Synthesis, molecular docking and ADME studies of thiazole-thiazolidinedione hybrids as antimicrobial agents

A new set of molecules was designed and synthesized by compilation of pharmacologically potential segments thiazole and quinoline bridged by 2-azetidinone as a linker in a single molecular skeleton. Structural analysis of synthesized molecules (5a-p) was executed by IR, 1H NMR, 13C NMR, and mass spectroscopy techniques. Aforesaid compounds were analyzed for investigation of their antimicrobial capability against several bacterial and fungal strains. The synthesized compounds 5b, 5f, 5h, 5i, 5k, and 5l were active against bacterial strains while compounds 5j and 5k were active against fungal strains. Synthesized compounds were found to be potential inhibitors against gram-negative bacterial strains Escherichia coli and Pseudomonas aeruginosa, while the same were not effective against gram-positive strains of Staphylococcus aureus and Streptococcus pyogenes. Compounds with electron-releasing substituents were active molecules against all fungal strains used in screening. Also, the influence of substituents on the antimicrobial activity of target molecules (5a-p) was discussed. Molecular docking study against crucial microbial target β-Ketoacyl-acyl carrier protein (ACP) synthase III (FabH) could provide valuable insights into their plausible mechanism of action.

Ten hexahydropyrimido[4,5-d]pyrimidine derivatives have been synthesized by using a green and time-efficient microwave method. The synthesized motifs were evaluated for their anticancer activity, antimicrobial activity, molecular docking, drug likeliness and ADMET studies. Comparatively, the hetero-aromatic pyrazole substituted compound 4a exhibited the highest anticancer activity [Mean growth percent: 35.57], while EDG [-N(CH3)2] substituted compound 4i indicated very good activity [Mean growth percent: 60.92] against various cell lines. From the computational studies, Compound 4a passed the drug-likeness and ADME properties, fewer toxic properties, and potent inhibitory potential against the RIPK2 with significant binding affinity. In-silico molecular docking revealed that the compound 4a has significant binding energy (-9.8kcal/mol) and dissociation constant (0.54µM) properties. Additionally, synthesized motifs were evaluated for antimicrobial activity by MIC referencing the standards. According to the SAR evaluations, the compounds 4f (4-NO2), 4g (3-NO2), and 4h (2-Cl) that include EWGs substituted aldehydes performed well as antimicrobials against selected bacterial and fungal strains. Thus, the synthesized pyrimido[4,5-d]pyrimidine with the heterocyclic and EWGs substituents could act as a potential candidate after further structural optimization for anticancer and antimicrobial drug discovery, respectively.

A series of chalcone derivatives were synthesized and characterized using UV-vis, FT-IR, 1H NMR, and mass spectrometry, followed by the evaluation of their antimicrobial and antioxidant properties. In vitro screening against six bacterial strains (Staphylococcus aureus, Bacillus subtilis, Salmonella typhimurium, Escherichia coli, Pseudomonas aeruginosa, and Citrobacter freundii) and two fungal strains (Aspergillus niger and Trichoderma harzianum) revealed outstanding antibacterial activities, particularly with compound 5b, 5d, and 5e against S. aureus, and compounds 5c and 5h against B. subtilis. Notably, compounds 5f and 5g exhibited significant effects against P. aeruginosa, while compound 5b showed the highest antifungal activity against T. harzianum. All compounds demonstrated remarkable antioxidant activities, with 5h (IC50 values of 0.005 μM) and 5c (IC50 values of 0.006 μM) being the most potent, comparable to ascorbic acid (IC50 values of 0.007 μM). In silico evaluations confirmed favorable drug-likeness and pharmacokinetic properties for all analogues, adhering to both Lipinski's rule of Five and Veber's rule. Molecular docking studies of potent antibacterial compounds (5e and 5h) indicated strong binding affinities to the PBP-1b receptor in S. aureus, while DFT calculations provided valuable insights into their molecular reactivity and biological properties. Ligand-based enzymatic target predictions indicate that chalcone analogues (5a-m) show potential as inhibitors of oxidoreductases, kinases, enzymes, proteases, or ligands for family A GPCR. These findings position chalcone derivatives as promising candidates for therapeutic applications in combating bacterial infections and oxidative stress.

