Tetrahydropyrimidine Derivatives Research Articles

Structural and electrochemical properties of a Cu(I) Schiff-base complex: Catalytic application to the synthesis of tetrahydropyrimidine derivatives

Herein, we report the synthesis and spectroanalytical characterization of one-dimensional polymeric Cu(I) complex [Cu(L2Br)I]n, incorporating N,N′-bis(2-bromobenzylidene)ethane-1,2-diamine Schiff base ligand, L2Br. Single crystal X-ray diffraction (SC-XRD) was used to examine the specific organization of atoms in thecomplex. The results showed that the Cu ion was coordinated only throughthe N donor sitesof the Schiff base. The complex’s tetrahedral shape was distorted, as demonstrated by the bond angles around the metal atom. The natural bond orbital and atoms in molecules investigations were also carried out in order to gain greater knowledge of the Cu(I) complex’s intermolecular charge transfer characteristics. The redox nature of the the complex was assessed by the cyclic voltammetry (CV) technique. The Cu(I)/Cu(II) redox arrangement has been observed to exhibit characteristics consistent with a quasi-reversible method. Furthermore, the catalytic activity of the Cu(I) complex was executed in the first-time synthesis of new tetrahydropyrimidine derivatives by treating various aryl nitriles with 2,2-dimethyl-1,3-propanediamine under conventional thermal conditions. A mechanism for the catalytic reaction was suggested and investigated by density functional theory (DFT).

Synthesis, characterization and antimicrobial activity of new thioxo tetrahydropyrimidine derivatives

A sequence of thioxotetrahydropyrimidenes derivatives, N-(4-chloro/methoxyphenyl)-3-formyl-6-methyl-4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides (4a-l) were synthesized by the formylation of N-(4-chloro/methoxyphenyl)-6-methyl-4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides (3a-l) by dry dimethyl formamide (DMF) and phosphorous oxychloride at room temperature. Formerly, compounds (3a-l) were synthesized by the condensation of N-(4-chloro/methoxyphenyl)-3-oxobutanamide (1), various aromatic aldehydes (2a-f) and thiourea with catalytic amount of concentrated hydrochloric acid under reflux temperature. The structures of the synthesized various thioxotetrahydropyrimidenes have been characterized by using elemental analysis, Infrared, 1H-NMR, 13C-NMR spectroscopy and further supported by Mass spectroscopy. All the products have been screened for their in-vitro biological assay like antibacterial activity towards Gram-positive and Gram-negative bacterial strains and antifungal activity towards Aspergillus niger at a concentration of 40 µg/ml. It was showing that the compounds 4a, 4e, 4g, 4h, 4i and 4l displayed inspirational antibacterial and antifungal activity compared to the used reference standard.

Synthesis, evaluation of the cytotoxicity, apoptosis induction in AGS cell line and gene expression and molecular modeling studies of novel tetrahydropyrimidine derivatives

Cancer is a complex disease that remains a leading cause of death worldwide owing to the lack of effective and efficient drugs. Compounds known as tetrahydropyrmidine have shown great potential as anti-cancer agents. Here, novel compounds based on tetrahydropyrimidine scaffold were successfully synthesized by the multicomponent reaction of Biginelli reaction. The biological functions of the selected compounds in AGS cells, including cytotoxicity, apoptosis induction, caspase3/7 activity, and gene expressions such as P53, CDNK2A, and Caspase-8/9, were evaluated. All synthesized compounds displayed moderate to good activity against the AGS cell line. Four compounds 4c, 4d, 4i, and 4 m induced apoptosis and activated caspase-3/7. Among them, compound 4c exhibited the highest cytotoxicity (IC50 = 69.60 µM), apoptosis induction, and caspase-3/7 activity. In comparison to other compounds, 4i showed a higher stimulation in the expression of P53, CDNK2A, and Caspase 9 genes. However, even though there was an increasing trend in the genes related to apoptosis and the cell cycle pathways, and the expression of caspase 9 was higher than caspase 8, these differences were not large enough to be significant. In addition, molecular docking studies and MD simulations were carried out to recognize the likely mechanism of the anti-cancer effect. Findings of docking revealed compounds fitted in the active site with good binding. MD simulations showed that compounds 4c, 4d and 4 m made a steady complex with the Eg5 enzyme. Thus, the possible mechanism of anti-cancer activity of these compounds can be through inhibition of the Eg5 enzyme.

