Position Of Ring Research Articles

Topliss Modified Approach for Design and Synthesis of 1,3 Thiazines as Antimicrobials

In the series of 6-[4-substitutedphenyl]-4-phenyl-6H-1,3-thiazine-2-amines and N-[6-(4-substitutedphenyl)-4-phenyl-6H-1,3-thiazine-yl]acetamides, substituents at fourth position of the phenyl ring were selected according to the Topliss modified approach and synthesized initial set of compounds. The antimicrobial screening revealed that compounds with methoxy substituent having negative sigma (-0.04) and negative pi (-0.27) values are good antimicrobials showing low minimum inhibitory concentration (MIC). Based on the observation hydroxyl group with more negative sigma (-0.61) and pi (-0.37) values was selected to synthesize second set compounds and were found better antimicrobials than the initial set of compounds. The study revealed that electron donating polar substituents at fourth position of the phenyl ring are required to improve antimicrobial potential in the series of 6-[4-substitutedphenyl]-4-phenyl-6H-1,3-thiazine-2-amines and N-[6-(4-substitutedphenyl)-4-phenyl-6H-1,3-thiazine-yl]acetamides.

Current Advances in Synthesis and Therapeutic Applications of Thiazole and its Derivatives

Thiazole, a five-membered heterocyclic compound with sulfur and nitrogen atoms, serves as a fundamental scaffold in medicinal chemistry. The aromatic nature and diverse substitution patterns of the thiazole ring system enable its extensive applications in drug development. Multiple synthetic routes, from classical Hantzsch synthesis to modern methods, yield varied thiazole derivatives under specific reaction conditions. The biological importance of thiazole-containing compounds extends to anticancer, antimicrobial, and antidepressant activities. Several thiazole-based drugs have demonstrated significant therapeutic effects - dasatinib and dabrafenib as antitumor agents target specific kinases to inhibit cancer cell growth, while ampicillin and myxothiazole exhibit broad-spectrum antimicrobial properties. Structure-activity relationship studies have revealed that substituents at different positions of the thiazole ring significantly influence the biological activity. For instance, attachment of thiourea linker at position 2 enhances anticancer properties, while aryl/alkyl substitutions affect chemical stability and pharmacokinetic properties. The mechanistic understanding of thiazole-based compounds has led to targeted drug development. Recent synthetic methods have produced novel thiazole derivatives with enhanced therapeutic properties, particularly in antimalarial activity where thiazolyl benzenesulfonamide carboxylates show promising results against Plasmodium falciparum

Combinatorial Synthesis of Indole Derivatives as Anti-oomycetes Agents.

Developing high-efficiency and low-risk small-molecule green fungicide is the key to effective control of the plant pathogenic oomycetes. Indole is an important raw material for drug synthesis. Due to its unique structural skeleton, indole, and its derivatives have exhibited a wide range of biological activities. However, a study on the synthesis of novel indole derivatives as fungicidal agents against Phytophthora capsici has not yet been reported. The important intermediates 2a-c and 3a-c were synthesized in high yields by Vilsmeier- Haack and Knoevenagel reactions with indole as the lead compound. Furthermore, different substituted benzenesulfonyl groups were introduced into the NH position of the indole ring, and twelve indole derivatives (I-a-l) were prepared. Their structures were well characterized by 1H NMR, HRMS, and melting point. The results showed that 2-[(N-(4-nitrobenzenesulfonyl)-indole-3)-methylene]-diethyl malonate (I-d) and 2-[(N-(4-nitrobenzenesulfonyl)-5-cyanoindole-3)-methylene]-diethyl malonate (I-l) showed more anti-oomycete activity against P. capsici than the commercialized fungicide zoxamide, with corresponding EC50 values of 26.53, 23.48 and 28.16 mg/L, respectively, and the protective effect of the compounds against P. capsici in vivo further confirmed the above results. The preliminary structure-activity relationship showed that the formyl group modification at the C-3 position of the indole ring was acceptable, and the different anti-oomycete activities of R1 and R2 were significantly different, with R1 being 5-CN > H > 6-Me, and R2 being 4-NO2 > 3-NO2, H > 4-Me.

