5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones: Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives (original) (raw)
Related papers
2018
CDK2, which plays a vital role as a regulator of cell growth, is one of the intensely studied TK targets of anticancer inhibitors. The present investigation dealt with design (docking and binding energy), which used to select the promising proposed compounds for the synthesis of novel, diverse 14 pyrido[2,3-d]pyrimidine derivatives as potential anticancer agents targeting CDK2. All the newly synthesized compounds were screened for their anticancer activity against MCF-7 and CaCO2 and 14 compounds were found to be active. Compounds 6c and 8d showed significant activity with IC50 values 7.4 and 5.5 on MCF-7 respectively. Most of the synthesized compounds were subjected to enzyme assay (CDK2 TK) for measuring their inhibitory activity. The preliminary results revealed that compound 8d, which proves potent inhibitory activity toward tumor growth and potent activity on the CDK2 TK enzyme with 89% inhibition compared to ATP would be a potential anticancer agent.
Journal of Biomolecular Structure & Dynamics, 2023
Synthesis of novel and potent hit molecules has an eternal demand. It is our continuous study to search novel bioactive hit molecules and as a part of this, a series of novel N'isonicotinoyl-2-methyl-4-(pyridin-2-yl)-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3carbohydrazide analogues (5a-5n) were synthesized with good yields by the conventional method. The various novel compounds have been characterized and identified by many analytical technique such as IR, 1 H-NMR, 13 C-NMR, mass spectral analysis, and elemental analysis. All the synthetic analogs (5a-5n) are evaluated for their in vitro antibacterial and antimycobacterial activities against different bacterial strains. Molecular docking and Molecular dynamics studies were helped in revealing the mode of action of these compounds through their interactions with the active site of the Mycobacterium tuberculosis enoyl reductase (In-hA) enzyme. The calculated ADMET descriptors for the synthesized compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new Anti-mycobacterial agents.
International journal of drug delivery technology, 2020
Dihydropyrimidinone and dihydropyrimidine derivatives are reported to possess broad biological activities. Many synthetic samples have been studied as antibacterial, antiviral, and anticancer agents. We decided to synthesize novel compounds of new pyrimidine derivatives. The present work involves the synthesis of new dihydropyridine derivatives. The starting vanillin, compound (1) was used as the key intermediate to prepare the 5-acetyl-4-(4-hydroxy-3-methoxyphenyl)-6-methyl pyrimidine-2(1H)-one(2),Ethyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate (3), 4-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetrahydro quinazoline-2(1H)-one (4), respectively, through the reaction with urea and acetylacetone or ethyl acetoacetate or cyclohexanone but 4-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetrahydro quinazoline-2(1H)-thione (5) reacted with thiourea and cyclohexanone. FTIR, 1 H-NMRand 13 C-NMR spectroscopy characterized all the synthesized compounds. The synthesized derivatives were screened for their in vitro, antibacterial activity against two gram-positive bacteria: Bacillus subtilis, and Staphylococcus aureus and two gram-negative bacteria: Klebsiella pneumonia and Salmonella typhi and the results showed that most of them have good antibacterial activity. While their antifungal activity against three fungi species: (Aspergillus fumigates, Aspergillus niger, and Rhizopus), revealed that compounds (1-5) displayed the most potent antifungal activity. Density functional theory (DFT) calculations for the synthesized compounds (1-5) were conducted, using a molecular structure with optimized geometry. Highest occupied molecular orbital/lowest unoccupied molecular orbital energies and structures are demonstrated. The antimicrobial activity indicates that compounds 3 and 4 are the most active than the compounds 2 and 5. Molecular docking revealed that compounds (4) and (5), with cyclohexyl groups are important to block the active centers of glucose-6-phosphate synthase in the bacteria and fungi.
Quantitative structure activity relationships (QSAR) are mathematical models that can be used to assess the toxicity, using physical characteristics of already analyzed chemical structures (usually known as molecular descriptors). Acute toxicity is an example of the extent of toxicity that can be predicted using Risk and Control Self-Assessment (RCSA). Toxicity parameters estimated by QSAR model can also be used as a predictive tool for unknown compounds if previously similar molecules were tested. In order to determine the new molecule properties, avoid costly and intensive biological tests, and a lot of time required to establish the level of toxicity, the use of molecular descriptors has been proved as a valuable asset. The aim of this article is to prove that when laboratory conditions do not allow traditional bioassays, QSAR can be a viable alternative to conventional biological tests in order to assess toxicity for very specific molecules.
Antiviral chemistry & chemotherapy, 2001
Several 5-alkyl, 5-alkenyl, 5-iso-alkyl, 5-halo, 5-aminomethyl and 5-carboxy derivatives of S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-benzyloxopyrimidines), DATNOs (dihydro-alkylthionaphthylmethyl-oxopyrimidines) and F2-S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-2,6-difluorobenzyl-oxopyrimidines) have been prepared and tested as anti-HIV-1 agents. S-DABO derivatives bearing at C-6 position monosubstituted phenylmethyl or heteroarylmethyl units have also been synthesized. 2-Alkylthio-3,4-dihydropyrimidin-4(3H)-one derivatives of F2-S-DABO series bearing small alkyl groups at C-5 proved to be potent inhibitors of HIV-1 replication in vitro with selectivity indexes ranging from 250 to >2,500.
