Synthesis, crystal structure and cytotoxic activity of novel 5-methyl-4-thiopyrimidine derivatives

Abstract

This article presents the synthesis of three new 4-thiopyrimidine derivatives obtained from ethyl 4-methyl-2-phenyl-6-sulfanylpyrimidine-5-carboxylate as the starting material, namely, ethyl 4-[(4-chlorobenzyl)sulfanyl]-6-methyl-2phenylpyrimidine-5-carboxylate, C 21 H 19 ClN 2 O 2 S, (2), {4-[(4-chlorobenzyl)sulfanyl]-6-methyl-2-phenylpyrimidin-5-yl}methanol, C 19 H 17 ClN 2 OS, (3), and 4-[(4-chlorobenzyl)sulfanyl]-5,6-dimethyl-2-phenylpyrimidine, C 19 H 17 ClN 2 S, (4), which vary in the substituent at the 5-position of the pyrimidine ring. The compounds were characterized by 1 H NMR, 13 C NMR, IR and mass spectroscopies, and also elemental analysis. The molecular structures were further studied by single-crystal X-ray diffraction. Compound (2) crystallizes in the space group P1 with one molecule in the asymmetric unit, whereas compounds (3) and (4) crystallize in the space group P2 1 /c with two and one molecule, respectively, in their asymmetric units. The conformation of each molecule is best defined by the dihedral angles formed between the pyrimidine ring and the planes of the two aryl substituents attached at the 2-and 4-positions. The only structural difference between the three compounds is the substituent at the 5-position of the pyrimidine ring, but they present significantly different features in the hydrogenbond interactions. Compound (2) displays a one-dimensional chain formed by hydrogen bonds and the chains are further extended into a two-dimensional network. Molecules of (3) and (4) generate one-dimensional chains formed through intermolecular interactions. The study examines the cytotoxicity of compounds (3) and (4) against Human umbilical vein endothelial cells (HUVEC) and HeLa, K562 and CFPAC cancer cell lines. The presence of the hydroxymethyl and methyl groups in (3) and (4), respectively, offers an interesting new insight into the structures and behaviour of these derivatives. Compound (4) was found to be nontoxic against CFPAC and HUVEC; however, it shows weak activity against the HeLa and K563 cell lines. The presence of a hydroxy group in (3) significantly increases its cytotoxicity towards both, i.e. the cancer (HeLa, K562 and CFPAC) and normal (HUVEC) cell lines.

Synthesis, Crystal Structure, and Biological Evaluation of Novel 5-Hydroxymethylpyrimidines

“…Generally, pyrimidines possessing a 4-benzylsulfanyl group (3a and 3b) exhibit stronger toxicity than their amino analogues (3c-3j). Considering our previous observation [14], it appears that the substitution in the phenyl ring of the benzyl group, with both electron-withdrawing (4-Cl) and electron-donating groups (2-CH 3 , 3b), enhances their toxic properties. Compound 3b decreased the cell viability in low concentration and, for this reason, was excluded from further biological investigations.…”

“…Its MIC ranged from 4 to 32 mg/mL, depending on the strain [13]. Additionally, we observed that the hydroxylation of 4-[(4-chlorobenzyl)sulfanyl]-5,6-dimethyl-2phenylpyrimidine to its 5-hydroxymethyl derivative enhances the cytotoxicity significantly towards both normal (survival of normal human endothelial cells, 58% vs. 1%) and cancer cell lines (IC50 in the range > 100-55 µM vs. 17-38 µM, depending on the cancer cell line) [14].…”

“…The substrates 1a and 1b were prepared as described previously [15,16]. The benzylsulfanyl esters 2a and 2b were obtained using the method exploited in our previous publication (Figure 2) [14]. In short, substrate 1a was dissolved in a methanolic solution of NaOH and coupled with appropriate benzyl chloride.…”

An Experimental and Computational Exploration on the Electronic, Spectroscopic, and Reactivity Properties of Novel Halo-Functionalized Hydrazones

“…FMOs can play a significant role during molecular interactions . The chemical reactivity and stability might be determined by the energy gap of FMO. − The electronic properties of CPFH, CCPH, and BCPH were determined by FMOs at the CAM-B3LYP/6-311G (d,p) level. The FMOs consist of HOMO, LUMO, HOMO – 1, LUMO + 1, HOMO – 2, LUMO + 2, and their energy gaps (Δ E ) are presented in Table .…”

Experimental and DFT Investigation of 6‐arylated‐pyridin‐3‐yl methanol Derivatives

“…[47] The energy gap of FMO may influence photo-catalytic activity and stability. [48][49][50][51][52][53][54][55][56] The HOMO-LUMO energy difference has a low value, indicating strong reactivity, and poor mechanical strength. [57] If the HUMO LUMO energy break is large, the inverse is true.…”