Compounds 4h Research Articles

Design, synthesis, and anti-breast cancer activity evaluation of novel 3-cyanopyridine derivatives as PIM-1 inhibitors

AbstractA novel series of cyanopyridines 7a-j were synthesized via a one-pot multicomponent reaction of arylidene 4 with ammonium acetate 5 and respective methylaryl/heterylketones 6a-j in ethanol using vanillin as a natural starting material. Moreover, the regioselective alkylation reaction was studied by the treatment of cyanopyridines 7a-f and 7j with CH3I in the presence of K2CO3 in DMF to afford O-methylcyanopyridines 8a-g (major) and N-methylcyanopyridines 9a-g (minor), whereas bipyridine 7h gave bipyridinium iodide salt 10. All of the designed cyanopyridines were evaluated as anti-breast cancer (MCF-7) cell lines via PIM Kinase inhibitory activity, and the results displayed that some of them showed high activities, especially compounds 7h and 8f, which showed excellent activities against MCF-7 with IC50 values of 1.89 and 1.69 μM, respectively, more potent than the reference drug doxorubicin. Mechanistically, compounds 7h and 8f exhibited strong in vitro PIM-1 kinase inhibitory activity with an IC50 of 0.281 and 0.58 μM, respectively, compared to the reference staurosporine. Moreover, compound 7h arrested the tumor cells at the S phase and caused cell death mainly by inducing early and late apoptosis. Molecular docking studies against PIM-1 revealed good binding modes of the synthesized compound and showed agreement with the biological results. Graphical abstract

Potent Antimicrobial Azoles: Synthesis, In Vitro and In Silico Study

Background/Objectives: The increase in fungal infections, both systemic and invasive, is a major source of morbidity and mortality, particularly among immunocompromised people such as cancer patients and organ transplant recipients. Because of their strong therapeutic activity and excellent safety profiles, azole antifungals are currently the most extensively used systemic antifungal drugs. Antibacterial properties of various topical antifungals, such as oxiconazole, which features oxime ether functionality, were discovered, indicating an exciting prospect in antimicrobial chemotherapy. Methods: In this study, eleven new oxime ether derivatives with the azole scaffold (5a–k) were synthesized and tested for their antimicrobial effects using the microdilution method to obtain broad-spectrum hits. Results: Although the title compounds showed limited efficacy against Candida species, they proved highly effective against dermatophytes. Compounds 5c and 5h were the most potent derivatives against Trichophyton mentagrophytes and Arthroderma quadrifidum, with minimum inhibitory concentration (MIC) values lower than those of the reference drug, griseofulvin. The MIC of 5c and 5h were 0.491 μg/mL and 0.619 μg/mL against T. mentagrophytes (MIC of griseofulvin: 2.52 μg/mL). The compounds were also tested against Gram-positive and Gram-negative bacteria. Briefly, 5c was the most active against Escherichia coli and Bacillus subtilis, with MIC values much better than that of ciprofloxacin (MIC of 5c = 1.56 μg/mL and 1.23 μg/mL, MIC of ciprofloxacin = 31.49 and 125.99 μg/mL, respectively). Molecular docking suggested a good fit in the active site of fungal lanosterol 14α-demethylase (CYP51) and bacterial FtsZ (Filamenting temperature-sensitive mutant Z) protein. Conclusions: As a result, the title compounds emerged as promising entities with broad antifungal and antibacterial effects, highlighting the utility of oxime ether function in the azole scaffold.

