Pyrimidine Derivatives Research Articles

Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies

A new efficient and versatile one-pot three-component synthesis of substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives has been developed. It is based on a multistep cascade reaction from 2-aminothiophenes and 2-hydroxy-4-oxobut-2-enoic acids, and derivatives of cyanoacetic acid catalyzed by diisopropylethylamine. As a result, novel pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives (21 compounds) were synthesized in a mild reaction conditions with a high yield. The structures of the developed compounds were confirmed by NMR and elemental analysis. The influence of electron-withdrawing or electron-donor substituents on the antitumor activity of the developed compounds has been identified. In vitro screening analysis of 21 compounds revealed six lead candidates (12aa, 12dc, 12hc, 12ic, 12lb, and 12mb) that demonstrated the most significant antitumor activity against B16-F10, 4T1 and CT26 cells. Necrosis/apoptosis assay showed that apoptosis was the predominant mechanism of cell death. Molecular docking analysis revealed several potential targets for tested compounds, i.e. phosphatidylinositol 5-phosphate 4-kinase (PI5P4K2C), proto-oncogene serine/threonine-protein kinase (Pim-1), nicotinamide phosphoribosyltransferase (NAMPT) and dihydrofolate reductase (DHFR). The lead compound (12aa) can effectively induce cell apoptosis, possesses a high yield (98 %) and requires low-cost starting chemicals for its synthesis. In vivo experiments with melanoma-bearing mice confirmed that 12aa compound resulted in the significant tumor inhibition on 15 d after the therapy. In particular, tumor volume was ∼0.19 cm3 for 50 mg/kg versus ∼2.39 cm3 in case of untreated mice and tumor weight was ∼71.6 mg for 50 mg/kg versus ∼452.4 mg when considered untreated mice. Thus, our results demonstrated the high potential of the 12aa compound in the treatment of melanoma and can be recommended for further preclinical studies.

Design, synthesis and biological evaluation of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives as Mnk1/2 inhibitors

The Mnk-eIF4E axis plays a crucial role in tumor development, and inhibiting Mnk kinases is a promising approach for cancer therapy. Starting with fragment WS23, a series of 4-(indolin-1-yl)-6-substituted-pyrido[3,2-d]pyrimidine derivatives were designed and synthesized. Among these derivatives, compound 15b showed the highest potency with IC50 values of 0.8 and 1.5 nM against Mnk1 and Mnk2, respectively. Additionally, it demonstrated good selectivity among 30 selected kinases. 15b significantly suppressed MOLM-13 and K562 cell lines growth and caused cell cycle arrest. Furthermore, the Western blot assay revealed that 15b effectively downregulated the downstream proteins p-eIF4E, Mcl-1, and c-myc. Additionally, 15b exhibited remarkable stability in rat plasma and rat and human microsomes. In vivo anti-tumor activity study suggested that treatment with 15b suppressed tumor growth in LL/2 syngeneic models. These findings highlight the potential of 15b as a novel and potent Mnks inhibitor, which deserves further investigation.

Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors

The targeting of cyclin-dependent kinase 7 (CDK7) has become a highly desirable therapeutic approach in the field of oncology due to its dual role in regulating essential biological processes, encompassing cell cycle progression and transcriptional control. We have previously identified a highly selective thieno[3,2-d]pyrimidine-based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2-d]pyrimidine core to discover a novel series of CDK7 inhibitors with improved potency and pharmacokinetic (PK) properties. Through extensive structure–activity relationship (SAR) studies, compound 20 has emerged as the lead candidate due to its potent inhibitory activity against CDK7 and remarkable efficacy on MDA-MB-453 cells, a representative triple negative breast cancer (TNBC) cell line. Furthermore, 20 has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization.

