions resulted in aminouracil-tethered tri-substituted methane derivatives 4 in aqueous medium. Similarly, the four-component reaction of 2-hydroxy-1,4-naphthaquinone, o-phenylenediamine, aldehydes and aminouracil derivatives resulted in aminouracil-tethered tri-substituted methane derivatives 6 under the same reaction conditions. The notable features of this protocol are simple experimental procedure, cheap catalyst, readily available starting materials, moderate-to-good yields of the products having biologically active important moieties such as aminouracil, hydroxy-naphthaquinone/benzophenazine.

Design, synthesis and evaluation of novel pyrazolo-pyrimido[4,5-d]pyrimidine derivatives as potent antibacterial and biofilm inhibitors.[Pubmed:28209374]

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1451-1457.

An efficient four-component reaction of 6-Amino-1,3-dimethyluracil, N,N-dimethylformamide dimethylacetal, 1-phenyl-3-(4-substituted-phenyl)-4-formyl-1H-pyrazoles and aromatic amines was conducted in the presence of [Bmim]FeCl4 ionic liquid as a promoting medium. This strategy provided a convenient route without any additional catalyst or metal salt under mild conditions. All the synthesized pyrazolo-pyrimido[4,5-d]pyrimidines derivatives were evaluated for their antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition, intracellular ROS accumulation and protein leakage activities. The results revealed that among all the screened derivatives, the compounds 5c, 5i, 5l and 5m were quite promising with MIC values ranging between 3.9 and 15.6mug/mL, while the MBC values were 2-fold the antibacterial activity values. The biofilm inhibition activity revealed that the compounds 5l and 5m exhibited promising activity with IC50 values ranging between 1.8 and 8.2mug/mL. It was observed that at a concentration of 0.5mug/mL, the compound 5l treated biofilms of Micrococcus luteus showed increased levels of intracellular ROS accumulation. Further, the protein leakage study revealed that the Micrococcus luteus cells treated with compound 5l caused membrane permeability which resulted in protein leakage and subsequent bacterial cell death.

Hydrogen Bonding in Bis(6-amino-1,3-dimethyluracil-5-yl)-methane Derivatives: Dynamic NMR and DFT Evaluation.[Pubmed:27070193]

J Phys Chem A. 2016 May 5;120(17):2737-48.

Three bis(6-Amino-1,3-dimethyluracil-5-yl)-methane derivatives were studied experimentally by variable-temperature (1)H NMR in polar aprotic solutions (CD2Cl2, C5D5N, C2D2Cl4) and computationally by DFT. The unusual for diarylmethanes coplanar conformation of dimethyluracil rings of each molecule is held by a pair of unequal intramolecular N-H...O hydrogen bonds. We show the presence of two dynamic processes involving breakage/formation of these bonds. First, it is two independent NH2 group rotations, each coupled to nitrogen inversion. Second, it is uracil ring rotations (ring flips). The thermodynamic parameters (DeltaH(double dagger), DeltaS(double dagger), and DeltaG(double dagger)) of both processes were estimated by the full line shape analysis of NMR signals and also by DFT calculations. We demonstrate that, though the ring flips exchange pairs of NH protons, the two processes are not coupled: during the ring flip NH2 groups do not rotate, and during the NH2 rotation the rings do not necessarily rotate. Unlike in many other diarylmethanes, the ring flips in the studied compounds are happening stepwise; i.e., the configuration when both rings are "in flight" at the same time is energetically unfavorable (small degree of "cog wheel effect"). The signs of the DeltaS(double dagger) values indicate that the molecular flexibility increases during the NH2 rotations, but decreases during the ring flips.

Three-component green reaction of arylaldehydes, 6-amino-1,3- dimethyluracil and active methylene compounds catalyzed by Zr(HSO4)4 under solvent-free conditions.[Pubmed:23092170]

Comb Chem High Throughput Screen. 2013 Feb;16(2):150-9.

A convenient one-pot, three-component reaction of aromatic aldehydes, 6-Amino-1,3-dimethyluracil and active methylene compounds in the presence of Zr(HSO4)4 as a heterogeneous catalyst, under solvent-free conditions brings a very simple and highly efficient method for the preparation of pyrimido[4,5-b]quinolines, pyrimido[5',4':5,6]pyrido[2,3- d]pyrimidines, indeno[2',1':5,6]pyrido[2,3-d]pyrimidines and a new class of pyrimidinedione derivatives in excellent yields. This approach is general and provides several advantages such as simple reaction set-up, very mild reaction conditions, high yields, recyclability of the catalyst and environmentally friendly benign.