Synthesis and Mesomorphism of New Calamitic Schiff Bases-Ester Possessing Dialkylamino Terminal Substituent

: New calamitic liquid crystals, 4-[{[4-(diethylamino)phenyl]methylidene}amino]phenyl 4- alkyloxybenzoate (nEABAA) containing mesogenic core system which made of three phenyl rings were reported. The ester and imine linkages connected the phenyl rings. At one end of the molecule, the core system was attached to an alkyloxy chain with a variable length -(CH2)n- (where n = 2-10, 12, 14, 16 and 18). At the other end of the molecule, the para position of the phenyl ring is bonded to the diethylamino group. The molecular structure of the current compounds was confirmed by using spectroscopic methods. The mesomorphic characteristics of the title compounds were studied by using a differential scanning calorimeter and a polarizing optical microscope attached to a heating stage. Through observation under microscopy, it was found that all synthesized compounds exhibited only a single (nematic) phase. The exhibition of the monophase variance (nematic) in the current compounds is caused by the presence of the diethylamino group that is attached to the terminal position of the benzylideneaniline core system. The diethylamino group has caused the molecular breadth to increase and this results in a weaker overall lateral intermolecular attraction. Subsequently, it depressed the mesophase thermal stability of the compounds. Thermal properties of the current compounds were compared with the earlier reported analogous and the structure-property relationships of the current compounds have been inferred through this comparison.

Essential Structural Profile of Novel Adenosine Derivatives as Antiplatelet Aggregation Inhibitors based on 3D-QSAR Analysis

Aims: In this research, 3D-QSAR evaluation on a set of fresh purinoid compounds that we produced was conducted. This analysis aims to illustrate the correlation between the structure of purine and its ability to prevent platelet aggregation. Our findings could pave the way to discovering novel antithrombotic medications. Background: The incidence of cardiovascular disease triggered by the clumping of platelets poses a significant danger to human health. Purine derivatives are important molecules with antiplatelet aggregation activity. Objective: The objectives of this research are to establish the correlation between the structure of purine and its ability to prevent platelet aggregation. Such a correlation could aid in the development of innovative antithrombotic medications. Methods: In this study, 3D-QSAR investigation on a collection of 75 new purine derivatives, which we synthesized, was conducted, utilizing Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Results: Significant correlation coefficients (CoMFA, q2= 0.843, r2= 0.930, F value= 266.755, SEE= 0.165; CoMSIA, q2= 0.869, r2= 0.918, F value= 222.571, SEE= 0.179) were obtained, and assessed the model's predictive capabilities by validating it with the test set. Conclusion: Our findings indicate that the introduction of an appropriately sized structure at position 2 of the compound yields significant benefits. Conversely, the attachment of an excessively large group is detrimental. Direct attachment of a bulky substituent at C-6 of the compound is not feasible, and its activity increases when the structure with low electron cloud density is added. Moreover, the presence of a voluminous functional group at the 5' position of the compound is advantageous, and its activity will be further increased by the presence of hydrogen bond receptors in this region. These discoveries furnish significant comprehension for the formation of innovative structures with heightened efficacy.

Oxidative and non-oxidative photo-cyclization reaction of pyrazoles

A series of 5-(dimethoxyphenyl)-1,3-diphenylpyrazoles containing two methoxy groups on the different C5-aryl ring positions were synthesized and the electronic and steric effects, especially the position of the methoxy substitutions on the outcome of their photoreaction were investigated. Furthermore, the effect of the type and nature of solvent (chloroform or cyclohexane) in the progress of the photoreaction are also investigated. The photochemical results indicated the formation of two different phenanthridine products depending on the used solvent. Based on the proposed photo-induced electron-transfer mechanism in CHCl3 solution, the methoxy group on the ortho-position is eliminated during the photo-cyclization process and a chlorine atom is added to one of the allowed C5-aryl ring positions. While the observed photo-cyclization reaction in cyclohexane solvent occurs via complexation mechanism, which strongly requires the presence of the methoxy group on the ortho-position. In this case, complexation of the ortho-methoxy group to the N1-phenyl ring started the cyclization process, resulting in the formation of the phenanthridine photoproducts by elimination of this group. The phenanthridine products of both photoreactions are characterized by the analysis of their FT-IR, 1H NMR, 13C NMR, UV–Vis and Mass spectra. In addition, DFT computational studies were carried out to support the results of the experimental study.