Determination of enantiodiscrimination of chiral acids and tetrahydropyrimidine derivatives by bis-thiourea derived chiral solvating agents by NMR spectroscopy

Synthesis of four derivatives of chiral bis-thiourea have been prepared from (S)-(1- isocyanatoethyl)benzene and diamines. The bis-thiourea derivatives were scanned as Chiral Solvating Agents (CSA) for detecting discrimination of optically pure acids by 1H NMR spectroscopy. Addition of amine during NMR experiments was found essential to effect deprotonation of carboxylic acid substrates. The present CSA were found to show effective chiral discrimination of neutral analytes such as tetrahydropyrimidine derivatives. Further they showed good molecular recognition in case of 1,4-dihydropyridine carboxylic acid, an intermediate of cardiovascular drug Benidipine-HCl and ibuprofen.

An improved eco-friendly and solvent-free method for the one-pot synthesis of tetrahydropyrimidine derivatives via Biginelli condensation reaction using ZrO2/La2O3 catalysts

The objective of the present study is focused on the facile synthesis of ZrO2/La2O3 catalyst and the catalytic performance was evaluated towards one-pot synthesis of tetrahydropyrimidne derivatives through Biginelli condensation reaction. The synthesized catalyst was characterized by using FTIR, XRD, BET, SEM, EDX and UV-DRS techniques. All catalysts perform better than the without catalyst based reactions, which is the formation of tetrahydropyrimidne derivatives (IVa-n) conversion averaging 85–95 % at 50 °C temperature and 3–40 min under identical reaction conditions. Also, it maintains good stability. The relative ease of reducing the catalyst plus its porous nature are responsible for its performance. All the products were characterized by comparing their physical and spectral data including FTIR, 1H NMR, and ESI-MS with those of authentic compounds reported in the literature.

Synthesis, biological assessment, and computational investigations of nifedipine and monastrol analogues as anti-leishmanial major and anti-microbial agents.

Leishmaniasis includes a range of parasitic diseases caused by numerous types of the protozoan kinetoplastid parasite. Fungal and bacterial pathogens have led to infectious illnesses causing some main public health problem in current years. A series of dihydropyridine and tetrahydropyrimidine derivatives having fluoro, bromo, and nitro substituents at para-phenyl ring on C4 of dihydropyridine and tetrahydropyrimidine rings were synthesized. Then, anti-leishmanial and antimicrobial potencies of compounds were assessed. All compounds were synthesized via Hantzsch and Biginelli reactions. All derivatives were evaluated for their anti-leishmanial and antimicrobial activities. Moreover, docking and molecular dynamics simulation calculations of the compounds in PRT1 binding site were performed to report the results of anti-leishmanial and antimicrobial activities. Compounds 4a and 4b showed the highest anti-amastigote and anti-promastigote activities. Compound 4a revealed the highest antimicrobial activity against E. coli, P. aeruginosa, and C. albicans strains. In addition, compound 4c showed the highest activity against S. aureus. The fluoro, bromo, and nitro substituents in para-position of phenyl group at C4 of dihydropyridine and tetrahydropyrimidine moieties as well as the bulk and length of the chain linking to the ester moieties are essential for anti-leishmanial and anti-microbial activities of these derivatives. Low cytotoxicity was shown by most of derivatives against macrophages. The molecular docking studies were in agreement with in vitro assay. Moreover, hydrogen binds, RMSF, RMSD, and Rg, strongly showed the steady binding of 4a and 4b compounds in PRT1 active site.

Trimethylsilyl chloride catalyzed synthesis of fluoro substituted tetrahydropyrimidines: Molecular docking and antidiabetic studies

A novel series of tetrahydropyrimidine derivatives containing azepino indole and aryl substitution was achieved by a multicomponent synthetic approach using Biginelli condensation. Various catalysts were employed in the reactions for yield increment but trimethylsilyl chloride gave the highest yield. Moreover, all synthesized molecules were checked for in vitro antidiabetic potential. In addition, molecular docking of these synthesized molecules was studied using barley alpha-amylase isozyme 1 (amy1) (1RPK). The result revealed that compounds 4a and 4c have a good inhibitory potential.

Synthesis and antimicrobial activity of new 1,2,3,4-tetrahydropyrimidine-5-carbonyl glycinate silver nanoparticle derivatives

A series of silver nanoparticle (AgNPs) with 1,2,3,4 tetrahydropyrimidine derivatives were synthesized and elucidate their structures using physical and spectroscopic techniques (UV.VIS, FTIR, NMR, X-ray diffraction, and SEM). Each of these novel compounds produced spectroscopic data that matched the suggested structures. Pathogenic bacteria and C.albicans were used as test subjects for the antimicrobial activity by using agar well diffusion assay. The AgNPs agents show intermediate activity antimicrobial activities as compare with ciprofloxacin as positive control.

