Pyrazole Nucleus Research Articles

An Insight into the Structure-Activity Relationship of Benzimidazole and Pyrazole Derivatives as Anticancer Agents.

Cancer is a leading cause of death worldwide, driving the urgent need for new and effective treatments. Benzimidazole and pyrazole derivatives have gained attention for their potential as anticancer agents due to their diverse biological activities. The development of resistance in cancer cells, toxicity concerns, and inconsistent efficacy across different types of cancer are a few of the challenges. To overcome these challenges, optimisation of these nuclei using the structure-activity relationships is necessary. This review aimed to examine various benzimidazole, pyrazole, and their hybrid derivatives by focusing on their structure-activity relationships (SAR) as anticancer agents. Results of the most potent and least potent benzimidazole, pyrazole compounds, and their hybrid derivatives published by researchers were compiled. The findings of different researchers working on benzimidazole and pyrazole nuclei were reviewed and analysed for different targets and cell lines. Moreover, substitutions on different positions of pyrazole, benzimidazole, and their hybrid were summarised to derive an optimised pharmacophore. Based on our analysis of existing studies, we anticipate that this review will guide researchers in creating potent pyrazole, benzimidazole, and hybrid derivatives crucial for combating cancer effectively. Structure-Activity Relationship (SAR) studies can help in developing pyrazolebenzimidazole hybrids that are more powerful and selective in targeting specific aspects of cancer.

Structure-Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents.

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10-22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

Pyrazole: an emerging privileged scaffold in drug discovery.

Pyrazole or 1H-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small molecule have been reported in clinical and preclinical studies for the potential treatment of several diseases. The number of drugs containing a pyrazole nucleushas increased significantly in the last 10years. Some of the best-selling drugs in this class are ibrutinib, ruxolitinib, axitinib, nirapariband baricitinib, and are usedto treat different types of cancers; lenacapavir to treat HIV; riociguat to treat pulmonary hypertension; and sildenafil to treat erectile dysfunction. Several aniline-derived pyrazole compounds have been reported as potent antibacterial agents with selective activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Here, we discuss the pyrazole-deriveddrugsreported up to September 2023.

Pharmacophore-based synthesis of pyrazole analogues as artificial antibiotics targeting Salmonella Typhi

The pharmacological potential of the pyrazole moiety is demonstrated by their presence in a wide range of therapeutic agents spanning various categories. Notable examples include: Celecoxib: A potent anti-inflammatory drug, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB): An antipsychotic medication, Rimonabant: An anti-obesity drug, Difenamizole: An analgesic, Betazole: An H2-receptor agonist, Fezolamide: An antidepressant agent. These examples underscore the versatility and efficacy of the pyrazole nucleus in the development of pharmacologically active compounds across different therapeutic domains [1–12]. In our study, we computationally designed 23 different derivatives of pyrazole compounds and analysed their Pharmacokinetics (ADMET) properties in the QikProp module on Schrodinger's Maestro platform. Among them, high throughput optimised and promising analogues of 11 pyrazole compounds were synthesised and analysed by NMR and LCMS for structural configuration. The synthesised compounds were initially analysed for cytotoxicity by MTT assay and found to have lower toxicity profiling in 7 pyrazole derivatives. Further, the compounds were investigated for their antibacterial activity against Salmonella Typhi by broth dilution and disk diffusion methods, where four compounds (P4, P14, P19, and P20) exhibit a potential growth inhibitory activity as compared with standard antibiotics which commercially used for S. Typhi infection. Further, to explore the mode of action on the growth suppression of S. Typhi was investigated by performing molecular docking with outer membrane protein (cell wall inhibition) and DNA-dependant RNA polymerase (transcriptional arrest) of S. Typhi, wherein all four tested probes exhibited the binding interaction localised at the active domains of the foresaid target protein. The P14 compound exhibits the maximum score of least binding energy at -8.174 kcal/mol against OMP C, whereas the P4 remains at -5.575 kcal/mol against the DNA-dependent RNA polymerase. This observation is clearly evident in the antagonistic effects of the synthesised derivatives on the growth of S. Typhi.