Synthesis and Antibacterial Activity of Ficuseptine and its Derivatives: Determination of Structure–Activity Relationships

The indolizinium natural product ficuseptine produced by the tropical fig tree Ficus septica has been reported to have antibacterial properties. Herein, the synthesis of ficuseptine, ten analogues with differing aryl substituents, and two aryl regioisomers is reported. Despite several previous total syntheses, synthetically prepared ficuseptine has not been subjected to biological testing to confirm its activity. In our hands, ficuseptine was moderately active in Gram-positive B. spizizenii, with an MIC of 32 μg/mL, which was maintained for most aryl substituents. The position of the aryl rings was crucial, however, since regioisomeric ficuseptine analogues, mimicking related natural products, were found to be inactive. Finally, all ficuseptine derivatives were inactive (MIC >128 μg/mL) against Gram-negative E. coli. Understanding these Structure–Activity Relationships (SAR) is helpful for future studies to understand the molecule’s mechanism of action or further develop its antibacterial properties.

Optically Active Sulfoxides from 2(5H)-Furanone and Monoterpene Alcohols: Synthesis, Structure, and Antibacterial Activity

A series of optically active 5(S)-(l-bornyloxy)- and 5(S)-(l-menthyloxy)-2(5H)-furanones with an arylthio group at the C(4) position of the γ-lactone ring was synthesized and studied for its oxidation reactions with various reagents. Novel 2(5H)-furanone sulfoxides were obtained as mixtures of two diastereoisomers through the oxidation of arylthioethers with m-chloroperbenzoic acid (m-СРВА) or hydrogen peroxide in acetic acid. Individual stereoisomers of these sulfoxides were isolated using recrystallization and high-performance liquid chromatography (HPLC) and characterized by IR and NMR spectroscopy. The molecular structures of eight stereoisomerically pure compounds were confirmed by X-ray diffraction (XRD) analysis. The antibacterial activity of the novel sulfoxides against Staphylococcus aureus and Escherichia coli was assessed, with a number of compounds found to inhibit bacterial growth and biofilm formation in S. aureus.

Structural, catalytic, antimicrobial and antioxidant properties of Cu(II)-complexes prepared by o-hydroxy Schiff bases with fluorine and ethoxy substituents

Cu(II) complexes of three Schiff bases were synthesized and characterized via X-ray diffraction, Fourier transform infrared, and UV–vis spectroscopies. The Schiff bases act as bidentate ligands, chelating Cu(II) ions in seesaw coordination geometry. Changing the substituent types and positions creates various non-covalent interactions within the crystal packings, yielding notable topological differences. GC–MS analysis reveals that Cu(II) complexes induce 1.38%–11.43% efficacy in Suzuki–Miyaura cross-coupling reactions. The biological activity of complexes correlates with substituent type and position in the aromatic ring. The one with ethoxy exhibits antimicrobial effects solely against Candida parapsilosis, while those with fluorine enhance the activity, particularly in the meta position.

Thelazia leesei Railliet & Henry, 1910 (Spirurida: Thelaziidae) of dromedary camel Camelus dromedarius: further morphological description, molecular characterization, and epidemiology in Iran

BackgroundIn camels, thelaziosis is mainly caused by Thelazia leesei Railliet & Henry, 1910, a little-known eyeworm species. Given the paucity of scientific data, this study aimed to provide new insights into the morphology, molecular characterization, and phylogenetic relationship of T. leesei and its occurrence in camels from Iran, where animals suffer from the high burden of eyeworms.MethodsFrom December 2020 to November 2022, slaughtered camels (n = 400) of different sex and age groups were examined in Sistan-va-Baluchestan province in Southeast Iran’s local abattoirs. Adult eyeworms were fixed and stored for morphological identification by light and scanning electron microscopy (SEM). Polymerase chain reaction (PCR) products corresponding to the partial sequences of the mitochondrial cytochrome c oxidase subunit I (cox1) of eyeworms were Sanger sequenced and analyzed phylogenetically.ResultsA total of 118 (29.5%) camels from all five counties examined were infected with eyeworms, with an abundance of 0.9 and a mean intensity of 3.2 (i.e., up to 18 worms from a single animal). The infection rate was higher in camels older than 4 years of age (P = 0.01901). Lachrymation was associated with infection in animals (P < 0.00001). The morphology of our specimens resembled that of T. leesei, with the exception of the position of the nerve ring and esophagus length. Genetic analysis showed that the cox1 partial sequences of our T. leesei specimens had genetic distances of 8.8% to 13.5% compared with other Thelazia species.ConclusionsOn the basis of the morphometrics and morphological characteristics, we identified our specimens as T. leesei. In the phylogenetic tree, T. leesei herein isolated formed a monophyletic group together with its congeners, and T. leesei formed a sister clade to T. lacrymalis. In addition, we demonstrated the epidemiology of the infestation of T. leesei in camels in the endemic areas of southeastern Iran. The data presented are crucial for better understanding the pathogenic role of T. leesei and developing effective treatment strategies. In particular, studies on the intermediate host(s) of T. leesei in these regions will support effective control strategies for this parasitosis.Graphical

Discovery of Potent Kappa Opioid Receptor Agonists Derived from Akuammicine.