Synthesis of Paracetamol‐Appended Bis 1,2,3‐Triazole Analogues as Anti‐Inflammatory Agents

AbstractParacetamol‐based bis 1,2,3‐triazole analogues were synthesized involving copper‐catalyzed click chemistry protocol. The new compounds were characterized by 1H NMR, 13C NMR, and mass spectral techniques. All the compounds were evaluated for their in vitro anti‐inflammatory properties using diclofenac as standard reference. The compound 6b with chlorine and fluorine functions displayed outstanding activity with IC50 values of 7.34 ± 0.45 µM and 7.84 ± 0.47 µM, respectively. Compound 6g with methyl and fluorine functions displayed best activity with IC50 values of 9.34 ± 0.22 µM and 9.40 ± 0.35 µM, respectively. Compound 6i, 6k, 6f, 6a, 6e, 6h, 6j, and 6l exhibited promising activity with respect to diclofenac. Using PyRx tool, the molecular docking study against crystal structure of COX‐2 proved the binding efficacies with notable binding interactions.

Discovery of tetrazole thioethers: An efficient, environmentally friendly and metal-free S-arylation using diaryliodonium salts

An efficient, environmentally friendly, and metal-free method for the synthesis of functionalized tetrazole thioethers via the S-arylation of tetrazole-5-thiones using diaryliodonium salts as aryl transfer reagents has been developed. This novel methodology provides rapid access to tetrazole thioether derivatives under facile conditions. Our study underscores the chemoselectivity of unsymmetrical diaryliodonium salts, emphasizing their preference for the transfer of sterically hindered and electron-deficient aryl groups. Notably, the synthesized compound 3h exhibits antitumor activity against A2789 (ovarian cancer) and MDA-MB-231 (breast cancer) tumor cells. In silico studies predict these compounds to possess good drug-likeness and low toxicity risk. These findings highlight the potential of functionalized tetrazole thioethers as antiproliferative agents and pave the way for further development and optimization in future investigations.

Quinoline Based thiazolidinediones: Design, Synthesis, In Silico, In Vitro, Antioxidant and Antidiabetic Evaluation

AbstractIn the present research work a sequence of substituted quinoline based thiazolidinedione moieties (12a–h) were designed and synthesized as potential antidiabetic agents. Pancreatic α‐amylase (PAA) and intestinal α‐glucosidase (IAG) enzymes were considered as potential targets for effective treatment of diabetes. The potential of all compounds (12a–h) was assessed in vitro against PAA and IAG using acarbose as standard. The results suggested that compound 12h has shown superior PAA and IAG inhibitory activity with respective to standard (IC50 = 4.683 ± 0.06 µM and 2.456 ± 0.07 µM). Furthermore, using computational (in silico) studies like AutoDock and Desmond, predicted the significant binding interactions responsible for the activity of all compounds (12a–h) at the active site of enzymes, while SwissADME and Osiris property explorer tools computed in silico drug likeliness and toxicity properties. The RMSD, RMSF, Rg and protein ligand contacts, confirmed the stable binding of compound 12h and 12g with the both PAA and IAG proteins. The in silico results confirmed the 12h molecule as a superior drug with high binding affinity and good drug likeness against PAA and IAG, confirming in vitro results. We also studied antioxidant activity (AOA) of all synthesized compounds and results confined that the compound 12h has good antioxidant potential (IC50 = 5.04 ± 0.054 µM) among all other compounds. In conclusion, in vitro, in silico and antioxidant studies revealed 12h compound was found to be potential compound.

Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV -2

Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CLpro inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CLpro, with IC50 values ranging from 21 nM to 53 nM. Notably, compounds 9b and 9h displayed improved enzymatic inhibition (IC50 = 25 nM and 21 nM, respectively) compared to nirmatrelvir (47 nM). Compound 9b showed enhanced stability in human and mouse liver microsomes compared to nirmatrelvir, whereas 9h exhibited similar stability to nirmatrelvir in both species. Furthermore, compound 9h displayed exceptional potency in cellular assays targeting the SARS-CoV-2 replicon within Huh7 cells, with a single-digit nanomolar activity that is 5.6 times better than that of nirmatrelvir. In a pharmacokinetic study in mice (PO, 20 mg/kg), compound 9h exhibited a prolonged plasma half-life (T1/2 = 2.58 h) compared to nirmatrelvir (T1/2 = 0.51 h) and demonstrated an AUC(0-t) value (1106 h∗ng/mL) equivalent to that of nirmatrelvir (1023 h∗ng/mL). These findings indicate that compound 9h is a promising lead for developing a novel 3CLpro inhibitor against SARS-CoV-2.

