Synthesis,Characterization, and Molecular Docking of Novel bis‐thiazolyl Thienothiophene Derivatives as Promising Cytotoxic Antitumor Drug

A novel, facile reaction for the synthesis of series of bis‐thiazole derivatives has been developed from the reaction of the appropriate thiosemicarbazone derivatives and bis‐2‐bromoacetylthieno[2,3‐b ]thiophene derivatives in ethanol under reflux. The structures of the newly synthesized products were established on the basis of spectral data (mass, IR, and ¹H and ¹³C NMR) and elemental analyses. Fifteen compounds of the synthesized compounds were evaluated for their anticancer activity against human liver hepatocellular carcinoma cell line (HepG2). All compounds showed anticancer activity but differs in potency comparable with the reference drug Cisplatin. Moreover, molecular docking study using MOE software predicted the best binding mode between the most active compound 5o into the active site of human heat‐shock protein 90. The computational studies are confirming the results in biological activity.     

Synthesis,Enzyme Inhibition,and Molecular Docking Studies of Hydrazones from Dichlorophenylacetic Acids

A series of hydrazones 5a–i were synthesized by the condensation of hydrazides derived from dichlorophenylacetic acids with different aromatic aldehydes and ketones. Their structures were confirmed by spectroscopic data and elemental analysis. Hydrazones 5a–i were evaluated for α‐glucosidase and urease inhibition activities. Five compounds exhibited potent α‐glucosidase inhibitory potential with IC₅₀ values 8.5 ± 0.3, 22.2 ± 0.78, 32.9 ± 1.5, 34 ± 2.4, and 170.6 ± 7.5 μM, respectively, which are many times better than that of the standard inhibitor acarbose (IC₅₀ = 840 ± 1.73 μM). Furthermore, molecular docking study was performed to explore the binding mode in the active sites of α‐glucosidase and urease enzymes.     

cis‐Nitenpyram Analogues Containing 1,4‐Dihydropyridine: Synthesis,Insecticidal Activities,and Molecular Docking Studies

A novel series of cis‐nitenpyram analogues ( 2a – 2p ) were designed and prepared by introducing the 1,4‐dihydropyridine, with their cis‐configuration confirmed by X‐ray diffraction. Preliminary bioassays showed that most compounds exhibited good insecticidal activities at 20 mg/L against Aphis medicagini, and analogues 2a and 2d afforded the best activity, and both of them had 100% mortality at 4 mg/L. In addition, molecular docking studies were also performed to model the ligand‐receptor complexes, and the results explained the structure‐activity relationships observed in vitro, which may provide some useful information for future design of new insecticides.     

Chemopreventive Effect on Human Colon Adenocarcinoma Cells of Styrylquinolines: Synthesis,Cytotoxicity, Proapoptotic Effect and Molecular Docking Analysis

Seven styrylquinolines were synthesized in this study. Two of these styrylquinolines are new and were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, and normal cells (HaCaT). According to the results, compounds 3a and 3d showed antiproliferative activity in SW480 and SW620 cells, but their effect seemed to be caused by different mechanisms of action. Compound 3a induced apoptosis independent of ROS production, as evidenced by increased levels of caspase 3, and had an immunomodulatory effect, positively regulating the production of different immunological markers in malignant cell lines. In contrast, compound 3d generated a pro-oxidant response and inhibited the growth of cancer cells, probably by another type of cell death other than apoptosis. Molecular docking studies indicated that the most active compound, 3a, could efficiently bind to the proapoptotic human caspases-3 protein, a result that could provide valuable information on the biochemical mechanism for the in vitro cytotoxic response of this compound in SW620 colon carcinoma cell lines. The obtained results suggest that these compounds have chemopreventive potential against CRC, but more studies should be carried out to elucidate the molecular mechanisms of action of each of them in depth.     

