Abstract
In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile 1, 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile 2, and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate 3. An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds (3) crystallized with a water molecule. A cyclic motif (R22(8)) mediated by N–H···O hydrogen bond was formed in compounds 1 and 2, whereas the corresponding motif was not favorable, due to the water molecule, in compound 3. The crystal packing of these compounds was analyzed based on energy frameworks performed at the B3LYP/6-31G(d,p) level of theory. Various inter-contacts were characterized using the Hirshfeld surface and its associated 2D-fingerprint plots. Furthermore, a molecular docking simulation was carried out to assess the inhibitory potential of the title compounds against the human dihydrofolate reductase (DHFR) enzyme.
Highlights
Pyrimidine moiety was early discovered as an important scaffold in several chemotherapeutic agents [1]
The chemotherapeutic efficacy of pyrimidine-based drugs is attributed to their inhibitory effect on the biosynthesis of vital enzymes responsible for nucleic acids, such as thymidylate synthetase (TSase), thymidine phosphorylase (TPase), dihydrofolate reductase (DHFR), and reverse transcriptase (RTase)
The crystal structures of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives were determined at the room temperature
Summary
Pyrimidine moiety was early discovered as an important scaffold in several chemotherapeutic agents [1]. The molecular packing was mainly stabilized by a pair of N1–H···O1 (H···O = 1.795 Å, N···O = 2.800 (2) Å, ∠NHO = 174◦) hydrogen bonds which form between the NH and carbonyl groups of two centrosymmetrically-related pyrimidine rings (Figure 2b). These hydrogen bonds led to a cyclic inversion dimer with a R22(8) graph-set motif. In the electrostatic energy framework, the large vertical cylindrical tubes correspond to cyclic N–H···O hydrogen bonds, and small horizontal tubes bridge the large cylindrical tubes These horizontal tubes represent the intermolecular C–H···N interaction in which the nitrile N atom acts as an acceptor (C13–H13···N3; H13···N3 = 2.60 Å and ∠CHN = 122°). Binding poses of (a) compounds 1 (orange), (b) 2 (blue), and (c) 3 (magenta) inn tthhe aaccttiivvee ssiittee ooff hDHHFFRR ((aaccttiivvee ssiittee rreessiidduueess aanndd wwaatteerrmmoolleeccuulleessaarreerreepprreesseenntteeddaassttuubbeessaannddlliiggaannddssininaabbaallllaannddsstticickkmmooddeel)l.)
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