Semi-Preparation and X-ray Single-Crystal Structures of Sophocarpine-Based Isoxazoline Derivatives and Their Pesticidal Effects and Toxicology Study.

Recently, research and development of novel pesticides from natural plant products have received much attention. To accelerate the application of sophocarpine as the agrochemical candidate, a series of novel sophocarpine-based isoxazoline derivatives were prepared by the 1,3-dipolar [2 + 3] cycloaddition reaction of sophocarpine with different chloroximes. Their structures were well characterized by high-resolution mass spectra, infrared spectra, and proton/carbon-13 nuclear magnetic resonance spectra. Eight steric configurations of compounds 5a, 5e', 5f, 5g, 5h, 5i, 5r, and 5u' were further determined by X-ray single-crystallography. Against Aphis citricola Van der Goot, compounds 5n (LD50: 0.032 μg/nymph) and 5o (LD50: 0.024 μg/nymph) exhibited greater than 3.7- and 4.9-fold potent aphicidal activity compared to sophocarpine (LD50: 0.118 μg/nymph). Against Tetranychus cinnabarinus Boisduval, derivative 5g displayed the most promising acaricidal activity with the LC50 value of 0.247 mg/mL, which was 14.2-fold that of sophocarpine. Compounds 5d and 5g also exhibited good control efficacy against T. cinnabarinus. Scanning electron microscopy images indicated that compound 5g can destroy the mite cuticle layer. These results will provide the foundation for the structural modification and use of sophocarpine derivatives as agrochemicals in the future.

In-vitro and in-silico studies based discovery of 2-aryl-N-(4-morpholinophenyl)thiazol-4-amines as promising DNA gyrase inhibitors

Background: DNA gyrase is an important enzyme for the survival of bacteria. Many DNA gyrase inhibitors are in clinical practice. However, these inhibitors also encompass certain toxic and drug/food interactions. This warrants the development of a new template as DNA gyrase inhibitors. Therefore, this study aimed to deliver morpholine-based thiazoles (5a-5l) as safer DNA gyrase inhibitors.Methods: The 5a-5l were prepared by reacting compound 3 with various aryl thioamides. The structures of 5a-5l were ascertained by their spectral records. The 5a-5l were subjected to their antibacterial activity potential (serial plate dilution method), DNA gyrase inhibiting activity, and toxicity analysis (MTT assay) against HepG2 & Vero cell lines. The in-silico studies (pharmacokinetic parameters and molecular docking) of 5a-5l were likewise performed.Results: It was surprisingly observed that the MIC values of 5a-5l were equal to the MIC values of ciprofloxacin (12.5 µg/ml) against the tested bacteria, whereas the DNA gyrase inhibitory activity (IC50 in µg/ml) of 5h (3.52), 5g (3.76), 5f (3.88), 5e (4.08), 5l (4.11), 5b (4.28), 5k (4.28), 5i (4.30), and 5d (4.32) was equal/better than ciprofloxacin (4.32). The MTT assay also implied the non-cytotoxic nature of 5a-5l against HepG2 & Vero cell lines up to 200 µg/ml concentration. The docking outcomes indicated a similar binding pattern of 5a-5l and ciprofloxacin at the active site of DNA gyrase, wherein 5a-5l displayed a better binding affinity for the active site. The in-silico toxicity data employing the ProTox-II web server indicated no hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, or cytotoxic effect of 5a-5l. Also, the SwissADME software supported the drug-likeliness properties and high gastrointestinal absorption of 5a-5l.Conclusion: Compounds 5h, 5g, 5f, 5e, 5l, 5b, 5k, 5i, and 5d are potent DNA gyrase inhibitors with promising safety profiles.Keywords: Discovery; Morpholine; Thiazole; DNA gyrase; MTT assay; Docking