Novel 5-aminopyrazoles endowed with anti-angiogenetic properties: Design, synthesis and biological evaluation

The promising anti-angiogenetic properties of previously synthesized pyrazolyl ureas provided the rationale for the synthesis of novel 5-aminopyrazoles 2–5, differently decorated on the pyrazole nucleus. All the derivatives were tested by MTT assays and proved to be non-cytotoxic against eight different tumor cell lines and normal fibroblasts. An EdU proliferation assay was carried out on human foreskin fibroblasts and VEGF stimulated human umbilical vein endothelial cells which confirmed the absence of cytotoxicity of the compounds on human cells up to 20 μM concentration. To evaluate the influence of the newly synthesized pyrazoles on MAPK and PI3K signaling pathways, the phosphorylation of ERK1/2 and Akt was analyzed by Western blots from HFF and HUVEC cell lysates stimulated with growth factors in the presence or absence of the compounds. Pyrazoles 3b and 3c showed a significant inhibition of Akt phosphorylation in both tested cell lines with lower phosphorylation levels than the reference compound GeGe-3 in HUVEC. Furthermore, derivatives 2 and 3 appeared to strongly affect the migration of HFF cells in a wound healing assay, confirming their potential ability to interfere with the angiogenesis process. The new pyrazole library extends the structure-activity relationships of the previously isolated compounds and highlights the attractiveness of this chemical class for pathological cell migration and angiogenesis.

Research on Synthesis and Pharmacological Evaluation of Subsituated Chalcone deriatives for Antimicrobial and Antifungal activity

The Pyrazole nucleus in general and its chemistry has found much more attention during the last few decades because of out-standing biological activities. It acts as Antipyretic, analgesic, anti-inflammatory, kinase inhibitors, and as insecticides. It has good properties as antibacterial, antifungal, and an antiparasitics, as well, considering all those benefits and in continues of our work to synthesize new hetero starting from 1,3-diphenyl-4-carboxaaldehyde, we introduce here in several new pharmacophores, such as pyrimidine, pyramidinethoine and thiazole moieties onto the pyarazole nucleus to obtain compounds with enhanced potency.

Amino-Pyrazoles in Medicinal Chemistry: A Review.

A pyrazole nucleus is an easy-to-prepare scaffold with large therapeutic potential. Consequently, the search for new pyrazole-based compounds is of great interest to the academic community as well as industry. In the last ten years, a large number of papers and reviews on the design, synthesis, and biological evaluation of different classes of pyrazoles and many pyrazole-containing compounds have been published. However, an overview of pyrazole derivatives bearing a free amino group at the 3, 4, or 5 position (namely, 3-aminopyrazoles, 4-aminopyrazoles, and 5-aminopyrazoles, respectively) and their biological properties is still missing, despite the fact that aminopyrazoles are advantageous frameworks able to provide useful ligands for receptors or enzymes, such as p38MAPK, and different kinases, COX and others, as well as targets important for bacterial and virus infections. With the aim to fill this gap, the present review focuses on aminopyrazole-based compounds studied as active agents in different therapeutic areas, with particular attention on the design and structure-activity relationships defined by each class of compounds. In particular, the most relevant results have been obtained for anticancer/anti-inflammatory compounds, as the recent approval of Pirtobrutinib demonstrates. The data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "aminopyrazole" as the keyword.

