(searched for: doi:10.5155/eurjchem.8.1.76-81.1542)
Journal of Molecular Structure, Volume 1247; https://doi.org/10.1016/j.molstruc.2021.131314
This work aimed to synthesize a safe antimicrobial agent based on dihydroquinoxalinedione derivatives. The structure of the synthesized compounds was established based on different spectral data. The antimicrobial activity for the tested compounds was evaluated against eight pathogens. Also, the ADMET was measured to identify toxicity prediction, lipophilicity, bioactivity, and pharmacophores for antimicrobial activities for these compounds. The presence of the tautomerism process is the chief factor that governs the direction of antimicrobial activity. Thus, the DFT has been performed for the identification of physicochemical parameters at B3LYP/6- 311G* level to gain a clear view of global and local molecular reactivity. Besides, the molecular features for the synthesized compounds were identified through, HOMO, LUMO and MEP (Molecular electrostatic potential) were plotted to determine the charge transfer within the molecules. Also, DFT calculations have been used to gain a clear view of global and local molecular reactivity. NLO property was discussed for synthesized compounds, which showed a higher character than reference metrical. The molecular docking via DHPS was performed to rationalize the observed antimicrobial activity. The compounds 2 and 5 represented a significant interaction score. The stability of docked ligands was examined through molecular dynamic simulation, which showed high stability for tested compounds into the active site. The theoretical and experimental investigations suggested that these compounds have promising antimicrobial activity with good oral bioavailability without any observed carcinogenesis effect.
Journal of the Iranian Chemical Society pp 1-25; https://doi.org/10.1007/s13738-021-02319-4
Twenty compounds of pyrazolo[1,5-a]pyrimidines 14a–j and pyrazole derivatives as Schiff bases 16a–j have been synthesized by the reaction of 5-amino-pyrazole derivatives 9a, b with 2-(arylidene)malononitriles 10a–e or various aldehydes 15a–e, respectively. The biological activity of the pyrazolo[1,5-a]pyrimidines 14a–j and pyrazole derivatives 16a–j was evaluated and showed a variation in antimicrobial inhibitory activity. In particular, the three pyrazolo[1,5-a]pyrimidines (14b, 14e, and 14j) and four pyrazole Schiff bases (16c, 16d, 16 h, and 16i) have possessed a broad spectrum of activity with the inhibition zone range from 15 to 20 mm. Also, the structure–activity relationship study was done. Furthermore, physicochemical properties, drug-likeness model score, bioactivity scores, ADME, and toxicity properties were predicted in silico and some products possessed acceptable and a good results. Finally, the molecular docking studies performed inside the active site of DNA gyrase (PDB: 2XCT), the secreted aspartic protease from C. albicans (PDB: 1ZAP), and exhibited lower binding energy with different types of binding mode. Besides, the electrostatic potential maps were generated to determine the charge distribution around a molecule and therefore determine the regions that could form hydrogen bonding donors and acceptors that confirmed the binding mode in the docking study. The results suggested that these derivatives could act as antimicrobial agents.
Journal of Molecular Structure, Volume 1242; https://doi.org/10.1016/j.molstruc.2021.130748
Over the world and especially the developing countries, one of the major threats to human health is antibiotic resistance due to antibiotics abuse. This challenge can be solved by discovering new targets and inhibitors. The current study involved synthesis quinoline based thiazole analogues for quinoline antibiotic class using classic organic synthesis. The designed derivatives were tested against eight standard microbial pathogens. Among them, seven derivatives showed good antimicrobial activity with MIC and MBC values ranged between (0.97-62.5) µg/mL, and (1.94-118.7) µg/mL, respectively. Additionally, the active derivatives displayed good activity against three MDR bacterial stains. Compounds 11b, and 5a exhibited to be the most active derivatives against S. aureus and E. coli with MIC (1.95-7.81) µg/mL and MBC (3.31-15.62) µg/mL followed by other derivatives compared with Ciprofloxacin and Vancomycin. Besides, compounds 6, 11c, and 15 appeared the most active derivatives against MDR P. aeruginosa with MIC and MBC values lower than 10 µg/mL. These derivatives considered effective for treating bacterial infection by inhibiting DHFR enzyme that showed IC50 values (10.02-25.11) µM in comparison to Trimethoprim (18.95 µM). Molecular docking study against DHFR enzyme (1DLS) was carried out, and the active derivatives bind to some the nearly the same amino acid residues as MTX that support our hypothesis. Furthermore, the MEP surfaces were generated using DFT calculation to determine the regions might be responsible for forming different types of interaction and confirm the binding mode in docking study.