Akuammicine (1), an alkaloid isolated from Picralima nitida, is an agonist of the kappa opioid receptor (κOR). To establish structure-activity relationships (SARs) for this structurally unique κOR ligand, a collection of semisynthetic derivatives was synthesized. Evaluating these derivatives for their ability to activate the κOR and mu opioid receptor (μOR) revealed key SAR trends and identified derivatives with enhanced κOR potency. Most notably, substitutions to the C10 position of the aryl ring led to a > 200-fold improvement in κOR potency and nearly complete selectivity for the κOR. A selection of the most potent ligands was shown to possess differing abilities recruitment of β-Arrestin-2 to the κOR, indicating they have distinct signaling properties from each other and existing κOR ligands. The discovery of these κOR agonists underscores the potential of using natural products to identify new classes of potent and selective ligands and provides new tools to probe the κOR.

Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids.

The poor prognosis of glioblastoma multiforme, inadequate treatment options, and growing drug resistance urge the need to find new effective agents. Due to the significant anti-cancer potential of harmicens, hybrid compounds which comprise harmine/β-carboline and ferrocene moiety, we investigated their antiglioblastoma potential in vitro and mechanism of action (inhibition of DYRK1A, Hsp90, anti-oxidative activity). The results have shown that triazole-type harmicens, namely 5, with a ferrocene moiety in C-3 position of the β-carboline ring (IC 50 = 3.7 ± 0.1 µmol L-1, SI = 12.6) and 9, the C-6 substituted harmicene (IC 50 = 7.4 ± 0.5 µmol L-1, SI = 5.8) exert remarkable activity and selectivity against human malignant glioblastoma cell line (U251) in vitro. On the other hand, amide-type harmicens 10, 12, and 14 exhibited strong, but non-selective activity, in the low micro-molar range. Mechanistic studies revealed that among active compounds, amide-type harmicens 12 and 14 inhibit DYRK1A and Hsp90 CTD, whereas compound 14 showed pronounced antioxidative activity. Therefore, the antiproliferative activity of harmicens might be a combination of complex molecular interactions.

4-Furanylvinylquinoline derivative as a new scaffold for the design of oxidative stress initiator and glucose transporter inhibitor drugs

In the present study, a detailed analysis of the effect of a substitution at the C4 position of the quinoline ring by styryl or furanylvinyl substituents on the structure-antitumour activity relationship was conducted. After analysing a library of derivatives from the styrylquinoline and furanylvinylquinoline groups, we selected the most active (IC50 below 100 nM) derivative 13, which contained the strongly electron-withdrawing nitro group in the furan substituent. The mechanism of action of this compound was studied on cell lines that differed in their p53 protein status. For this derivative, both cell cycle arrest (in G2/M phase in both HCT 116 cell lines and S phase for U-251 cell line) and the induction of apoptosis (up to 66% for U-251 cell line) were revealed. These studies were then confirmed by other methods at the gene and protein levels. Interestingly, we observed differences in the mechanism of action depending on the presence and mutation of the p53 protein, thus confirming its key role in cellular processes. Incubation with derivative 13 resulted in the induction of oxidative stress and triggered a cascade of cellular defence proteins that failed in the face of such an active compound. In addition, the results showed an inhibition of the GLUT-1 glucose transporter, which is extremely important in the context of anti-cancer activity.

On the Nature of the Out-Of-Plane Distortions in Subporphyrins.

The field of subporphyrins has garnered great interest in recent years owing to its unique structure and associated properties. They exhibit spectroscopic features similar to porphyrins and find applications in various optoelectronic devices, photodynamic therapy etc. Most of the synthesized subporphyrins have boron coordination with an axial ligand and exhibits a bowl-shaped geometry. The first isolation of a stable free-base subporphyrin is achieved recently with mesityl groups at two of the meso positions and anthracene at the other. X-ray studies reveal a markedly non-planar structure different from the bowl shape and is attributed to the steric hindrance of the inner N-H bonds. Herein, we report a systematic quantum chemical investigation assisted by symmetry principles on molecular models to characterize the out-of-plane (OOP) distortions observed so far in subporphyrins and unveil the electronic reasons. Correlation of the frontier molecular orbital (FMO) landscape between the D4h porphyrin and D3h subporphyrin gives insight into their electronic structure relative to one another and the nature of OOP distortions. Further the effect of a π-donor cum σ-acceptor substituent at the meso/beta positions of the subporphyrin ring as well as the impact of boron incorporation in the central cavity on the OOP distortions are also discussed.