Synthesis,Characterization, Molecular Docking,and Anticancer Evaluation of 4‐Thiazolidinone Analogues

Scaffolds containing one or more heteroatoms are ubiquitous in nature and are responsible for almost every biological processes in flora and fauna. The fact that heterocyclic cores have high propensity for biological targets, several nitrogen, oxygen, and sulfur‐containing heterocyclic compounds have been reported in the last few decades. One such intriguing class is 4‐thiazolidinone that exhibit diverse range of pharmacological activities. In the present study, we report synthesis, characterization, molecular docking, and anticancer evaluation of 10 new 4‐thiazolidinone analogues ( 5 – 14 ). One of the compounds ( 11 ) was structurally characterized using single crystal X structure. Anticancer evaluation against hepatocellular carcinoma cell line (HepG2) revealed that compound ( 7 ) was the most potent (IC₅₀ = 75 μM) while other showed moderate to low activity (85–530 μM). To underpin the druggability and possible modes of action, drug‐likeness was determined and docking studies were carried out against β‐carbonic anhydrase receptor (PDB ID: 3IA). Attempts have also been made to establish a structure–activity relationship of the reported compounds.     

Design,Synthesis, and Molecular Docking Studies of Pyrazine Containing 1,2,3‐Triazole Derivatives

Here, we demonstrate on the design and synthesis of novel pyrazine containing 1,2,3‐triazole derivatives ( 7a , 7b , 7c , 7d , 8a , 8b , 8c , 8d , and 12a , 12b , 12c , 12d ) using various chemicals, bases, and catalysts synthesized with excellent yields (78–92%) as described in the procedures. The development of this methodology is simple, efficient, and easier to handle; milder reaction conditions and higher selectivity under versatile coupling reagent useful for both amide and ester bond formations have also been developed. The synthesis of amide coupling derivatives prepared by ( 6a , 6b , 6c , 6d ) was coupled with N‐ethylpiperazine to afford ( 7a , 7b , 7c , 7d ) and morpholine to afford ( 8a , 8b , 8c , 8d ) by using 1‐[Bis(dimethylamino)methylene]‐1H‐1,2,3‐triazolo[4,5‐b ]pyridinium 3‐oxid hexafluorophosphate (HATU) and N ,N‐diisopropylethylamine (DIPEA) in dichloromethane at room temperature for 10 h. The derivatives ( 6a , 6b , 6c , 6d ) were coupled with alcohol ( 11 ) by using N ,N′‐dicyclohexylcarbodiimide and 4‐dimethylaminopyridine in dichloromethane (DCM) at room temperature for 16 h to give final compounds ( 12a , 12b , 12c , 12d ). In silico docking approach has been applied to these compounds to screen their efficacy against selected drug targets of cancer and diabetes. The docking approach may facilitate the prediction of activity profile for future experimental findings.     

Synthesis,Insecticidal Assay and Molecular Docking Study of Novel Neonicotinoids N‐Oxide Analogues

Eight novel neonicotinoids N‐oxide analogues were designed and synthesized. All the compounds have been identified by ¹H NMR and HRMS. The N‐oxide analogues exhibit high insecticidal activity against cowpea aphids (Aphis craccivora) at 250 mg·L^?1. The influence of N‐oxide formation on the biological activity was elucidated by computational chemical study, and it indicated that the water bridge hydrogen bonding network was broken due to the influence of the O atom connected with the pyridine ring.     

Synthesis,Biological Evaluation,and Molecular Docking Studies of Some N‐thiazolyl Hydrazones and Indenopyrazolones

Two new series of N‐thiazolyl hydrazones ( 3a – h ) and indenopyrazolones ( 4a – h ) were synthesized by the reaction of various 2‐acyl‐(1H)‐indene‐1,3(2H)‐diones, thiosemicarbazide, and phenacyl bromide/substituted phenacyl bromides. The in vitro antimicrobial activity of these synthesized compounds was assayed against four bacteria, namely, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, and two fungi, namely, Candida albicans and Aspergillus niger, by employing serial dilution method. Ciprofloxacin and fluconazole were used as antibacterial and antifungal reference drugs, respectively. Results of antimicrobial assay showed that the tested compounds have broad range of activity. The compounds 3h and 4a against C. albicans displayed more potency than fluconazole whereas 3b and 3c against B. subtilis showed activity comparable with ciprofloxacin. The synthesized indenopyrazolones ( 4a – h ) were evaluated for their in vitro antioxidant activity by 2,2‐diphenyl‐1‐picrylhydrazyl radical scavenging assay using ascorbic acid as reference. Compound 4b exhibited the highest 2,2‐diphenyl‐1‐picrylhydrazyl radical scavenging with IC₅₀ value 33.14 μg/mL. The observed results of antimicrobial activity were supported by molecular docking study performed to understand the binding interaction of hydrazones ( 3a – h ) and indenopyrazolones ( 4a – h ) with lanosterol 14α‐demethylase.     