α‐Aryl‐β,β‐Ditosyloxy Ketones as Versatile Precursors: Convenient, Direct, Metal‐free and Regioselective Synthesis of 4,5‐Diaryl/1,4,5‐Triaryl Pyrazoles

AbstractThe present study demonstrate the synthetic applications of α‐aryl‐β,β‐ditosyloxy ketones 3 as 1,3‐dielectrophilic three carbon atom versatile precursors to synthesize scarcely underexplored 4,5‐diaryl/1,4,5‐triaryl pyrazoles as small aza‐heterocycles. The exact regiochemistry around pyrazole nucleus has been confirmed by single crystal XRD analysis along with spectroscopic data (1H & 13C‐NMR, IR) and HRMS analysis. The single crystal‐XRD analysis exposed that, crystallization of 4,5‐diaryl pyrazoles 5 b in trigonal systems with R‐3 space group. The strategy was found advantageous especially owing to (i) operationally simplicity of procedure (ii) high regioselectivity (iii) less reaction timing (iv) versatile reactivity due to presence of two p‐toluenesulfonyloxyl groups which behaves as excellent leaving group as well as electron withdrawing group. Additionally, we conjectured that present methodology can broaden the aspects of synthetic chemistry in ongoing medicine chemistry programs for designing and synthesis of regioisomeric analogues of some well‐recognised drugs like celecoxib.

Microwave Assisted Synthesis of a Novel Schiff Base Scaffolds of Pyrazole Nuclei: Green Synthetic Method

Aim: The research aims to develop a sustainable microwave-assisted scheme for Synthesizing 5-(benzylidene amino)-1-phenyl-1H-pyrazole-4-carbonitrile congeners. Background: 5-(benzylideneamino)-1-phenyl-1H-pyrazole-4-carbonitrile scaffolds are novel molecules having various pharmacological activities such as neurodegenerative, anti-microbial, anticancer. Schiff base congeners are considered as efficient pharmacophores for research. These activities are due to the presence of azomethine (CH=N) group in the Schiff base compounds. Objectives: To synthesise different novel Schiff base compounds of pyrazole nuclei by green chemistry with a decent yield. Methods: The 5-(benzylideneamino)-1-phenyl-1H-pyrazole-4-carbonitrile scaffolds were prepared by two-step reactions. Both steps were microwave-assisted. The first step was to synthesize 5- amino-1-phenyl-1H-pyrazole-4-carbonitrile as an intermediate compound. This compound was synthesized by using phenyl hydrazine and 2-(ethoxymethylene)malononitrile. The temperature, pressure, and time required for this reaction were 102°C, 300W, and 45 minutes respectively. In the second step, the final Schiff base congeners were attained by reacting this compound with several aromatic aldehydes. The yield, reaction condition, and time consumption were all acceptable for the green synthetic methods rather than the conventional schemes. Results: The microwave-assisted method was more efficient. The reactions were less timeconsuming, and the overall yield of the all-synthesized compounds was 75-82%. Different spectroscopic methods characterized the synthesized congeners. The IR peak is considered the main functional group (azomethine) at 1611 cm-1 wavelength. Conclusions: This microwave-assisted synthetic scheme thus appears more environmentally due to a significant reduction in organic solvents, resulting in fewer hazardous residues. Using this scheme, we prepared different Schiff base congeners with satisfactory chemical yields.

DESIGN, SYNTHESIS AND EVALUATION OF PYRAZOLE SUBSTITUTED BENZIMIDAZOLE AS AN ANTI-TUBERCULAR, ANTI-FUNGAL AND ANTI-MICROBIAL AGENT

Objective: A series of pyrazole substituted benzimidazole derivatives were subjected to in silico studies to identify a new lead for anti-tubercular, antimicrobial and antifungal activity. Methods: Docking studies was carried out against Mycobacterium tuberculosis InhA bound with ETH-NAD adduct-PDB ID: 2H9I and Crystal structure of S. aureus TyrRS in complex with SB-239629-PDB ID: 1JIJ. Results: Based on the binding interactions, binding energies, and ADMET predictions, the most active compounds were produced, consisting of a para-halo phenyl substitution at the pyrazole nucleus that was connected to benzimidazole. The synthesized compounds were evaluated for tuberculostatic activity using microplate Almar blue assay method, and anti-microbial and anti-fungal activity by disc diffusion method. Conclusion: Compound 5c with chloro substituted phenyl ring on the pyrazole showed moderate anti-tubercular, mild antifungal and anti-microbial activity. This compound may thus represent a novel, multi target molecule having a selective class of anti-tubercular, anti-fungal and anti-microbial activity.