Research on the Method of Depth-Sensing Optical System Based on Multi-Layer Interface Reflection.

In this paper, a depth-sensing method employing active irradiation of a semi-annular beam is proposed for observing the multi-layered reflective surfaces of transparent samples with higher resolutions and lower interference. To obtain the focusing resolution of the semi-annular aperture diaphragm system, a model for computing the diffracted optical energy distribution of an asymmetric aperture diaphragm is constructed, and mathematical formulas are deduced for determining the system resolution based on the position of the first dark ring of the amplitude distribution. Optical simulations were performed under specific conditions; the lateral resolution δr of the depth-sensing system was determined to be 0.68 μm, and the focusing accuracy δz was determined to be 0.60 μm. An experimental platform was established under the same conditions, and the results were in accord with those of the simulation results, which validated the correctness of the formula for calculating the amplitude distribution of the diffracted light from the asymmetric aperture diaphragm.

Design, synthesis, biological and computational analysis of isatin-based bis-thiourea analogues as anti-diabetic and anti-nematode agents

A new series of isatin derivatives were synthesized, characterized by 1HNMR, 13CNMR and HREI-MS, and screened for α-glucosidase and alpha amylase inhibition. All the analogues were found to be dual inhibitors and showed good inhibitory potentials with IC50 values ranging from 5.28 ± 0.10 to 38.66 ± 0.30 µM (against alpha-amylase), and 5.45 ± 0.10 to 39.25 ± 0.50 µM (against alpha-glucosidase), as compared to the standard drug acarbose (IC50 = 11.12 ± 0.15 and 11.29 ± 0.07 µM, respectively). The most potent inhibitor among the series was analogue 24 (IC50 = 5.28 ± 0.10 for alpha-amylase and IC50 = 5.46 ± 0.10 µM for alpha-glucosidase), which has a nitro group attached at the meta-position of the phenyl ring A and the para position of phenyl ring B. Structure-activity relationship has been established mainly based on the position, nature and number of the substituent(s) attached to the phenyl ring. To investigate the binding interaction of the potent analog with the active site of an enzyme, molecular docking studies were carried out. To study the drug-likeness properties, the ADME study was also carried out. The most active compounds engage most of the amino acids composing the active site and display maximum interactions. These interactions majorly include formation of strong hydrogen bonds, which might be due to the presence of highly electronegative heteroatoms on aromatic rings. All the analogues were also tested for in vivo anti-nematodal activity against C. elegans to assess their cytotoxicity in comparison to the reference Levamisole. The cytotoxicity profile demonstrated that analogues 2, 7, 20 and 22 displayed minimum cytotoxicity at every concentration.

Cavitation dynamics in creeping flow

We investigate the heterogeneous cavitation phenomenon in water when a spherical surface is abruptly separated from a nearby flat substrate, at a distance of approximately 10 nm. By tracking the surface separation using Newton ring positions, and capturing the bubble evolution with a high-speed camera on a microscope, we compare our experimental findings with hydrodynamic predictions at low Reynolds numbers. Upon upward movement of the spherical surface, the resulting bubble develops branched fingers through the Saffman–Taylor instability. Simultaneously, negative liquid pressures in the range $\sim$ 10 atm are observed. These large tension values occasionally lead to secondary nucleation events. The bubble sizes satisfy a predicted Family–Vicsek scaling law where the bubble area is proportional to the inverse bubble lifetime. The fact that creeping flow cavitation bubbles are more short-lived the larger they are separates them from bubbles that are governed by inertial dynamics.

Design And Synthesis Of Novel Thiazole Linked Tetrahydropyridine Analogues As Anticancer Agents.