Indolyl Linked Meta‐Substituted Benzylidenes as Novel Ligands: Synthesis,Biological Evaluation,and Molecular Docking Studies

Synthesis of indolyl linked benzylidene based meta‐substituted phenyl containing thiazolidinediones ( 4a – b ), rhodanine ( 5a – b ), and 1,3‐dicarbonyl based acyclic analogs of isoxazolidinediones ( 6a – 7b ) in an effort to develop novel α‐glucosidase inhibitors in the management of hyperglycemia for the treatment of type 2 diabetes is reported. The structure of all the novel synthesized compounds was confirmed through the spectral studies (LC–MS, ¹H‐NMR, ¹³C‐NMR, and FTIR). Comparative evaluation of these compounds revealed that the compound 5b showed maximum inhibitory potential against α‐amylase and α‐glucosidase giving an IC₅₀ value of 0.28 ± 0.01 μM. Furthermore, binding affinities in terms of G score values and hydrogen bond interactions between all the synthesized compounds and the AA residues in the active site of the protein (PDB code: 3TOP) to that of Acarbose (standard drug) were explored with the help of molecular docking studies. Compound 5b was considered as promising candidate of this series.     

Novel O‐Alkylated Chromones as Antimicrobial Agents: Ultrasound Mediated Synthesis,Molecular Docking and ADME Prediction

In the development of novel antimicrobial agents, we synthesized novel O‐alkylated chromones 4a–f by ultrasound‐assisted method. The synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. All compounds were assessed in vitro for their efficacy as antimicrobial agents against four bacteria (Staphylococcus aureus , Bacillus subtilis , Escherichia coli , Pseudomonas aeruginosa ) and three fungi (Candida albicans , Candida glabrata , Candida tropicalis ). In particular, compounds 4a , 4b , 4d , 4e , and 4f exhibited potent antimicrobial activity. Molecular docking study was used to rationalize binding interaction at the active site, and the result showed good binding interaction. The compounds were also processed for in silico ADME prediction, and the result showed that compounds could be exploited as an oral drug candidate.     

New Biphenyl‐Based Bispyrazolines: Synthesis,Antimicrobial, and Docking Studies

In this study, a series of new bispyrazolines 8 ( a – f ) have been prepared from the cyclization reactions of bischalcones 7 ( a – f ) with phenyl hydrazine by refluxing under the alkaline alcoholic (KOH/EtOH) conditions. The O‐alkylation reactions of hydroxyl substituted chalcone 6 with different 1,ω‐dibromoalkanes in the presence of anhydrous potassium carbonate, tetrabutylammonium iodide, and dry acetone afforded the symmetrical new bischalcones 7 ( a – f ) in good yields. Chalcone 6 was realized by using the Claisen–Schmidt reaction of m‐hydroxyacetophenone with bipheny‐4‐carboxaldehyde. The various spectroscopic parameters such as IR, ¹H‐NMR, ¹³C‐NMR, and ESI‐MS have been thoroughly used for the structural interpretations of the newly prepared products. The in vitro antibacterial and antifungal activities of these compounds have been examined with the help of serial tube dilution method, and many of the tested products were found to be revealing the promising antimicrobial properties, which were evident from their minimum inhibitory concentration values. The molecular docking simulations of the synthesized substances have also been achieved to observe the structural association into the active site of the Escherichia coli FabH (PdB: 3IL9). Docking results of these compounds suggested that bispyrazoline 8b demonstrated the lowest binding energy that describes its higher stability into the pocket of E. coli. The excellent inhibitory activity of this bisheterocycle against E. coli FabH may be ascribed on the basis of hydrophobic and van der Waals interactions.     