Enhanced Antibacterial Activity of a Cationic Macromolecule by Its Complexation with a Weakly Active Pyrazole Derivative.

Molecules containing the pyrazole nucleus are widely reported as promising candidates to develop new antimicrobial compounds against multidrug-resistant (MDR) bacteria, where available antibiotics may fail. Recently, aiming at improving the too-high minimum inhibitory concentrations (MICs) of a pyrazole hydrochloride salt (CB1H), CB1H-loaded nanoparticles (CB1H-P7 NPs) were developed using a potent cationic bactericidal macromolecule (P7) as polymer matrix. Here, CB1H-P7 NPs have been successfully tested on several clinical isolates of Gram-positive and Gram-negative species, including relevant MDR strains. CB1H-P7 NPs displayed very low MICs (0.6–4.8 µM), often two-fold lower than those of P7, on 34 out of 36 isolates tested. Upon complexation, the antibacterial effects of pristine CB1H were improved by 2–16.4-fold, and, unexpectedly, also the already potent antibacterial effects of P7 were 2–8 times improved against most of bacteria tested when complexed with CB1H. Time-killing experiments performed on selected species established that CB1H-P7 NPs were bactericidal against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Selectivity indices values up to 2.4, determined by cytotoxicity experiments on human keratinocytes, suggested that CB1H-P7 NPs could be promising for counteracting serious infections sustained by most of the isolates tested in this study.

Potent and Broad-Spectrum Bactericidal Activity of a Nanotechnologically Manipulated Novel Pyrazole.

The antimicrobial potency of the pyrazole nucleus is widely reported these days, and pyrazole derivatives represent excellent candidates for meeting the worldwide need for new antimicrobial compounds against multidrug-resistant (MDR) bacteria. Consequently, 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), recently reported as a weak antiproliferative agent, was considered to this end. To overcome the CR232 water solubility issue and allow for the determination of reliable minimum inhibitory concentration values (MICs), we initially prepared water-soluble and clinically applicable CR232-loaded nanoparticles (CR232-G5K NPs), as previously reported. Here, CR232-G5K NPs have been tested on several clinically isolates of Gram-positive and Gram-negative species, including MDR strains. While for CR232 MICs ≥ 128 µg/mL (376.8 µM) were obtained, very low MICs (0.36–2.89 µM) were observed for CR232-G5K NPs against all of the considered isolates, including colistin-resistant isolates of MDR Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemases (KPCs)-producing K. pneumoniae (0.72 µM). Additionally, in time–kill experiments, CR232-G5K NPs displayed a rapid bactericidal activity with no significant regrowth after 24 h on all isolates tested, regardless of their difficult-to-treat resistance. Conjecturing a clinical use of CR232-G5K NPs, cytotoxicity experiments on human keratinocytes were performed, determining very favorable selectivity indices. Collectively, due to its physicochemical and biological properties, CR232-G5K NPs could represent a new potent weapon to treat infections sustained by broad spectrum MDR bacteria.

Methyl-linked Pyrazoles: Synthetic and Medicinal Perspective.

Pyrazoles, an important and well-known class of the azole family, have been found to show a large number of applications in various fields, especially medicinal chemistry. Pyrazole derivatives, particularly methyl-substituted pyrazoles, have been reported as potent medicinal scaffolds that exhibit a wide spectrum of biological activities. The present review is an attempt to highlight the detailed synthetic approaches for methyl-substituted pyrazoles along with an in-depth analysis of their respective medical significances till March 2021. It is hoped that literature sum-up in the form of present review article would certainly be a great tool in assisting medicinal chemists in generating new leads possessing pyrazole nucleus with high efficacy and less microbial resistance.