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors.

The urease enzyme, a metalloenzyme having Ni2+ ions, is recognized in some bacteria, fungi, and plants. Particularly, it is vital to the progress of infections induced by pathogenic microbes, such as Proteus mirabilis and Helicobacter pylori. Herein, we reported the synthesis of a series of tetrahydropyrimidine derivatives and evaluated their antiurease activity. Finally, quantitative and qualitative analyses of the derivatives were performed via in silico studies. Urease inhibitory activity was determined as the reaction of H. pylori urease with different concentrations of compounds, and thiourea was used as a standard compound. Docking and dynamics methodologies were applied to study the interactions of the best compounds with the amino acids in the active site. All compounds showed good to excellent antiurease activity. The potent compounds were not cytotoxic against the HUVEC normal cell line. Based on the docking study, compound 4e with the highest urease inhibitory activity (IC50 = 6.81 ± 1.42 µM) showed chelates with both Ni2+ ions of the urease active site. Further, compound 4f displayed a very good inhibitory activity (IC50 = 8.45 ± 1.64 μM) in comparison to thiourea (IC50 = 22.03 ± 1.24 μM). The molecular docking and dynamics simulation results were correlated with the in vitro assay results. Moreover, the derivatives 4a-n followed Lipinski's rule-of-five and had drug-likeness properties.

Microwave-assisted synthesis of bioactive tetrahydropyrimidine derivatives as antidiabetic agents.

Abstract.

New phosphorus-containing polycycles with a spiroamine group

Aim. To synthesize hexahydrospiro[cyclopropane-1,10’-pyrido[1,2-c]quinazoline] and 2-λ5-benzo[f][1,4,2]diazaphosphepine derivatives – new N-P containing heterocyclic compounds with the 6-azaspiro[2.5]octane fragment.Results and discussion. A new analog of the powerful electrophilic reagent – “Alder dimer” ‒ was obtained from the interaction of triflic anhydride and spiro(4-cyclopropane) piperidinyl formamide, and further used to synthesize new Nʹ-PV- and PIII-substituted Νʹ-phenyl, Νʹʹ-hexahydro(azaspiro)octylformamidinium salts – precursors of acyclic N-phosphorylated diamino carbenes with a spiroamine group. It has been shown that acyclic N-phosphorylated diaminocarbenes are transient species affording various products. The structure of the final product is primarily determined by nature of the phosphorus-bearing substituent, namely a phosphoryl or phosphino-group. N-PV-substituted carbene undergoes a 1,2-phosphorus shift with the formation of (selenophosphoryl)formamidine in a high yield. For N-PIII-substituted carbene a compatible 1,3-H shift also occurs with the formation of an intermediate azomethine ylide converted into a new heterocyclic system – hexahydrospirocyclopropane -1,10’-pyrido[1,2-c]quinazoline. Under the action of acid an unexpected further expansion of the 6-member ring occurs with the formation of a diazepine derivative.Experimental part. The reaction of Alder reagent with N-PV-seleno phosphoryl arylamides afforded N-phosphorus substituted formamidinium salts, which are easily reduced to PIII analogues. In addition to the corresponding formamidines, the new N-phosphorylated spiroamine-containing polycyclic system was isolated from the reaction mixture formed by the deprotonation of such salts with a strong non-nucleophilic base.Conclusions. The Alder reagent approach allows synthesizing precursors of acyclic formamidine carbenes with the spiroamine group. Such carbenes are unstable. By converting these compounds N-PIII-substituted tetrahydropyrimidine and diazaphosphepine derivatives with the 6-azaspiro[2.5]octane fragment have been obtained for the first time.

A novel and efficient synthesis of 1, 2, 3,4-tetrahydropyrimidine carboxamide derivatives by Biginelli reaction and their in vitro antibacterial activity

Introduction and Aim: An efficient aspect of two step synthesis of tetrahydro pyrimidine carboxamide derivatives were developed by Biginelli reaction. The two-step synthesized 1,2,3,4-tetrahydropyrimidinecarboxamide compounds were evaluated by In-vitro studies like antifungal and bacterial activities. Few compounds were shown excellent zone of inhibition against fungal and Microbial activities. In this study showed significant effect of antifungal and bacterial action against tetrahydro pyrimidine derivatives. Materials and Methods: In this procedure to synthesize 1,2,3,4-tetrahydropyrimidinecarboxamide derivatives, ethyl acetoacetate, cytosine, para-toluene sulphonic acid and ethanol were used. Results: The synthesized compounds of 1,2,3,4-tetrahydropyrimidine carboxamide derivatives through Biginelli reaction used an efficient catalyst such as para-toluene sulphonic acid and solvent ethanol. In this study tested compounds have developed into two step protocol for synthesis of diversely substituted novel pyrimidines. Conclusion: In this study the synthesized 1,2,3,4-tetrahydropyrimidine carboxamide (THPC) shows significant inhibiting action against Gram +ve, Gram –ve bacterial and fungal growth.