Synthesis and in vitro antitumor evaluation of new thieno[2,3-d]pyrimidine derivatives as EGFR and DHFR inhibitors

New thienopyrimidine derivatives 2–16 have been synthesized and their in vitro cytotoxicity was evaluated against five different human cancer cell lines HCT-116, Hela, MDA-MB-231, MCF7 and PC3. Compounds 6e, 7a, 7b, 7d, 10c and 10e displayed the highest antitumor activity against all tested cell lines compared to Doxorubicin. Enzyme inhibition assay revealed that compounds 6e and 10e showed high inhibitory activity against EGFR-TK, with IC50 values of 0.133 and 0.151 µM, compared to Olmutinib (IC50 = 0.028 µM); while the highest DHFR inhibitory activity was shown by compounds 7d and 10e with IC50 values of 0.462 and 0.541 µM, compared to Methotrexate (IC50 = 0.117 µM). Cell cycle analysis following a flow cytometric study using colorectal HCT-116 cancer cell line proved that compound 6e induced cell cycle arrest in G0-G1 phase, while compound 10e arrested the cell cycle at both G0-G1 and S phases. Additionally, both compounds (6e and 10e) were potently able to induce apoptosis in HCT-116 cell line. Docking results of compounds 6e and 10e into the pocket of EGFR active site showed their similar main binding features with Olmutinib, while compounds 7d and 10e showed only moderate fitting into DHFR compared to methotrexate. In silico studies revealed that most of the tested compounds obeyed Lipinski’s RO5 and showed positive drug likeness scores.

Structure-Based Design of Novel Thiazolone[3,2-a]pyrimidine Derivatives as Potent RNase H Inhibitors for HIV Therapy.

Ribonuclease H (RNase H) was identified as an important target for HIV therapy. Currently, no RNase H inhibitors have reached clinical status. Herein, a series of novel thiazolone[3,2-a]pyrimidine-containing RNase H inhibitors were developed, based on the hit compound 10i, identified from screening our in-house compound library. Some of these derivatives exhibited low micromolar inhibitory activity. Among them, compound 12b was identified as the most potent inhibitor of RNase H (IC50 = 2.98 μM). The experiment of magnesium ion coordination was performed to verify that this ligand could coordinate with magnesium ions, indicating its binding ability to the catalytic site of RNase H. Docking studies revealed the main interactions of this ligand with RNase H. A quantitative structure activity relationship (QSAR) was also conducted to disclose several predictive mathematic models. A molecular dynamics simulation was also conducted to determine the stability of the complex. Taken together, thiazolone[3,2-a]pyrimidine can be regarded as a potential scaffold for the further development of RNase H inhibitors.

Synthesis, Antimicrobial Assessment of Chalcones and their Pyrimidine Derivatives

The aim of the study was to transform chalcones synthesized to their respective pyrimidine derivatives which was successful. The synthesized compounds were subjected to antimicrobial assay against bacteria and fungi organisms screened, however sample ZB had inhibitory effect against bacterial strains. Sample ZB is active against S. aureus and E. coli with an MIC of 5 and 1 mg/mL with a zone of inhibition 11 and 23 mm respectively. When compared to sample B had activity against E. coli with a minimum inhibitory concentration of 0.1 mg/mL and zone of inhibition of 20 mm. Modification of 4-(2-hydroxyphenyl)-6-(2,3,4-trimethoxyphenyl)pyrimidin-2-one to pyrimidin-2-one increases spectrum of activity against gram positive bacterial S. aureus. Sample A inhibits B. subtilis and P. marneffei with an MIC of 10 mg/mL with a zone of inhibition of 14 mm and 20 mm respectively. Transformation of Sample A to 2-aminopyrimidine drastically abolish the antibacterial and antifungal effect. Sample ZA is inactive against bacteria and fungi organisms, when compared to ZB which inhibits S. aureus and E. coli. The spectral analysis revealed that the samples are in line with literature and had a melting point (100-103oC and 115-117oC) for sample ZA and ZB respectively. The starting materials had a melting point (55-57oC and 95-100oC) for Sample A and B respectively.