A library of new thiazole linked tetrahydropyridines (6a-q) synthesized and screened for their invitro anticancer activity against human breast adeno carcinoma cell viz. MCF-7 and MDA-MB-231. The two compounds 6d containing -F and -Cl functions in para and meta position of phenyl ring (9.94 ± 1.02µM, 9.78 ± 1.08µM) and 6e with -Cl and -NH2 functions on pyridine ring (9.72 ± 0.91 µM,9.54 ± 0.95µM) demonstrated outstanding activity against both the cell lines when compared to Doxorubicin. The benzofuran analogue 6o presented good activity with an IC50 value of 12.19 ± 1.03µM (MCF-7) and 12.22 ± 1.07µM (MDA-MB-231). The molecular docking study of potent molecule 6e against crystal structure of breast tumor kinase presented promising docking score and binding interactions. Predicted pharmacokinetics properties of compounds 6a-q and presented boiled diagram of compounds 6d and 6e implied favourable drug-likeness properties.

Computer prediction of toxicity of new S-alkyl derivatives of 1,2,4-triazole

1,2,4-Triazole derivatives are of researchers’ significant interest due to their diverse biological properties, such as antimicrobial, anti-inflammatory, anticancer, and antioxidant activities. The integration of a 2-bromo-4-fluorophenyl fragment into the triazole structure can significantly enhance these activities. However, the evaluation of the toxicity of such compounds remains a critically important aspect for their practical application. To reduce the time and cost of experimental studies, QSAR (Quantitative Structure-Activity Relationship) methods are actively used, allowing the prediction of toxicity based on the molecular structure of compounds. Aim of the study. To assess the toxicity of new S-derivatives of 5-(2-bromo-4-fluorophenyl)-4-R-1,2,4-triazol-3-thiols using the QSAR method, specifically to predict acute toxicity parameters (LD50), and to determine the influence of different (length) radicals on the toxicity of these compounds. Materials and methods. The objects of the virtual study were derivatives of 5-(2-bromo-4-fluorophenyl)-4-ethyl-1,2,4-triazol-3-thiols. They were evaluated at the Department of Toxicological and Inorganic Chemistry of the Zaporizhzhia State Medical and Pharmaceutical University. The toxicity assessment was conducted using the nearest neighbor method via the Toxicity Estimation Software Tool (TEST). The prediction of the lethal dose (LD50) for rats was based on the structural similarity of the studied compounds with known substances, for which experimental toxicity data are available. Results. The conducted QSAR analysis demonstrated that structural changes in S-derivatives of 5-(2-bromo-4-fluorophenyl)-4-ethyl-1,2,4-triazol-3-thiols significantly affect the predicted toxicity. The primary factor influencing the changes in LD50 values is the variation of radicals at the 5th position of the triazole ring. Conclusions. The results of the study showed, that the toxicity of new S-alkyl derivatives of triazol-3-thiols depends on the type of alkyl substituent. Compounds with propyl to heptyl fragments exhibit increased toxicity, while derivatives with thiol, octyl, nonyl, and decyl residues are characterized by lower toxicity.

Design and Optimization of Quinazoline Derivatives as Potent EGFR Inhibitors for Lung Cancer Treatment: A Comprehensive QSAR, ADMET, and Molecular Modeling Investigation.

The epidermal growth factor receptor (EGFR) is part of a protein family that controls cell growth and development. Due to its importance, EGFR has been identified as a suitable target for creating novel drugs. For this research, we conducted a 2D-QSAR analysis on a set of 31 molecules derived from quinazoline, which exhibited inhibitory activity against human lung cancer. This investigation incorporated principal component analysis (PCA) and multiple linear regression (MLR), leading to the development of QSAR models with strong predictive capabilities (R 2 = 0.745, R 2_adj = 0.723, MSE = 0.061, R 2_test = 0.941, and Q 2_cv = 0.669). The reliability of these models was confirmed through internal, external, Y-randomization, and applicability domain validations. Leveraging the predictions from the QSAR model, we designed 18 new molecules based on the modifications at the N-3 and C-6 positions of the quinazoline ring, with electronegative substituents at these positions fostering optimal polar interactions and hydrophobic contacts within the ATP-binding site of EGFR, significantly enhancing the inhibitory activity against the lung cancer cell line. Subsequently, ADMET predictions were conducted for these 18 compounds, revealing outstanding ADMET profiles. Molecular docking analyses were performed to investigate the interactions between the newly designed molecules-Pred15, Pred17, Pred20, Pred21-and the EGFR protein, indicating high affinity of these proposed compounds to EGFR. Furthermore, molecular dynamics (MD) simulations were utilized to assess the stability and binding modes of compounds Pred17, Pred20, and Pred21, reinforcing their potential as novel inhibitors against human lung cancer. Overall, our findings suggest that these investigated compounds can serve as effective inhibitors, showcasing the utility of our analytical and design approach in the identification of promising therapeutic agents.