In silico Study and Solvent-free one-pot Synthesis of Tetrahydropyrimidine derivatives by Mechanochemistry Approach for Targeting Human Neutrophil Elastase against Lung Cancer.

Pyrimidine derivative has evinced its biological importance in targeting lung cancer by inhibiting neutrophil elastase. All THPM derivatives were synthesized by the grindstone method at ambient temperature followed by molecular docking study for efficient binding interaction of THPM compounds by targeting human neutrophil elastase (HNE) (PDB ID: 5A0A) and In-silico ADMET study using PkCSM. Moreover, all synthesized compounds were characterized by spectroscopy techniques and screened for anti-cancer activity using in vitro HNE assay kit. We reported a one-pot solvent-free mechanochemical approach for synthesizing tetrahydropyrimidine (THPM) derivatives from various aromatic aldehydes, ethyl cyanoacetate, and urea followed by in silico study and evaluation against human neutrophil elastase (HNE) for treatment of lung cancer. We calibrated the best molecules that bound to specific targets more efficiently using a molecular docking approach and provided the desired efficacy. In-silico ADMET studies revealed that all best-scored compounds had drug-like characteristics for potential use as human neutrophil elastase inhibitors (HNE) in lung cancer treatment. Additionally, the in vitro studies revealed that compounds 1, 2, and 8 show potent HNE inhibitory activity for lung cancer treatment. In a nutshell, the tetrahydropyrimidine (THPM) scaffold and its derivatives may serve as potential HNE inhibitors for the development of a promising anti-cancer agent.

Structure-Based Designing, Solvent Less Synthesis of 1,2,3,4-Tetrahydropyrimidine-5-carboxylate Derivatives: A Combined In Vitro and In Silico Screening Approach.

Objective: In this study, small molecules possessing tetrahydropyrimidine derivatives have been synthesized having halogenated benzyl derivatives and carboxylate linkage. As previously reported, FDA approved halogenated pyrimidine derivatives prompted us to synthesize novel compounds in order to evaluate their biological potential. Methodology: Eight pyrimidine derivatives have been synthesized from ethyl acetoacetate, secondary amine, aromatic benzaldehyde by adding catalytic amount of CuCl2·2H2O via solvent less Grindstone multicomponent reagent method. Molecular structure reactivity and virtual screening were performed to check their biological efficacy as an anti-oxidant, anti-cancer and anti-diabetic agent. These studies were supported by in vitro analysis and QSAR studies. Results: After combined experimental and virtual screening 5c, 5g and 5e could serve as lead compounds, having low IC50 and high binding affinity.

Determination of electronic characteristics of tetrahydro pyrimidine derivatives and investigation of usability as anti-corrosion

Corrosion of metallic structures is a serious problem in most industries worldwide. This problem can be controlled by the addition of chemicals capable of adsorption onto the metal surface. The metal can be isolated from the corrosive environment. These chemicals are often selected from groups containing free electron pairs and / or π electrons, which are rich in functional groups. In this study, electronic structures Highest Molecular Orbital (HOMO), Lowest Occupied Molecular Orbital (LUMO), MEP, energy gap (ΔE), ionization potential (I), electron affinity (A), chemical structure of pyrimidine derivative compounds containing unpaired electron pairs, π electrons, functional groups such as N, O and S hardness and softness (S), general electrophilic index (ω), transmitted electron fraction index (ΔN) and recovery (backEback-donation) properties of quantum chemical calculation methods to investigate the properties of the selected compounds in this direction and adsorbed to the surface with the quantum chemical calculation methods. The aim of this study is to determine the efficiency of synthesized compounds as anti-corrosion materials and to provide new gains to the industry in this sense.