Synthesis of Pyrano[2,3-d]Pyrimidine Diones Catalyzed by Cobalt-Doped Iron Tartrate Nanomaterial: A Sustainable and Efficient Approach

This study presents a novel and environmentally sustainable approach for the one-pot multicomponent green synthesis of pyrano[2,3-d]pyrimidine dione derivatives. The devised procedure involves a three-component condensation of aldehydes, malononitrile, and barbituric acid, employing a nanomaterial catalyst in the form of cobalt-doped iron tartrate. This catalyst, characterized by its nanoscale dimensions, demonstrates exceptional reusability and water solubility, contributing to its eco-friendly profile. The synthesis is conducted under reflux conditions, optimizing the reaction efficiency. Key attributes of the proposed protocol include the use of a non-toxic, cost-effective, and readily available catalyst. The high atom economy of the reaction signifies minimal waste generation, enhancing the sustainability of the synthetic process. Additionally, the reaction features a short duration, aligning with the principles of efficiency and resource conservation. Notably, the utilization of water as the solvent further enhances the green approach, minimizing the environmental impact. This innovative synthesis protocol not only addresses the growing demand for environmentally conscious methodologies but also showcases the potential for scalable and practical applications in organic synthesis. The integration of a reusable nanomaterial catalyst, coupled with the adoption of water as a solvent, positions this approach as a promising advancement in the pursuit of sustainable and green chemical practices. The study provides valuable insights into the development of efficient and environmentally benign synthetic routes for the production of pyrano[2,3-d]pyrimidine dione derivatives, paving the way for the exploration of greener alternatives in the realm of organic chemistry.

Design, Docking, Characterisation, and Synthesis of Pyrimidine Derivatives for Antidepressant Activity.

According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives. The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent. The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity. The MolDock scores of the derivatives ranged from -147.097 to -182.095, whereas of active ligand IXX_801 was -115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (-101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively. Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.

K2S2O8 promoted C–H direct thiocyanation of pyrrolo[2,3-d]pyrimidine derivatives with ammonium thiocyanate

K2S2O8-promoted highly efficient and site-selective direct C–H thiocyanation of pyrrolo[2,3-d] pyrimidine (7-DAP) derivatives with NH4SCN at room temperature was developed. This protocol exhibits broad substrate scope, good functional group tolerance and operational simplicity. This methodology is favourable for the functional modification of pyrrolo[2,3-d] pyrimidines scaffold and enriches the library of thiocyanated 7-DAP compounds for the further biological evaluation. Importantly, the thiocyanated pyrrolo[2,3-d]pyrimidines are readily converted to other potential pharmaceutically important sulfur-containing motifs.

Dynamics of gonadotropin and thienopyrimidine derivative TP03 effects on ovulation and ovarian steroidogenesis in Follimag-stimulated immature female rats

BACKGROUND: Gonadotropin preparations, particularly human chorionic gonadotropin (hCG), are commonly used to induce ovulation and treat reproductive disorders in women, albeit with associated side effects. Low-molecular-weight allosteric agonists of the luteinizing hormone receptor (LHR), such as thieno[2,3-d]pyrimidine derivatives, offer a potential alternative. AIM: This study aims to compare the effects of thieno[2,3-d]pyrimidine TP03 and hCG on ovarian weight, corpus luteum formation, and plasma levels of estradiol, progesterone, and luteinizing hormone in immature female rats pre-treated with Follimag®. It also examines their impact on ovarian gene expression related to LHR and steroidogenesis. MATERIALS AND METHODS: TP03 and hCG were administered 48 h after the Follimag® injection at a dose of 20 mg/kg (i.p.) and 15 IU/rat (s.c.), respectively. Parameters were assessed at 1, 2, 4, 8, 16, and 24 h after TP03 and hCG administration. Plasma hormone levels were measured via ELISA, and ovarian gene expression was analyzed using real-time PCR. RESULTS: TP03 increased ovarian weight, progesterone levels in the blood, and expression of steroidogenic genes encoding the cholesterol-transporting protein StAR and the cytochromes CYP11A1 and CYP17A1. TP03 also stimulated corpus luteum formation (16–24 h after treatment). The temporal dynamics of its stimulating effects were similar to those of hCG, although their magnitude was slightly inferior to those of gonadotropin. TP03-induced decrease in blood estradiol levels and aromatase gene expression in the ovaries was also more moderate. Unlike hCG, which suppressed LHR gene expression 8 h after treatment, TP03 maintained a high LHR gene expression, preserving ovarian sensitivity to endogenous luteinizing hormone. CONCLUSIONS: TP03 exhibits potential as an ovulation inducer with milder stimulating effects on ovarian steroidogenesis than hCG, which reduces the risks of developing ovarian hyperstimulation syndrome and resistance to gonadotropins.