Chemistry & biodiversity, 2018
A series of tetrahydropyrimidine derivatives (2a - 2l) were designed, synthesized, and screened for anti-HIV-1 properties based on the structures of HIV-1 gp41 binding site inhibitors, NB-2 and NB-64. A computational study was performed to predict the pharmacodynamics, pharmacokinetics, and drug-likeness features of the studied molecules. Docking studies revealed that the carboxylic acid group in the molecules forms salt bridges with either Lys574 or Arg579. Physiochemical properties (e.g., molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors, and number of rotatable bonds) of the synthesized compounds confirmed and exhibited that these compounds were within the range set by Lipinski's rule of five. Compounds 2e and 2k with 4-chlorophenyl substituent and 4-methylphenyl group at C(4) position of the tetrahydropyrimidine ring was the most potent one among the tested compounds. This suggests that these compounds may serve as leads for development of n...
Medicinal Chemistry Research, 2014
The guanidine functionality has been found in numerous biologically active natural products and several drugs. We have, therefore, directed some of our efforts to synthesize analogs of 2-aminopyrimidine, a guanidinecontaining six-membered heterocyclic scaffold, using microwave irradiation. The synthesized compounds have shown structural similarity to ispinesib, a quinazolinonebased KSP inhibitor that has already entered clinical trials. Molecular docking study was carried out to understand the binding modes of these newly synthesized compounds. The results of docking studies showed that these compounds interact with the same active site residues like ispinesib. From the molecular docking study, it was confirmed that these compound might be act as a potential candidate for KSP inhibition. Further lead optimization of drug-like properties was evaluated through in silico predictions by ADMET predictor TM software. The blood brain barrier penetration for both the synthesized compounds is predicted to be high compared to ispinesib. Hence, it is predicted that these compounds have tendency to treat the glioblastoma-like brain cancers. Hence a combination of in silico ADMET studies and molecular docking can help to improve prediction success and these compounds might be act as a potential candidate for KSP inhibition.
Bioorganic & Medicinal Chemistry, 2010
a b s t r a c t 5,6-Disubstituted pyrimidine derivatives (4)(17) were prepared by intramolecular cyclization reaction of a-(1-carbamyliminomethylene)-c-butyrolactone (2) with sodium ethoxide and subsequent chemical transformation of 2-hydroxy group in C-5 side chain as well as lithiation reaction for introduction of acyclic side chain at C-6. All compounds were characterized by 1 H NMR, 13 C NMR and mass spectra. Structures of compounds 4, 7 and 14 were unambiguously confirmed by X-ray crystal structural analysis. Supramolecular structures of these three compounds differ significantly. Two N-HÁ Á ÁO and one C-HÁ Á ÁO hydrogen bonds in 4 form three-dimensional network. One O-HÁ Á ÁN hydrogen bond and one pÁ Á Áp interaction self-assemble the molecules of 7 into sheets. In supramolecular aggregation of 14, only pÁ Á Áp stacking interactions participate, so forming chains. The compounds were evaluated for their cytostatic activities against human malignant cell lines. Of all tested compounds, 2,4-dimethoxy-5-methoxytritylethylpyrimidine (9) and 2,4-dichloro-5-chloroethylpyrimidine (14) exhibited the most prominent inhibitory effects. Furthermore, compound 14 showed marked activity against human colon carcinoma (IC 50 = 0.4 lM).
TURKISH JOURNAL OF CHEMISTRY
Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized 3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reported for the synthesis of these derivatives, employing cobalt ferrite (CoFe 2 O 4 @SiO 2-SO 3 H) magnetic nanoparticles under microwave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessed against the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonic kidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxic molecule against the MCF-7 cell line (IC 50 of 0.17 µg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showed excellent cytotoxic activities against the AGS cell line, with an IC 50 of 4.90 and 4.97 µg/mL, respectively. Although they are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showed that the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential of the candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridine derivatives, compound 5m had the most free energy of binding (-9.52 kcal/mol) and lowest Ki (0.105 µM), and among the pyrimidine derivatives, compound 4r had the most free energy of binding (-7.67 kcal/mol) and lowest Ki (2.39 µM). Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding site via H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM and pyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpful in the further design of DHPMs and pyridine derivatives as potential anticancer agents.
Synthesis and Theoretical Study of the Novel 2-Oxopyrimidin-1(2H)-yl- Amides Derivative
The 1-amino-5-benzoyl-4-phenyl-1H-pyrimidine- 2-one/-thione (1a-b) were synthesized with the reaction of 4-benzoyl-5-phenyl-2,3-furandione and acetophenonsemicarbazone/-thiosemicarbazone. The study was extended to reactions of the compounds (1a-b) with acide chlorides (2a-d). Thus, some new pyrimidine derivatives (3a-h) were synthesized. The novel 2-oxopyrimidin- 1(2H)-yl-amides derivatives were characterized by elemental analysis, IR, 1H and 13C NMR spectral data. All of them were evaluated according to their previous analogues. In addition to experimental analysis, quantum-mechanical calculations for derivatives of 2-oxopyrimidin- 1(2H)-yl-amides were performed by using B3LYP method with the 6-311G(d,p), 6-311++G(2d,2p) basis sets in order to find molecular properties. As a result, both frontier orbital energies for the containing-sulphur molecules were found low while these energies were high for the containingoxygen molecules.