The novel tetrahydropyrimidine derivative as inhibitor of SARS CoV-2: synthesis, modeling and molecular docking analysis

N-(1,3-Benzothiazol-2-yl)-N-(1,4,5,6-tetrahydro-1H-pyrimidine-2-yl) amine was synthesized and characterized by elemental analysis, FT-IR, NMR and X-ray single crystal diffraction. The compound structure belongs to the triclinic system with the P-1 space group with unit cell parameters a = 11.9290(4), b = 13.2547(4) and c = 15.3904(5) Å. Hirhsfeld surface analysis is performed to revealintermolecular interactions with these interactions. The molecular structure, vibrational spectroscopic data and HOMOs and LUMOs analyses were calculated by using the DFT/B3LYP method with the 6-311 + G(d,p)) basis set. Some of pharmacokinetic parameters and drug-likeness properties of the compound were also performed. Besides these, the present work is a searching to test N-(1,3-benzothiazol-2-yl)-N-(1,4,5,6-tetrahydro-1H-pyrimidine-2-yl) amine as an inhibitor for the SARS-CoV-2. For this aim, the molecular docking analysis of the synthesized compound was applied along with Favipiravir. Besides the docking results, ADMET properties of the compound were also calculated. Communicated by Ramaswamy H. Sarma

Design, Green Synthesis, and Biological Evaluation of New Substituted Tetrahydropyrimidine Derivatives as Acetylcholinesterase Inhibitors

A series of novel tetrahydropyrimidin-4-yl)pyridine derivatives 6(a–h) have been designed and synthesized as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The chemical structures of all newly synthesized compounds were characterized by spectroscopic methods (IR, 1H NMR, 13C NMR) and elemental analyzes. The in vitro studies showed that all the synthesized derivatives showed significant BChE inhibitory activity more potent than donepezil as the standard (IC50 values less than 0.1 µM). All the target compounds demonstrated good AChE inhibitory effects comparable with donepezil as the reference drug with IC50 values ranging from 0.08 to 0.1 µM. The best results were obtained by 4-methyl substituted derivative 6d with IC50 value of 0.082 µM which was comparable with AChE inhibitory effects of donepezil (IC50 = 0.079 µM).

Self-reversible mechanofluorochromism of AIE-active C6-unsubstituted tetrahydropyrimidine derivatives.

The mechanofluorochromic properties of three C6-unsubstituted tetrahydropyrimidines (THPs), namely, diethyl 1,2,3-triphenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (1), dimethyl 1,2,3-tri(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (2), and dimethyl 1,2,3-tri(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (3), with aggregation-induced emission (AIE) characteristics were investigated. The blue-green/cyan emissions of the three THPs can be switched reversibly by a grinding–fuming/heating process, with the change in maximum emission wavelength (λem) up to 57 nm and the decrease of fluorescence quantum yields (ΦF). Interestingly, the green or cyan fluorescence of the ground powder (λem is located at 481, 470 and 477 nm for 1b, 2 and 3, respectively) can spontaneously recover to the original blue (λem is located at 434, 442 and 436 nm for 1b, 2 and 3, respectively) in 1–2 d at room temperature without any external stimulation. X-ray single-crystal diffraction, powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) studies demonstrate that the conversion between the molecular packing modes is the main reason for the mechanofluorochromism and the spontaneously recoverable mechanofluorochromism relates to intermolecular hydrogen bonds. The sensitively and/or spontaneously recoverable mechanofluorochromism of these THPs is expected to have great potential in sensing, optical recording and self-healing fluorescent materials.

On water synthesis of the novel 2-oxo-1,2,3,4-tetrahydropyrimidines

A simple on water approach for the synthesis of novel tetrahydropyrimidine (THPM) derivatives has been developed under a green and sustainable fashion. For the first time, a deuterated Biginelli’s hybrid was synthesized. Novel THPMs are suitable for further derivatization and could be an excellent toolkit for lead-oriented synthesis and/or cross-coupling reactions. • On water approach towards 2-oxo-1,2,3,4-tetrahydropyirmidines. • For the first time Biginelli deuterated compound is synthesized. • Olefinated Biginelli hybrids could be an excellent toolkit for lead-oriented synthesis. • Achieved outcomes will be a foundation for the future development of the Bignelli chemistry.

Design and Rapid Microwave Irradiated One-Pot Synthesis of Tetrahydropyrimidine Derivatives and Their Screening In Vitro Antidiabetic Activity

A rapid and efficient method has been developed for one-pot synthesis of some newly designed tetrahydropyrimidine derivatives with aid of 1,3,4-oxadiazole containing aldehyde, substituted acetoacetanilide and thiourea/guanidine in the occurrence of microwave irradiation. The significant yield of products, atom economy, less time consuming, and catalyst-free synthesis were considered preferences of microwave irradiation. All synthesized compounds were characterized by 1H NMR, 13C NMR, IR, and mass spectrometry techniques. All synthesized compounds were evaluated bioassay for in vitro antidiabetic screening viz α-amylase inhibition strategy and checked their potency against standard reference drug acarbose.