Synthesis and Study of Steering of Azido-tetrazole Behavior in Tetrazolo[1,5-c]pyrimidin-5-amine-Based Energetic Materials.

Tetrazoles and their derivatives are essential for compound synthesis due to their versatility, effectiveness, stability in air, and cost-efficiency. This has stimulated interest in developing techniques for their production. In this work, four compounds, tetrazolo[1,5-c]pyrimidin-5-amine (1), N-(4-azidopyrimidin-2-yl)nitramide (2), tetrazolo[1,5-c]pyrimidin-5(6H)-one (3), and tetrazolo[1,5-a]pyrimidin-5-amine (4), were obtained from commercially available reagents and straightforward synthetic methodologies. These new compounds were characterized by infrared (IR), 13C, and 1H NMR spectroscopy, differential scanning calorimetry (DSC), and single-crystal X-ray diffraction. The solvent, temperature, and electron-donating group (EDG) factors that were responsible for the steering of azido-tetrazole equilibrium in all compounds were also studied. In addition, the detonation performance of the target compounds was calculated by using heats of formation (HOFs) and crystal densities. Hirshfeld surface analysis was used to examine the intermolecular interactions of the four synthesized compounds. The results show that the excellent properties of 1-4 are triggered by ionic bonds, hydrogen bonds, and π-π stacking interactions, indicating that these compounds have the potential to be used in the development of high-performance energetic materials. Additionally, DFT analysis is in support of experimental results, which proved the effect of different factors that can influence the azido-tetrazole equilibrium in the synthesized pyrimidine derivatives in the solution.

One-pot multicomponent synthesis and antimicrobial evaluation of steroidal benzo[4,5]imidazo[1,2-a]pyrimidines with hemolytic assay and molecular docking studies

A novel class of steroidal benzo[4,5]imidazo[1,2-a]pyrimidine derivatives was successfully synthesized via one-pot three component synthesis of pregnenolone, malononitrile, and 2-aminobenzimidazole using triethylamine as a catalyst. All the synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR and mass spectra. The synthesized compounds were tested for antifungal and antibacterial activities, and strong antifungal and antibacterial activities were observed in compounds 6 and 9. The antifungal activity of the synthesized compounds was screened against C. albicans, C. glabrata, and C. tropicalis. Compound 6 exhibited a MIC of 420 μg/ml for C. albicans and C. glabrata whereas C. tropicalis showed a slightly higher MIC of 440 μg/ml. Compound 9 gave an MIC of 465 μg/ml for C. albicans, 470 µg/ml for C. glabrata while 485 μg/ml for C. tropicalis. The antibacterial activity against gram-positive (E. coli) and gram-negative (S. aureus) was investigated. Compound 6 showed MIC 12 μg/ml for E. coli and 12 μg/ml for S. aureus. While compound 9 showed MIC 6 μg/ml and 12 μg/ml for E. coli and S. aureus respectively. The hemolytic assay was also performed on human red blood cells. Compounds 6, 8 and 9 were found to be least toxic to human RBCs, showing 7.32 %, 7.27 % and 7.68 % cell inhibition at MIC, respectively. Furthermore, molecular docking analysis was carried out.