Synthesis of Novel Substituted Phenyl‐3‐Hydrazinyl‐Quinoxaline‐2‐Amine Derivatives: Evaluation of Antimicrobial Activity and Its Molecular Docking Studies

New series of quinoxaline derivatives ( 4a–4h ) were synthesized by treating 2‐chloro‐3‐hydrazinyl quinoxalin ( 3 ) with various anilines. Compound 3 was obtained from the 2,3‐dichloroquinoxaline 2 which was prepared from 4‐dihydroquinoxaline‐2,3‐dione ( 1 ). All synthesized compounds ( 4a–4h ) were characterized by various spectral techniques, that is, IR, ¹H‐NMR, mass spectroscopy, and elemental analysis and completion of reaction were confirmed by TLC. In vitro antimicrobial activity of synthesized compounds was evaluated using disc diffusion assay against gram‐positive and gram‐negative microbial strains, and then, the minimum inhibitory concentration and IC₅₀ values of compounds were also determined. The results of antimicrobial study revealed that compounds 4e , 4g , and 4a were active and exhibited better inhibitory activities as compared with standard drug amoxicillin. Docking studies were performed by using Argus lab, and all the compounds exhibited good docking scores between −9.53 and −7.94 kcal/mol against dihydrofolate reductase protein fragment from Staphylococcus aureus (PDB ID‐4XE6). Among all compounds, 4e has shown the maximum docking score and found in agreement to in vitro studies.     

Synthesis and Molecular Docking Studies of Novel 2‐Phenyl‐4‐Substituted Oxazole Derivatives as Potential Anti‐cancer Agents

A novel series of 2,4‐disubstituted oxazole derivatives were synthesized, screened for their anti‐tumor activity against three cell lines MCF‐ 7 , TK‐10, and UACC‐62. Molecular docking study was carried out against epidermal growth factor receptor. A new series of 2‐phenyl‐4‐substituted oxazole derivatives were synthesized. A series of chiral α‐amino acid derivatives 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 were synthesized by coupling various l ‐acylated amino acid azide 3. The synthesized compounds were tested for their in vitro antitumor activity against MCF‐7, TK‐10, and UACC‐62 cell lines. Compound 6 exhibited the strongest inhibitory activity against TK cell lines, while compound 12 showed the highest activity against MCF‐7 cell lines. Compound 14 was the most active against UACC‐62 cell lines. Furthermore, a molecular docking study of the most active compounds was carried out using epidermal growth factor receptor X‐ray 3D structure (protein data bank ID 1 M17). Docking results revealed that compound 6 showed the highest binding energy of ΔG = ?78.17 Kcal/mol.     

Design,Synthesis, Safener Activity,and Molecular Docking of Novel N‐Substituted Thiazide/Thiazole Derivatives

A series of novel substituted thiazide/thiazole compounds were designed by splicing active groups and bioisosterism. The title compounds were synthesized via the cyclization, acylation, and carbamylation. All the compounds were characterized by IR, ¹H‐NMR, ¹³C‐NMR, and HRMS. The single crystal of compound 3f was determined by X‐ray crystallography. The biological activity tests indicated that all the compounds showed potential safener activity to the herbicide chlorsulfuron, in which compound 3e showed almost the same level as the commercialized safener AD‐67. The molecular docking results were in good agreement with the bioassay results, which demonstrated that compound 3e might compete with chlorsulfuron in the acetolactate synthase active site, causing the herbicide ineffective in maize.     

Synthesis,Antimicrobial Activity and Molecular Docking Studies of 1,3‐Thiazole Derivatives Incorporating Adamantanyl Moiety

Synthesis, characterization and investigation of antimicrobial activity of 11 novel adamantanyl‐thiazoles are presented. Their structures were determined using ¹H and ¹³C NMR, EI(+)‐MS, HRMS, and elemental analyses. Among the derivatives, compound 3c showed very strong activity, especially against Candida albicans ATCC 10231 and Candida parapsilosis ATCC 22019 with minimal inhibitory concentration (MIC) values ranging from 1.95 to 7.81 µg/ml. Compounds 3a and 3b showed good antifungal activity. Among the examined compounds, the widest spectrum of antibacterial activity possessed 3f that showed good activity, especially against Staphylococcus epidermidis ATCC 12228, Micrococcus luteus ATCC 10240, Bacillus subtilis ATCC 6633 with MIC values ranging from 31.25 to 62.5 µg/ml. Molecular docking studies of all compounds on the active sites of microbial enzymes indicated possible targets sterol 14α‐demethylase, secreted aspartic proteinase (SAP), N‐myristoyltransferase (NMT), and topoisomerase II. Thiazoles 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j , 3k showed more favorable affinity to SAP and NMT than the native ligand.     