Antibacterial pyrazoles: tackling resistant bacteria.

Bacterial resistance to antibiotics threatens our progress in healthcare, modern medicine, food productionand ultimately life expectancy. Antibiotic resistance is a global concern, which spreads rapidly across borders and continents due to rapidtravel of people, animals and goods. Derivatives of metabolically stable pyrazole nucleus are known for their wide range of pharmacological properties, including antibacterial activities. Thisreview highlights recent reports of pyrazole derivatives targeting different bacterial strains focusing on the drug-resistant variants. Pyrazole derivatives target different metabolic pathways of both Gram-positive and Gram-negative bacteria.

Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies.

Pyrazole is a five-membered heterocycle bearing two adjacent nitrogen atoms. Both pharmaceutical agents and natural products with pyrazole as a nucleus have exhibited a broad spectrum of biological activities. In the last few decades, more than 40 pyrazole-containing drugs have been approved by the FDA for the treatment of a broad range of clinical conditions including celecoxib (anti-inflammatory), CDPPB (antipsychotic), difenamizole (analgesic), etc. Owing to the unique physicochemical properties of the pyrazole core, pyrazole-containing drugs may exert better pharmacokinetics and pharmacological effects compared with drugs containing similar heterocyclic rings. The purpose of this paper is to provide an overview of all the existing drugs bearing a pyrazole nucleus that have been approved or in clinical trials, involving their pharmacological activities and SAR studies.

Pyrazole-Based Water-Soluble Dendrimer Nanoparticles as a Potential New Agent against Staphylococci.

Although the antimicrobial potency of the pyrazole nucleus is widely reported, the antimicrobial effects of the 2-(4-bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4), found to be active against several other conditions, have never been investigated. Considering the worldwide need for new antimicrobial agents, we thought it noteworthy to assess the minimum inhibitory concentration (MICs) of BBB4 but, due to its scarce water-solubility, unequivocal determinations were tricky. To obtain more reliable MICs and to obtain a substance also potentially applicable in vivo, we recently prepared water-soluble, BBB4-loaded dendrimer nanoparticles (BBB4-G4K NPs), which proved to have physicochemical properties suitable for clinical application. Here, with the aim of developing a new antibacterial agent based on BBB4, the BBB4-G4K NPs were tested on several strains of different species of the Staphylococcus genus. Very low MICs (1.5–3.0 µM), 15.5–124.3-fold lower than those of the free BBB4, were observed against several isolates of S. aureus and S. epidermidis, the most pathogenic species of this genus, regardless of their resistance patterns to antibiotics. Aiming at hypothesizing a clinical use of BBB4-G4K NPs for staphylococcal skin infections, cytotoxicity experiments on human keratinocytes were performed; it was found that the nano-manipulated BBB4 released from BBB4-G4K NPs (LD50 138.6 µM) was 2.5-fold less cytotoxic than the untreated BBB4 (55.9 µM). Due to its physicochemical and biological properties, BBB4-G4K NPs could be considered as a promising novel therapeutic option against the very frequent staphylococcal skin infections.

A Review on Heteroaryl Substituted Pyrazolines with their Pharmacological Activity and SAR Studies