Design, synthesis and evaluation of a pyrazolo[3,4-d]pyrimidine derivative as a novel and potent TGFβ1R1 inhibitor

The transforming growth factor β1 (TGFβ1)/SMAD signaling pathway regulates many vital physiological processes. The development of potent inhibitors targeting activin receptor-like kinase 5 (ALK5) would provide potential treatment reagents for various diseases. A significant number of ALK5 inhibitors have been discovered, and they are currently undergoing clinical evaluation at various stages. However, the clinical demands were far from being met. In this study, we utilized an alternative conformation-similarity-based virtual screening (CSVS) combined with a fragment-based drug designing (FBDD) strategy to efficiently discover a potent and active hit with a novel chemical scaffold. After structural optimization in the principle of group replacement, compound 57 was identified as the most promising ALK5 inhibitor. Compound 57 demonstrated significant inhibitory effects against the TGF-β1/SMAD signaling pathway. It could markedly attenuate the production of extracellular matrix (ECM) and deposition of collagen. Also, the lead compound showed adequate pharmacokinetic (PK) properties and good in vivo tolerance. Moreover, treatment with compound 57 in two different xerograph models showed significant inhibitory effects on the growth of pancreatic cancer cells. These results suggested that lead compound 57 refers as a promising ALK5 inhibitor both in vitro and in vivo, which merits further validation.

Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-d]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that (S)-36 exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability (F = 59.6%). In the MOLM-13 subcutaneous xenograft model, (S)-36 could significantly suppress the tumor progression with a TGI of 67.81% at an oral administration dosage of 10 mg/kg without exhibiting obvious toxicity. Mechanistically, (S)-36 could robustly inhibit the PI3K/AKT pathway for significant suppression of cell proliferation and remarkable induction of apoptosis both in vitro and in vivo. Thus, compound (S)-36 represents a promising PI3Kδ inhibitor for the treatment of acute myeloid leukemia with high efficacy.

Novel Isoxazolylpyrimidine Derivatives: Design, Synthesis, Antifungal Activity and In‐Silico Studies

AbstractThe advancement of environmentally friendly chemical synthesis in both academic and corporate research has recently taken on enormous relevance. Pesticides are substances, either chemical or biological, that are used to get rid of or lessen the impact of pests. To control the fungi in crops a new set of isoxazolylpyrimidine derivatives were planned, synthesized, and characterized. The compounds indicated were synthesized in high yields, and their structures were determined using elemental analysis, 1H NMR, 13C NMR, and LCMS. HPLC was used to assess the purity of the synthesized molecules, and the purity of some compounds were found to be >98 % a/a while a couple were found to be >95 % a/a. The synthesized compounds were assessed for their antifungal activity. Among these, compounds 5d, 5h, and 5l exhibit substantial antifungal action and considerably suppress the growth of Rhizoctonia solani, Sclerotium rolfsii, and Macrophominaphaseolina. Macrophominaphaseolina inhibition percentages were 77.60, 70.49, 69.03, Sclerotium rolfsii inhibition percentages were 78.73, 74.03, 68.44, and Rhizoctonia solani inhibition percentages were 81.77, 76.29, and 71.01 for compounds 5 d, 5 h and 5 l respectively. The plausible mechanism of fungal inhibitory activities of rationally designed isoxazolyl pyrimidine derivatives is attributed to the blocking of the oxygen activation of HEME iron in membrane‐bound 14α‐demethylase. The presence of pyrimidine unit in designed materials is a vital factor for inducing antifungal activities, which was further corroborated through the density functional theory (DFT),molecular docking studies and molecular dynamics simulation studies.