Biginelli and Hantzsch-type reactions leading to highly functionalized dihydropyrimidinone, thiocoumarin, and pyridopyrimidinone frameworks via ring annulation with beta-oxodithioesters.[Pubmed:20979420]

J Org Chem. 2010 Nov 19;75(22):7785-95.

An efficient and highly convergent route to dihydropyrimidinones (DHPMs) and hitherto unreported dihydropyridopyrimidinones has been developed by one-pot, three-component cyclocondensation of aromatic aldehydes, beta-oxodithioesters, and urea/6-Amino-1,3-dimethyluracil in the presence of recyclable SiO2-H2SO4. On the other hand, salicylaldehyde, beta-oxodithioester, and urea reacted under similar conditions to afford the 3-aroyl/heteroaroyl-2H-chromen-2-thiones in high yields instead of Biginelli product. The attractive feature of this approach is the synthesis of three important bioactive heterocyclic frameworks from the same beta-oxodithioester under the similar reaction conditions, making this new strategy highly useful in diversity-oriented synthesis (DOS).

New one-pot four-component synthesis of disubstituted pyrido[2,3-d]pyrimidine-6-carboxamide derivatives.[Pubmed:19281247]

J Comb Chem. 2009 May-Jun;11(3):375-7.

In this work, 1,2,3,4,5,8-hexahydro-1,3,7-trimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carboxam ide derivatives were synthesized in a simple and efficient method from the four-component condensation reaction of diketene, an aliphatic or aromatic amine, an aromatic aldehyde, and 6-Amino-1,3-dimethyluracil in the presence of a catalytic amount of p-toluenesulfonic acid under mild conditions at ambient temperature in high yields.

Synthesis and pharmacology of pyrido[2,3-d]pyrimidinediones bearing polar substituents as adenosine receptor antagonists.[Pubmed:16377196]

Bioorg Med Chem. 2006 Apr 15;14(8):2837-49.

Amino-substituted pyrido[2,3-d]pyrimidinediones have previously been found to bind to adenosine A1 and A2A receptors in micromolar concentrations. The present study was aimed at studying the structure-activity relationships of this class of compounds in more detail. Most of the investigated compounds were provided with polar substituents, such as ethoxycarbonyl groups and basic amino functions, in order to improve their water-solubility. The compounds were synthesized starting from 6-Amino-1,3-dimethyluracil via different reaction sequences involving (cyano)acetylation, Vilsmeier formylation, or reaction with diethyl ethoxymethylenemalonate (EMME). The most potent and selective compound of the present series was 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-5-(2-naphthylmethyl)aminopyrido[2,3- d]pyrimidine-2,4-dione (11c) with a Ki value of 5 nM at rat and 25 nM at human A1 receptors. The compound was more than 60-fold selective versus A3 and more than 300-fold selective versus A2A receptors. It showed an over 300-fold improvement with respect to the lead compound. In GTPgammaS binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A1 receptor, 11c behaved as an antagonist with inverse agonistic activity. A regioisomer of 11c, 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-7-(2- naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (7a) in which the 2-naphthylmethylamino substituent at position 5 of 11c was moved to the 7-position, was a relatively potent (Ki=226 nM) and selective (>20-fold) A3 ligand. In the series of compounds lacking an electron-withdrawing ethoxycarbonyl or cyano substituent in the 6-position, compounds with high affinity for adenosine A2A receptors were identified, such as 1,2,3,4-tetrahydro-1,3-dimethyl-5-(1-naphthyl)aminopyrido[2,3-d]pyrimidine-2,4-di one 16b (Ki human A2A=81.3 nM, Ki human A1=153 nM, and Ki human A3>10,000 nM).

Synthesis and positive inotropic activity of several 5-aminopyrido[2,3-d]pyrimidines. Part 5: Compounds with positive inotropic activity.[Pubmed:8415847]

Pharmazie. 1993 Jul;48(7):509-13.

Starting from 6-Amino-1,3-dimethyluracil two approaches were developed for the preparation of 5-amino-pyrido[2,3-d]pyrimidine derivatives as potential cardiotonic agents. 1. Gould-Jacobs reaction followed by chlorination of the intermediate 5-hydroxypyrido-[2,3-d]pyrimidine using DMF/POCl3. 2. Cyclization of C-acetylated as well as C-cyano acetylated 6-Amino-1,3-dimethyluracil by an application of the Vilsmeier reaction yielding 5-chloropyrido[2,3-d]pyrimidines. Subsequent nucleophilic substitution reactions formed the target compounds which were examined for positive inotropic activity on isolated left atria and papillary muscles from guinea-pig hearts. Structure-activity relationships indicated that the effect depended on the 4-aminopyridine-3-carboxylic acid derivative structure.