Background: The quaternary ammonium compounds (QAC) are the important group of chemical individuals with widespread usage in many fields of industry or science. The surface-active cationic surfactants are well known disinfection agents. Its effectivity against gram-positive, gramnegative bacteria, yeasts and some viruses is already used in many preparations. On the other hand, the emergence of resistance is the cause of an increasing necessity of new substances. Methods: The series of 5-alkyl-7-hydroxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-5-ium bromides has been synthesized as a novel potential antimicrobial agent. Reaction of the nucleophilic substitution type has been used. The novel compounds have been tested as disinfection agents against bacteria and fungi. The microdilution broth method was utilized for antimicrobial evaluation. Standard MTT test was used for cytotoxic evaluation. Results: We have prepared 5 new compounds based on 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ol with different length of lipophilic alkyl chain on the quaternary nitrogen (C10-18). The compounds were characterized with analytical data (NMR, HRMS) and evaluated as wide spectrum antimicrobial agents against pathogenic fungal and bacterial strains. We have observed the efficacy towards microbial cells of C12 and C14 compounds for only several antimicrobial strains (Staphylococcus aureus, Candida krusei, Candida glabrata, Trichophyton mentagrophytes). Conclusion: We report on the preparation and characterization of a set of novel cationic surfactant-like compounds based on 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ol. The novel compounds have been evaluated as wide spectrum antimicrobial agents against pathogenic fungal and bacterial strains. Only two compounds with alkyl chain C12 and C14 showed significant activity against microbes. So, these two compounds should be considered as the potential disinfectants with the selective effect against certain bacterial and fungal strains, not as wide spectra antimicrobial agents. Keywords: Cationic surfactants, quaternary ammonium compounds, synthesis, antimicrobial activity, disinfectants, fungal strain.

Novel substituted 1,2,4-dithiazolylchromones 3a–j were synthesized by the reaction of 3-formylchromones (1a–j) with two equivalents of p-chlorothiobenzamide (2) in dry xylene and characterized spectroscopically (IR, 1H and 13C NMR, mass) and elemental analysis. All synthesized compounds were screened for in vitro antimicrobial activity against various pathogenic bacterial and fungal strains and were found to possess good to moderate inhibitory potential against all tested strains. Antimicrobial results reveal that compounds bearing lipophilic electron withdrawing groups such as chloro and bromo displayed significant inhibitory potential against both bacterial and fungal strains. Particularly, compound 3c displayed significant inhibitory against bacterial strains and compound 3h exhibits significant inhibitory potential in comparison to standard drug fluconazole against fungal strain S. cerevisiae.

A series of hexahydroindazole analogues of curcumin were synthesized and investigated for in vitro and in silico antimicrobial activity. The structures of synthesized compounds were identified on the basis of satisfactory analytical and spectral data (1H NMR, 13C NMR, EI-MASS techniques and elemental analysis). Synthesized compounds showed moderate to high activity against both bacterial and fungal strains. All compounds were docked computationally to the active site of enzyme L-glutamine: D-fructose-6-phosphate amido-transferase [GlcN-6-P] (EC 2.6.1.16). The autodock programme 4.0 was employed to perform automated molecular docking. (E)-1-(7-(3-methoxybenzylidene)-3-(3- methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indazol-2-yl)ethanone (A7) turned out to be the most potent analogue of the series, showing best activity against bacterial and fungal strains. Compound A7 showed minimum binding and docking energy and may be considered as good inhibitor of GlcN-6-P synthase. Further investigation and optimization of this lead could provide new antimicrobial molecules. Keywords: Autodock 4.0, Bacterial strain, Fungal strains, GlcN-6-P synthase, Hexahydroindazole, In silico, cycloheaxanon, glacial acetic acid, ethlyl alcohol, Candida

A potent moiety of (E)-5-(4-(5-chlorothiophene-2-carbonyl) piperazin-1-yl)-N'-(substituted methylene) benzofuran-2-carbohydrazide: Molecular docking, synthesis and antimicrobial evaluation