Facile Synthesis,Antimicrobial Activity and Molecular Docking of Novel 2,4,5‐Trisubstituted‐1H‐Imidazole–Triazole Hybrid Compounds

In the present work, a series of 18 imidazole–triazole hybrids ( 4a–r ) has been synthesized in good yield from substituted naphthaldehydes and 1,2‐diketones in the presence of ammonium acetate. The synthesized imidazole–triazole hybrid compounds were characterized by spectral techniques and screened in vitro for their antimicrobial activity. Compound 4h was found to be most active against Staphylococcus epidermidis, and compound 4e exhibited promising activity against Escherichia coli. In the fungal species under test, compound 4q was most potent against Aspergillus niger, even better than the fluconazole. Further, compound 4e was docked in the binding site of DNA gyrase topoisomerase II of E. coli.     

A 1,2,4‐Triazole‐based Polynuclear Mixed‐valence MnIIMnIII Complex: Synthesis,Characterization, and Magnetic Property

A mixed‐valence Mn complex {[Mn^IIMn^III(HL)₂(4,4′‐bpy)(H₂O)₂] · (ClO₄)(DMF)₃(4,4′‐bpy)_0.5}_n ( 1 ) [H₂L = 3‐(2‐phenol)‐5‐(pyridin‐2‐yl)‐1,2,4‐triazole] was synthesized and characterized by X‐ray single‐crystal structure analysis and magnetic susceptibility. Single‐crystal X‐ray analysis revealed that complex 1 has a dinuclear core, in which adjacent central Mn^III atoms are linked by 4,4′‐bipyridine to form an infinite one‐dimensional (1D) molecular configuration. According to the Mn surrounding bond lengths and bond valence sum (BVS) calculations, we demonstrated that the Mn atom coordinated to the pyridine N atoms is in the +2 oxidation state, while another Mn atom coordinated to the phenolic oxygen atoms is in the +3 oxidation state. Magnetic susceptibility data of the complex 1 indicate that the ferromagnetic interaction dominates in this complex.     

Multistep Synthesis of Fluorine‐Substituted Pyrazolopyrimidine Derivatives With Higher Antibacterial Efficacy Based on In Vitro Molecular Docking and Density Functional Theory

Some new fluorine‐substituted pyrazolopyrimidine derivatives ( 1.3 – 1.5 ) have been synthesized by the multistep reactions, starting from reaction of 4‐fluorophenyl malanonitrile ( 1 ) with guanidine, followed by ring closure reaction with hydrazine to give 2,4‐diamino‐6‐aryl‐pyrimidine‐5‐carbonitrile ( 1.2 ). Structure of the compounds was conformed by the spectral and elemental analyses. The antibacterial activity of these compounds was tested in vitro by the disk diffusion assay against two Gram‐positive and two Gram‐negative bacteria, and then the minimum inhibitory concentration was determined with reference to the standard drug chloramphenicol. The results showed that compound 1.5 is better at inhibiting growth as compared with chloramphenicol of both types of bacteria (gram‐positive and gram‐negative). Molecular orbital calculations were carried out by using the density functional theory. The B3LYP/6‐311 + G** level of theory was employed to explore LUMO–HOMO gap energy and charge distribution of compounds 1.1 to 1.5 . Docking studies were performed on bacterial glucosamine‐6‐phosphate synthetase enzyme. Density functional theory calculations and docking studies support the in vitro findings.     

Synthesis,Antimicrobial Evaluation,and Docking Studies of Substituted Acetylphenoxymethyl‐triazolyl‐N‐phenylacetamides

A series of molecules containing acetylphenoxymethyl, triazole, and N‐phenylacetamide moieties were synthesized via the click chemistry approach. All the synthesized compounds were screened for their antimicrobial activities in vitro. The synthesized compounds 8a , 8b , 8m , and 8n showed better activities. We further performed exploratory docking studies to gain some insight regarding the molecular mechanism of antibacterial action of these compounds that could guide further structure‐activity relationship (SAR) studies. We examined the interaction of the most active compound with DNA gyrase (pdb id:1KZN). Based on antimicrobial and docking studies, the compounds 8a , 8b , 8m , and 8n were identified as potential antimicrobial agents.