In vitro and In Silico Molecular Modeling Studies of Newly Synthesized Pyrrole Derivatives for their Antimicrobial and Anticancer Properties

Background: Pyrroles are biologically active scaffolds that can have a number of different effects. They also have unique pharmacophores inside their ring system that make it easier to make molecules that are more active. Significantly, in the past ten years, research has been conducted on the anti-bacterial properties, with a particular emphasis on drug-resistant Gram-positive and Gram-negative pathogens such as mycobacteria. Additionally, scaffolds based on pyrroles were utilized in the production of anti-tumor medicines that function by modulating or suppressing genes. Objective: This research aimed to create new pyrrole derivatives by chemical means and evaluate their antimicrobial and anticancer properties. Methods: By reacting diverse 1H-pyrrole-2-carbohydrazide derivatives with benzaldehyde under normal conditions, a number of pyrrole variations were created. IR, mass spectroscopy, NMR, and elemental analysis were used to characterize the synthesized compounds. The serial dilution method was used to assess antimicrobial activity, along with a molecular docking study against the enzyme α-topoisomerase II (α-Topo II), which effectively controls the topology of DNA. This enzyme is strongly expressed in rapidly dividing cells and is crucial for transcription, replication, and chromosome structure. Pyrrole and its synthetic derivatives are known to exhibit strong anticancer activity by specifically targeting α-Topo II, which has led multiple researchers to investigate α-Topo II inhibitors as potential anticancer medicines. Consequently, designing pyrroline derivatives is interesting since the succinimide portion of the joined heteroaromatic molecule can selectively engage with the ATP binding pocket via the hydrogen bond network. Newer synthesized compounds were also docked via Schrodinger 2022-4 into the active pocket of the three-dimensional crystallographic structure of the ATP site of human topoisomerase IIα (htopo IIα) (PDB ID: 1zxm). Results: Among the newly synthesized pyrrole derivatives, compounds demonstrated significant anti- microbial activity. In addition, the AutoDock Vina application was used to perform in-silico docking computations. Compounds 1a and 1h were found to have a stronger antiproliferative effect than compounds against MCF-07 breast cancer cell linen our study, ligands 1a and 1b exhibited better binding energies of -5.049 and -5.035 kcal/mol, respectively. Most of the synthesized pyrrole derivatives showed promising antiproliferative effects; however, further in vivo investigations are needed to confirm or refute these results. Conclusion: The results of this investigation show that pyrrole derivatives have the potential to be effective antimicrobial and anticancer agents. While resolving safety issues, the structural alterations carried out in this study enhanced the compounds' medicinal capabilities. To clarify the underlying mechanisms of action and enhance the pharmacological characteristics of these new pyrrole derivatives, further research is necessary.

Pharmacophore‐Based Modeling, Synthesis, and Biological Evaluation of Novel Quinazoline/Quinoline Derivatives: Discovery of EGFR Inhibitors with Low Nanomolar Activity

AbstractThe main aim of this study is to obtain novel molecules that are more selective on cancer cells compared to healthy cells. For this purpose, four hit molecules are identified using 11 new pharmacophore hypotheses followed by scanning the in‐house database. Then, based on those hit molecules, the synthesis and analysis of four different series (three quinazolines and one quinoline series) are carried out, and their anticancer activity is investigated. Finally, by using molecular docking and dynamics simulation methods, binding mode and structure–activity relationship are examined. Among the quinazolin‐4(3H)‐one derivatives, those containing halogen atom are found to be potentially effective, while the best epidermal growth factor receptor (EGFR) inhibition and apoptosis induction are displayed by compounds containing 4‐amino‐1,2,4‐triazole moiety. Notably, four compounds (4h, 8d, 8l, and 8m) show EGFR inhibition activity at 5.298 ± 0.164, 5.46 ± 0.221, 2.670 ± 0.124, and 2.191 ± 0.908 × 10−9 m, their inhibitory activity is similar to or stronger than gefitinib (IC50: 4.169 ± 0.156 × 10−9 m). In addition, EGFR inhibitor concentration of 4g, 8e, and 8o is determined as 27588 ± 6.945, 52.41 ± 2.312, and 33657 ± 8.512 × 10−9 m. These findings indicate that generated pharmacophore hypotheses successfully determine new EGFR inhibitors. In conclusion, four novel compounds, more active than gefitinib with fewer side effects, are reached, and the structure–activity relationships are clarified.