A series of new quinoline pyrazolyl‐chalcone hybrids ( 4 a – 4 s ) was obtained from 4‐acetyl‐5‐methylquinolylpyrazole and aromatic aldehydes and the structure of these hybrids were established with the help of FTIR, 1D NMR ( 1 H and 13 C), 2D NMR and HRMS data. The anticancer potential of selected quinoline pyrazolyl‐chalcone hybrids was evaluated against colon cancer (HT‐29, HCT‐116), lung cancer (A549), and prostate cancer (PC‐3) cell lines. ( E )‐1‐(5‐Methyl‐1‐(4‐methylquinolin‐2‐yl)‐1 H ‐pyrazol‐4‐yl)‐3‐(2,4,6‐trimethoxyphenyl)prop‐2‐en‐1‐one ( 4 j ) displayed good cytotoxicity with IC 50 values of 5.4, 3.2 and 2.8 μM against HT‐29, A549, and PC‐3 cancer cell lines, respectively. The antimicrobial potential of quinoline pyrazolyl‐chalcone hybrids was tested against three bacterial strains ( B. subtilis , S. aureus and E. coli ) and two fungal strains ( A. niger and C. albicans ). ( E )‐1‐(5‐Methyl‐1‐(4‐methylquinolin‐2‐yl)‐1 H ‐pyrazol‐4‐yl)‐3‐(3‐nitrophenyl)prop‐2‐en‐1‐one ( 4 r ) exhibited significant activity against Gram positive bacteria ( B. subtilis and S. aureus) and fungal strains with MIC value of 15.6 μM. Molecular docking analysis was conducted to determine the binding interactions of quinoline pyrazolyl‐chalcone hybrids with their respective biochemical targets viz . Epidermal growth factor receptor tyrosine kinase (EGFR), Thymidylate kinase (TMK) and C. albicans N‐myristoyltransferase.

A series of novel piperazine based cinnamic acid bearing coumarin derivatives were designed and synthesized by piperazine based cinnamic acids esterification with 4-hydroxycoumarin and characterized by various spectral techniques like infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass. The novel bioactive compounds (7a-7m) screen their potential against different bacterial and fungal strains. Compound 7g (minimum inhibitory concentration [MIC] = 12.5 µg/ml) exhibited potent antibacterial activity against Escherichia colistrain. Compounds 7d, 7f, 7g, 7k, 7l, and 7m showed potent antibacterial activity against all bacterial strains. Compounds 7a, 7g, 7h, 7k, 7l, and 7m exhibited potent antifungal activity against all fungal strains. Furthermore, a molecular docking study revealed that compounds 7d, 7f, 7g, and 7k could bind to the active site of E. coli DNA gyrase subunit B protein and form hydrogen bonding with crucial amino acid residues Arg136 in the active sites. Comprehensively, our study recommends that 7d, 7f, 7g, and 7k could be a promising lead for developing more efficient antimicrobial drug candidates and DNA gyrase inhibitors.

A series of 5-aryl-3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-(pyridin-4-yl)thiazolidin-4-ones were synthesized and evaluated for their antibacterial and antifungal activities. Various spectral techniques e.g., IR, 1H NMR, 13C NMR and Mass spectrometry were used to determine structure of novel synthesized compounds. The title compounds showed good to excellent inhibition potency for respective Gram-positive bacterial strains and Gram-negative bacterial strains. These compounds exhibited a broad spectrum of inhibitory activity. Molecular docking studies against microbial DNA gyrase sub unit B could provide valuable insights into the binding affinity of these molecules and their plausible mechanism of antimicrobial action. Compounds 5a, 5d, 5f and 5h, 5i, 5j, 5o exhibited excellent activity against bacterial and fungal strains respectively.

Synthesis, X-ray crystallography, antimicrobial, molecular docking, and DFT study of bis-triazoles linked ampyrone

Background: In the past few decades, mankind is suffering from tormented life-threatening infectious diseases caused by multidrug-resistant bacteria. As a result, new antimicrobial classes with distinct modes of action are required to combat multidrug-resistant infections. Objective: The pyrazole-based pyrimidine and pyrazolone motifs were synthesized, characterized, and screened for their antimicrobial activity. Molecular docking was carried out for the development of antimicrobial agents based on the results of biological activity obtained. Methods: We have synthesized a new series of pyrazole containing pyrimidine-pyrazolone hybrids by using multi-step reactions in the search of antimicrobial agents (7a-o). The structures were determined by 1H NMR, 13C NMR, IR, and mass spectroscopy techniques. Moreover, synthesized compounds were evaluated for their antimicrobial activity by using serial Broth dilution method. Results: Antimicrobial activity of synthesized compounds has been tested against bacterial and fungal strains. Compound 7o was most effective against S. aureus with MIC = 0.096 M/mL. A molecular docking study against microbial DNA gyrase revealed important information about the mechanisms underlying antimicrobial efficacy. Through significant interactions with active site residues, all of the compounds were able to dock well into the enzyme's active site. Furthermore, Compounds 7a (0.531 M/mL), 7b (0.456 M/mL), and 7m (0.485 M/mL) showed excellent antifungal activity against C. albicans compared to the positive control griseofulvin. Conclusion: It has been concluded that compounds containing electron-donating groups are found to be most active against bacterial strains while compounds having both electron-donating as well as electron-withdrawing groups are most favorable for antifungal activity.