In step with the development of organic chemistry, heterocyclic compounds play an important part. Electron-rich nitrogen containing heterocyclic compounds and their derivatives play key role in diverse biological activities. The wide-ranging functionality and stereochemical complexity in a five-member ring structure is shown by the pyrazole nucleus, which has two nitrogen atoms and exhibit aromatic character. The medicinal chemists have been using the relationship between chemical structure and biological activity of a molecule in drug discovery as the driving force to guide synthetic efforts, to design new chemical derivatives. It has been reported that pyrazoline derivatives possess a broad spectrum of biological activities such as antibacterial, antimicrobial, anti-inflammatory, antioxidant, antidiabetic, anticancer, antifungal, antitubercular, antidepressant, anticonvulsant and analgesic activities. They also possess some potent receptor selective biological activities like monoamine oxidases (MAOs) inhibitor, Nitric oxide synthase (NOS) inhibitor, Angiotensin converting enzyme (ACE) inhibitor, cholecystokinin-1 receptor antagonist and estrogen receptor (ER) ligand activity. Hence in this article, we focus on the pyrazole derivatives having heteroaryl substituents and their pharmacological activities along with their structure–activity relationships in order to create opportunities to explore the full potential of these compounds. Keywords: Heterocyclic compounds, Pyrazolines, Claisen-Schmidt condensation, Chalcone.

Preparation and Physicochemical Characterization of Water-Soluble Pyrazole-Based Nanoparticles by Dendrimer Encapsulation of an Insoluble Bioactive Pyrazole Derivative.

2-(4-Bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4) was synthetized and successfully evaluated concerning numerous biological activities, except for antimicrobial and cytotoxic effects. Due to the antimicrobial effects possessed by pyrazole nucleus, which have been widely reported, and the worldwide need for new antimicrobial agents, we thought it would be interesting to test BBB4 and to evaluate its possible antibacterial effects. Nevertheless, since it is water-insoluble, the future clinical application of BBB4 will remain utopic unless water-soluble BBB4 formulations are developed. To this end, before implementing biological evaluations, BBB4 was herein re-synthetized and characterized, and a new water-soluble BBB4-based nano-formulation was developed by its physical entrapment in a biodegradable non-cytotoxic cationic dendrimer (G4K), without recovering harmful solvents as DMSO or surfactants. The obtained BBB4 nanoparticles (BBB4-G4K NPs) showed good drug loading (DL%), satisfying encapsulation efficiency (EE%), and a biphasic quantitative release profile governed by first-order kinetics after 24 h. Additionally, BBB4-G4K was characterized by ATR-FTIR spectroscopy, NMR, SEM, dynamic light scattering analysis (DLS), and potentiometric titration experiments. While, before the nanotechnological manipulation, BBB4 was completely water-insoluble, in the form of BBB4-G4K NPs, its water-solubility resulted in being 105-fold higher than that of the pristine form, thus establishing the feasibility of its clinical application.

Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists.

N‐formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4‐(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6‐membered compounds, all exhibiting the same 4‐bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five‐membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.

Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Thiazole–Pyrimidine Linked Amide Derivatives

A library of new amide-based thiazole–pyrimidines (13a–j) was designed by considering vital pharmacophoric features of the potential multi-acting anticancer agents. The analogs were synthesized by linking with fused imidazo–pyrazole nucleus and confirmed their structures by 1H NMR, 13CNMR, and mass spectral analysis. The newly designed thiazole–pyrimidine analogs were subjected to investigate against various human cancer cell lines such as A549 (lung), MCF-7 (breast), Colo-205 (colon), and A2780 (ovarian) by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay technique. The anticancer screening data suggested that, the analogs with tri/di substitution are found to have much potential than mono-substituted analogs. The 13b and 13h depicted maximum anti-cancer activity against all of the tested cell lines and superior than reference standard Etoposide. Furthermore, the molecular interaction analysis against different enzymatic targets such as ribonucleotide reductase (RR), epidermal growth factor reductase (EGFR), APC–asef (Adenomatous Polyposis Coli (APC) directly interacts with the Rho guanine nucleotide exchange factor 4 (Asef)) protein–protein interaction interface, and ATR kinase has been carried out to find the possible binding protein. The comparative binding energies and violin plot suggested the current series of analogs as potential ATR kinase binders. The required substantial interactions of 13b and 13h with active site residues of ATR kinase has been discussed by comparing with lowest active analogs. In addition, the ADMET parameters of the current analogs is also provided with drug likeness and druggability scores.