Exploring Benzo[h]chromene Derivatives as Agents against Protozoal and Mycobacterial Infections

Background/Objectives: In this study, the efficacy of benzo[h]chromene derivatives as antiprotozoal and antimycobacterial agents was explored. Methods: A total of twenty compounds, including benzo[h]chromene alkyl diesters and benzo[h]chromene-triazole derivatives, were synthesized and tested against Trypanosoma cruzi, Leishmania braziliensis, L. infantum, and strains of Mycobacterium abscessus and Mycobacterium intracellulare LIID-01. Notably, compounds 1a, 1b, 2a, and 3f exhibited superior activity against Trypanosoma cruzi, with IC50 values of 19.2, 37.3, 68.7, and 24.7 µM, respectively, outperforming the reference drug benznidazole (IC50: 54.7 µM). Results: Compounds 1b and 3f showed excellent selectivity indices against Leishmania braziliensis, with SI values of 19 and 18, respectively, suggesting they could be potential alternatives to the commonly used, but more selective, miltefosine (IC50: 64.0 µM, SI: 43.0). Additionally, compounds 1a, 1b, and 3f were most effective against Leishmania infantum, with IC50 values of 24.9, 30.5, and 46.6 µM, respectively. Compounds 3f and 3h were particularly potent against various Mycobacterium abscessus strains, highlighting their significance given the inherent resistance of these bacteria to standard antimicrobials. Conclusions: The sensitivity of Mycobacterium intracellulare LIID-01 to these compounds also underscored their potential in managing infections by the Mycobacterium avium–intracellulare complex.

Design, Synthesis of Novel Pyrimidine Derivatives Containing Alkenyl Moieties With Herbicidal Activities

ABSTRACTTo identify lead compounds with potent herbicidal activity, a range of pyrimidine derivatives containing alkenyl groups were designed, synthesized, and characterized using nuclear magnetic resonance (NMR) spectroscopy and high‐resolution mass spectrometry (HRMS). The synthetic pathways for producing these compounds involved substitution reactions, cyclization, hydrolysis, and other processes. The starting materials for each reaction step were readily accessible, facilitating synthesis. The purification of the final product was straightforward, yielding approximately 80%, under mild reaction conditions. Moreover, a pot culture experiment was employed to assess the herbicidal efficacy of the aforementioned compounds. Compounds 6a, 6b, 6h, and 6j demonstrated a significant inhibition against Amaranthus retroflexus, comparable to fomesafen at 150 g a.i./hm2. This suggests that these compounds hold promise as potential lead structures for herbicidal agents. The docking results indicated that the binding energies of compound 6a with protoporphyrinogen oxidase (PPO) were both negative and spontaneous, with numerous interaction active sites. Thus, it is speculated that compound 6a is a PPO inhibitor.

Screening of synthesized perimidine compounds for the assessment of antimicrobial potential: in-vitro and in-silico molecular docking and molecular dynamics simulation studies