Antimicrobial resistance which is increasing at an alarming rate is a severe public health issue worldwide. Hence, the development of novel antibiotics is an urgent need as microbes have developed resistance against available antibiotics. In search of novel antimicrobial agents, a convenient route for the preparation of substituted 3-(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)-1-(2-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)prop-2-en-1-ones (6a-6o) has been adopted by using pyridine-3-carbohydrazide and various aromatic aldehydes. The newly synthesized compounds were characterized by using various spectral techniques, for example, IR, 1 H NMR, 13 C NMR, and mass spectroscopy. Synthesized hybrids were studied for in vitro antimicrobial potency against various bacterial and fungal strains. Antibacterial results revealed that compounds 6e, 6h, 6i, 6l, and 6m were found to be most active against bacterial strains as they showed minimum inhibitory concentration(MIC) value of 62.5 μg/mL while compounds 6d, 6e, and 6h showed MIC value of 200 μg/mL against Candidaalbicans. The quantum parameters that relate to the bioavailability of the compounds were computed, followed by docking with different bacterial and fungal targets like sortase A, dihydrofolate reductase, thymidylate kinase, gyrase B, sterol 14-alpha demethylase. The experimental and computational results are in good agreement.

In order to provide a straightforward, affordable, and environmentally friendly process for the synthesis of metallic nanoparticles, scientists are turning to natural ways like employing plant extract in response to rising antimicrobial resistance and the desire for novel biocidal agents. In this study, we evaluated the efficacy of phyto-fabricated silver nanoparticles and antimicrobial agents against selected indoor bacterial and fungal strains isolated from the lecture and office rooms of Chukwuemeka Odimegwu Ojukwu University, Uli Nigeria. The indoor microorganisms were isolated, identified, and quantified using standard methods. To prepare and generate the aqueous extract employed in the biological synthesis of the silver nanoparticle, fresh soursop seeds were room dried, crushed, heated to boiling, and double filtered. The phyto-fabricated nanoparticles were centrifuged, dried and used for physicochemical characterization and antimicrobial assay. The synthesized silver nanoparticles were characterized using UV-Vis spectrophotometry, Fourier transformed Infra-Red Spectroscopy and scanning electron microscopy analyses. The antimicrobial assay was carried out using agar well diffusion method. The results revealed that Aeromonas, Pseudomonas, Staphylococcus, Vibrio, Rhizopus, Aspergillus, Penicillium and Microsporum were identified as the predominant potential indoor bacterial and fungal pathogenic strains. The characterized biogenic nanoparticles revealed the optical, spectral and morphological features unique to silver nanoparticles. Also, the antibacterial screening revealed that the highest zone of inhibition was observed against Vibrio sp. (27.50 ± 7.5 mm) at a concentration of 30 μg/mL while standard antifungal drug (ketoconazole) had the highest zone of inhibition of 21.0 ± 1.0 mm at 3.25 μg/mL against Microsporum gypseum while standard antifungal drug (ketoconazole) and Ag-NPs had the lowest zone of inhibition of 11.0 ± 1.0 mm at 15.0 μg/mL and 7.5 μg/mL against Rhizopus sp. and Aspergillus flavus, respectively. The negative control (DMSO) had no zone of inhibition on any of the potential indoor bacterial and fungal pathogenic strains. Statistically, there was significant (P < 0.05) inhibition of bacterial and fungal pathogenic strains among the means of treatment doses of A. muricata AgNPs, ciprofloxacin and ketoconazole standard antibiotics. The excellent antimicrobial inhibition of the tested indoor bacterial and fungal strains by the A. muricata fabricated silver nanoparticles even at MIC of 3.25 μg/mL could be exploited as biostatic and biocidal agents where there is contamination or public health risk of pathogenic indoor bacteria and fungi.

Dimers of coumarin-1,2,3-triazole hybrids bearing alkyl spacer: Design, microwave-assisted synthesis, molecular docking and evaluation as antimycobacterial and antimicrobial agents