Synthesis and Antimicrobial Activity of New Dihydropyrazolo[1,5-a]pyrimidine Derivatives

Synthesis and Antimicrobial Activity of New Dihydropyrazolo[1,5-a]pyrimidine Derivatives

A novel boron-conjugated SRC inhibitor for Proton Boron Capture Therapy in glioblastoma treatment

The ability of protons to deliver the maximum dose at the tumor region can work synergistically with boron atoms to emit alpha particles, enhancing therapy effects with less damage to healthy tissue. Protons and boron nuclear fusion reaction is the principle for the so-called Proton Boron Capture Therapy, that can contribute to high therapy efficiency by using smaller flux than conventional proton therapy, especially for radioresistant brain tumors such as glioblastoma. Glioblastoma is the most infiltrating and aggressive tumor of the brain with a very low life expectancy, ranging from 6 to 24 months. In this study we evaluated the protons combined effectwithanovelboron-conjugated compound, which is a pyrazolo[3,4-d]pyrimidine derivative, acting as SRC tyrosine kinase inhibitor. Indeed, this drug includes a boron cluster, that can be directed in tumor cells using the ATP-competitive mechanism of the pyrazolo[3,4 d]pyrimidine ring in activated SRC form of glioblastoma cells, achieving tumor uptake of boron for Proton Boron Capture Therapy reaction. This preliminary study showed interesting results that could offer important contributions for further experiments.

Design, Synthesis, Quantum Chemical Study, and Biological Screening of Novel Pyrimidine Derivatives as Potent Antibacterial and Anti-inflammatory Agents

Design, Synthesis, Quantum Chemical Study, and Biological Screening of Novel Pyrimidine Derivatives as Potent Antibacterial and Anti-inflammatory Agents

Design, Synthesis, and Biological Evaluation of a New Series of 2,4-Position Modified Pyrimidine Derivatives

Design, Synthesis, and Biological Evaluation of a New Series of 2,4-Position Modified Pyrimidine Derivatives

Induction of breast cancer cell apoptosis by novel thiouracil-fused heterocyclic compounds through boosting of Bax/Bcl-2 ratio and DFT study

Breast cancer is a common public health disease causing mortality worldwide. Thus, providing novel chemotherapies that tackle breast cancer is of great interest. In this investigation, novel pyrido[2,3-d]pyrimidine derivatives 3,4,(6a-c),(8a,b),9–20 were synthesized and characterized using a variety of spectrum analyses. The geometric and thermal parameters of the novel thiouracil derivatives 3,4,6a,(8a,b),11,12,17,18, 19 were measured using density functional theory (DFT) via DFT/B3LYP/6–31 + G(d,p) basis set. All synthesized compounds were evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) method using MCF-7 and MDA-MB-231 breast cancerous cells, compound 17 had the maximum anticancer activity against both breast cancerous cells, recording the lowest half-maximal inhibitory concentration (IC50) values (56.712 μg/mL for MCF-7 cells and 48.743 μg/mL for MDA-MB-231 cells). The results were confirmed in terms of the intrinsic mechanism of apoptosis, where compound 17 had the highest percentage in the case of both cancer cells and recorded Bax (Bcl-2 associated X)/Bcl-2 (B-cell lymphoma 2) ratio 17.5 and 96.667 for MCF-7 and MDA-MB-231 cells, while compound 19 came after 17 in the ability for induction of apoptosis, where the Bax/Bcl-2 ratio was 15.789 and 44.273 for both cancerous cells, respectively. Also, compound 11 recorded a high Bax/Bcl-2 ratio for both cells. The safety of the synthesized compounds was applied on normal WI-38 cells, showing minimum cytotoxic effect with undetectable IC50. Compounds 17, 11, and 19 recorded a significant increase of p53 upregulated modulator of apoptosis (PUMA) expression levels in the cancerous cells. The DFT method was also used to establish a connection between the experimentally determined values of the present investigated compounds and their predicted quantum chemical parameters. It was concluded that Compounds 17, 11, and 19 had anti-breast cancer potential through the induction of apoptotic Bax/Bcl-2 and PUMA expression levels.