Presently, antimicrobial resistance is a major and worldwide concern due to high rate of mutation in microorganisms, widespread use, lack of efficacy of drugs, and low drug discovery rate. Considering the importance of N-heterocycles as antibiotics, perimidine derivatives 3(a–v) have been synthesized via cyclocondensation reaction of 1,8-diaminonaphthalene and aryl aldehydes. Further, the synthesized perimidines 3(a–v) were screened as potent antimicrobial agents via in-vitro, in-silico, ADME and MD simulation studies. All 22 derivatives 3(a–v) were studied against two-gram +ve (E. coli and P. aeruginosa), two-gram −ve (S. aureus and B. subtilis), and two fungal (A. niger and S. cerevisiae) strains using ciprofloxacin and fluconazole as reference drugs. The in-vitro study results showed that compounds 3e, 3h, 3l, and 3m were the most potent against S. aureus and 3(a–d), 3(g–i), and 3s were the most active against B. subtilis as compared to the standard. Furthermore, molecular docking studies were performed against Dihydrofolate reductase (PDB Id: 3SRW) from S. aureus, DNA gyrase (PDB Id: 4DUH) from E. coli, and ERG11 gene (PDB Id: 4LXJ). Compounds 3f, 3f/3m, and 3o were found to bind efficiently with the highest binding energy − 10.6, − 9.6, and − 11.3kcal/mol depicting the potential inhibitor of 3SRW, 4DUH, and 4LXJ receptor protein, respectively. The drug-likeness properties of compounds were studied using SwissADME program. To further validate these findings, molecular dynamics simulations were conducted to evaluate their binding stability. From simulation studies, it was observed that all the shortlisted compounds displayed stable binding within the active site of the selected proteins.Graphical abstract

Anti-Diabetic Activities and Molecular Docking Studies of Aryl-Substituted Pyrazolo[3,4-b]pyridine Derivatives Synthesized via Suzuki Cross-Coupling Reaction.

Pyrazolo[3,4-b]pyridine scaffolds have been heavily exploited in the development of nitrogen-containing heterocycles with numerous therapeutic applications in the field of medicinal and pharmaceutical chemistry. The present work describes the synthesis of eighteen biaryl pyrazolo[3,4-b]pyridine ester (6a-i) and hydrazide (7a-i) derivatives via the Suzuki cross-coupling reaction. These derivatives were subsequently screened for their therapeutic potential to inhibit the diabetic α-amylase enzyme, which is a key facet of the development of anti-diabetic agents. Initially, the ethyl 4-(4-bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate 4 was synthesized through a modified Doebner method under solvent-free conditions, providing an intermediate for further derivatization with a 60% yield. This intermediate 4 was subjected to Suzuki cross-coupling, reacting with electronically diverse aryl boronic acids to obtain the corresponding pyrazolo[3,4-b]pyridine ester derivatives (6a-i). Following this, the biaryl ester derivatives (6a-i) were converted into hydrazide derivatives (7a-i) through a straightforward reaction with hydrazine monohydrate and were characterized using 1H-NMR, 13C-NMR, and LC-MS spectroscopic techniques. These derivatives were screened for their α-amylase inhibitory chemotherapeutic efficacy, and most of the biaryl ester and hydrazide derivatives demonstrated promising amylase inhibition. In the (6a-i) series, the compounds 6b, 6c, 6h, and 6g exhibited excellent inhibition, with almost similar IC50 values of 5.14, 5.15, 5.56, and 5.20 μM, respectively. Similarly, in the series (7a-i), the derivatives 7a, 7b, 7c, 7d, 7f, 7g, and 7h displayed excellent anti-diabetic activities of 5.21, 5.18, 5.17, 5.12, 5.10, 5.16, and 5.19 μM, respectively. These in vitro results were compared with the reference drug acarbose (IC50 = 200.1 ± 0.15 μM), demonstrating better anti-diabetic inhibitory activity in comparison to the reference drug. The in silico molecular docking study results were consistent with the experimental biological findings, thereby supporting the in vitro pharmaceutical efficacy of the synthesized derivatives.

N‐Methoxy Pyrazole‐4‐Carboxamide Derivatives: Synthesis, Spectral Analyses, Antifungal Activity, In Silico Molecular Docking, ADMET, and DFT Studies

ABSTRACTSuccinate dehydrogenase inhibitor (SDHI) is an important fungicide to control grain diseases. For this reason, a series of novel pyrazole‐4‐carboxamide derivatives with an N‐methoxy group were designed and synthesized. All the target compounds were characterized by 1H NMR, 13C NMR, and HRMS. The compound 3c was further confirmed by X‐ray diffraction, which crystallized in the triclinic system, space group P‐1, Z = 2. The fungicidal activity results indicated that most of these compounds possessed good activity against Sclerotinia sclerotiorum at 50 ppm. Especially, compound 3h exhibited the best activity with the EC50 is 7.80 μg/mL, which is comparable with the positive control bixafen (EC50 = 6.70 μg/mL). Furthermore, the physicochemical properties, molecular docking simulation, ADMET analyses, DFT of compounds 3h, 3k and two commercial SDHIs, isoflucypram and pydiflumetofen, were investigated in this study.

Novel 1,2,3-triazole derivatives containing benzoxazinone scaffold: Synthesis, docking study, DFT analysis and biological evaluation

In order to address the drastic demand for novel broad-spectrum antibacterial and anticancer medicines with enhanced activity, computer modelling was utilized to rationally develop newer anticancer triazole based drugs. A unique series of benzo[d][1,3]oxazin-4-one linked 1,2,3-triazoles was synthesised in five steps, with good yields and an assessment of their antibacterial and anticancer activities. IR spectroscopy, 1H NMR, 13C NMR, and mass spectrometry were used to characterize the synthesis of triazole compounds. From antibacterial screening, the prepared derivatives namely, 8a, 8e, 8h and 8k showed excellent inhibitory potential against S. aureus with ZI of 28 ± 0.48, 30 ± 0.42, 30 ± 0.11, 35 ± 0.23 mm respectively, compared to moxifloxacin (33 ± 0.15 mm). Compared to doxorubicin (IC50 = 2.45 ± 0.14 μM), compounds 8h and 8k demonstrated superior and exceptional cytotoxicity against the A549 cell line (IC50 = 2.30 ± 0.26 and 1.90 ± 0.30 μM, respectively). Latter All the derivatives were further subjected to in silico docking studies against human lung (PDB: 2P85), VEGFR2 kinase domain (PDB: 3CP9) and could serve as ideal leads for additional modification in the field of anticancer research. Based on docking results, 8e showed that the amino acids Arg373(A), Gly113(A), Glu103(A), Asp108(A), Ser119(A), Asn375(A), Val374(A), Lys387(A), and Asn120(A) exhibited highly stable binding to cytochrome P4502A13 receptor of lung cancer. Furthermore, Density Functional Theory (DFT) calculations are performed to support the molecular docking studies. Compounds 8e, 8h, and 8k were discovered to have estimated energy gaps (eV) of 3.181, 4.034, and 3.539 eV, respectively. Triazole 8h exhibited the lowest chemical hardness (1.962 eV) and the highest chemical softness (0.252 eV), which also suggests that it is more reactive than all the other compounds under study. Moreover, these scaffolds physicochemical characteristics, filtration molecular properties, assessment of toxicity, and bioactivity scores were assessed in relation to ADME (absorption, distribution, metabolism, and excretion). In conclusion, we discovered a novel benzoxazinone linked 1,2,3-triazoles with promising antimicrobial and anticancer activity and a favorable pharmacokinetic profile.

Bcr-Abl Inhibitory Activities of Imatinib Derivatives

Background: Imatinib, a frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML), was a synthetic tyrosine kinase inhibitor approved by the US Food and Drug Administration. Objective: To expand the structural diversity of Bcr-Abl inhibitors, we synthesized nine novel imatinib analogues (1a-1i) and evaluated their cytostatic effects against human cancer cell lines in vitro. Method: Imatinib and its analogues were successfully synthesized by an improved method in six main steps. Inhibitory activities of all compounds were evaluated on K562, HL-60, MCF-7, A549 and PBMC in vitro. Then, the effect of the most active compound was studied using flow cytometer, real-time qPCR and western blot experiments to determine its mechanism action. Finally, the molecular docking of the most active compound were determined. Results: The IC50 of one imatinib analogue (compound 1h) for K562 and HL-60 was lower than imatinib itself. Further studies indicate that the pro-apoptotic effect of compound 1h on K562 cells was stronger than imatinib over a range of concentrations. Importantly, the real-time qPCR and western blot experiments showed that compound 1h was superior to imatinib in inhibiting Bcr-Abl expression. The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analogue. Introducing benzene (A ring) and piperidine (E ring) rings instead of pyridine (A ring) and piperazine (E ring) in imatinib significantly enhanced the potency of imatinib against K562 and HL-60 cell lines, which is consistent with the docking results. Conclusion: Imatinib analogue 1h showed a better inhibitory effect on leukemia cell lines than other cell lines, which was consistent with the imatinib-like structure, moreover, had little effect on PBMC. Overall, we conclude that compound 1h has the potential to treat chronic myeloid leukemia.

Exploring Acyl Thiotriazinoindole Based Pharmacophores: Design, Synthesis, and SAR Studies with Molecular Docking and Biological Activity Profiling against Urease, α-amylase, α-glucosidase, Antimicrobial, and Antioxidant Targets.

A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5h with para cyano group manifested the most pivotal biological activity among all, displaying IC50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5g possessing a p-CH3 at phenyl ring unfolded as most active, with calculated IC50 values 90.3 ± 1.1µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds.

Phytotoxic and Cytogenetic Assessment of Glycerol Triazole Derivatives in Model Plants and Weeds.

Weed invasion represents a challenge for farmers, who typically manage it with herbicides. However, this approach raises concerns about environmental and human health, as well as increasing resistance in these plants with continued use. Therefore, exploring alternative methods, such as heterocyclic compounds, triazoles, is essential due to their biological and environmental relevance. This study aimed to evaluate the effects of twelve 1,2,3-triazoles on the germination and early development of Lactuca sativa, Bidens pilosa, and Lolium multiflorum, as well as their impact on cell division in the cells of L. sativa. Triazole derivatives 4a, 4b, 4c, 4g, 4h, 4i, 4k, and 4l exhibited phytotoxicity, showing varying levels of inhibition in germination, germination speed index, and root growth. Chlorinated compounds were the most detrimental to lettuce development. B. pilosa was notably affected by compounds 4h, 4i, 4k, and 4l, while L. multiflorum responded most to triazoles 4c and 4l, with effectiveness comparable to that of the herbicide glyphosate. All derivatives, except 4l, exhibited aneugenic mechanisms of action, and 4a, 4b, 4c, 4e, 4f, and 4g showed clastogenic effects. This study demonstrated the potential of triazoles as effective agents against weed growth, with mechanisms that warrant further investigation for agricultural applications.

Synthesis, Molecular Docking Studies and Biological Evaluation of Thiazolyl Hydrazone Derivatives of Chromone-3-carbaldehyde as Potent Anti-Oxidant and Anti-Inflammatory Agents.

A series of 15 thiazolyl hydrazone derivatives of chromone-3- carbaldehyde have been designed and synthesized by the cyclization of thiosemicarbazone derivatives of chromone-3-carbaldehydes with 4'-substituted-2-bromo acetophenones. All these derivatives were evaluated for antioxidant activity by their direct scavenging activity objects to reactive oxygen species such as DPPH, and nitric oxide, as well as in vitro antiinflammatory activity by a protein denaturation method. Most of these synthesized compounds have shown significant antioxidant activity, among which the compounds 5b, 5c, 5e, 5g, and 5j showed very good antioxidant activities in comparison with the standard ascorbic acid. The in vitro anti-inflammatory activity revealed that the compounds 5b, 5g, and 5h possessed significant activity compared to standard diclofenac sodium. Additionally, molecular docking studies of these molecules using ovalbumin as the protein showed remarkable interactions with its active site residues, and the results indicated that the binding mode of these compounds closely resembled that of the reference compound, diclofenac sodium. Thus, these compounds represent an attractive template for the evaluation of new antiinflammatory and antioxidant agents and might be useful for exploring new therapeutic tools.