Journal of Molecular Structure, Volume 1236; https://doi.org/10.1016/j.molstruc.2021.130317
A new series of quinoxaline derivatives synthesized and pharmacologically evaluated against (HepG-2, HCT-116, and MCF-7) cell lines. Seven compounds were found to possess the highest activities against the examined cell lines with IC50 values ranging from (7.57 to 28.44 µM). To further analyze its apoptotic potential in MCF-7 cells, the most active 3a, 3b, 6, 7b, 7c, 7d, and 7f members have been selected. Interestingly, it found that the Bcl-2 level decreased by 1.95–3.99 folds, and the BAX level increased by 7.2-10.6 folds relative to the control. They also increased the active Caspase-3 level by 5.77-10.69 folds compared to untreated cells. WI38 cells were treated with these compounds to estimate the cytotoxicity level of those compounds in non-tumorigenic cells, and they displayed higher IC50 values (142.21-335.03μM), suggesting may less toxic effect on the normal ones. Further studies on the mechanism of the most promising compounds 3a, 6, 7b and 7d, revealed that it increases apoptotic cells and induced cell cycle arrest at pre-G1 and G2/M phases. Besides, both wild EGFRWT and mutant EGFRL858R-TK inhibitory activity for these derivatives showed that these derivatives had IC50 values ranging from 0.075-1.547 µM versus wild EGFRWT and 63.70-87.34 nM versus the mutant type. Erlotinib was used as a standard reference with IC50 values of 0.0656 µM and 59.56 nM versus both types. Finally, the molecular docking study of most potent quinoxaline derivatives exhibited a good binding inside the active site of EGFR (1M17), with binding energy ranged between (-15.86 to -16.97) compared to Erlotinib (-17.84) kcal/mol. Also, by applying Lipinski's parameters, it was found that these derivatives showed no violations and indicated promiscuity to formulate orally.
Bioorganic Chemistry, Volume 110; https://doi.org/10.1016/j.bioorg.2021.104794
A new series of 1,3,4-thiadiazolo-adamantane derivatives were synthesized through molecular hybridization approach, then used as starting material to synthesize chloro and cyano acetamide-thiadiazole derivatives 2, 3. The newly designed compounds 1–3 were treated with different reagents to design 5-adamantyl thiadiazole derivatives 4–17 and evaluate their in vitro anti-proliferative activity against three cancer cell lines (MCF-7, HepG-2 and A549). Doxorubicin was used as a positive control. The most promising compounds 5, 6, 10a, 10b, 14b, 14c, and 17 showed up-regulation for BAX and down-regulation of Bcl-2, these findings proved their role as hopeful apoptotic inducers. In addition, the inhibitory activity against both wild EGFRWT and mutant EGFRL858R-TK for these derivatives revealed that compounds 5, 14c, and 17 have IC50 value ranging from 85 nM to 71.5 nM against wild EGFRWT and 37.85–41.19 nM against the mutant type, Lapatinib was used as a reference standard with IC50 values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further evaluation against double mutant EGFR L858R/T790M and showed good IC50 values between (0.27–0.78 nM) compared to Lapatinib (0.18 nM) and Erlotinib (0.21 nM). Among them, thiazolo-thiadiazole adamantane derivative 17 exhibited the strongest inhibitory activity to the EGFR. Molecular docking studies were performed inside the active site of EGFR (1M17), and binding energy scores ranged between (−19.19 to –22.07 Kcal/mol) compared to Erlotinib (−19.10 Kcal/mol). Furthermore, oral bioavailability beside some pharmacokinetics properties of these derivatives were also investigated in this research work.
Antibiotics, Volume 10; https://doi.org/10.3390/antibiotics10020162
Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17–23.87 µM, and of DHFR, with IC50 values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.
Bioorganic Chemistry, Volume 104; https://doi.org/10.1016/j.bioorg.2020.104164
2,3-Dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride 1 was prepared via reaction of o-phenylene diamine with oxalic acid followed by chlorosulfonation with excess chlorosulfonic acid. A series of new sulfonylquinoxaline derivatives 2–6 were obtained upon reacting compound 1 with different types of amines. 2,3-Dichloro-6-morpholinosulfonylquinoxaline derivative 6 was subjected to further chemical reactions to afford many derivatives of 6-morpholino 2,3-disubstitutedquinoxalines, thus reaction of compound 6 with different secondary amines yielded mono and di secondary aminoquinoxaline derivatives 7–10 depending on the reactivity difference of the two chlorine atoms. Hydrazinolysis of compound 7 furnished hydrazino quinoxaline derivatives 11a-c. Additionally triazolo and pyrazolyl quinoxaline derivatives 12–14 were obtained through the reaction of compound 11a with phenyl isothiocyanate, formylpyrazole and ethyl acetoacetate. All the synthesized compounds were screened for their antibacterial and antifungal activities. Compounds 7a, 9b, 10a, 10c, 10f and 11c showed good to moderate antimicrobial activity against the tested Gram-positive, Gram-negative bacteria and fungi with MIC values ranging from 2.44 to 180.14 μM. Their MBC values were also evaluated using the same tested microorganisms. Moreover, screening against multi-drug resistant strains revealed the promiscuity of these new derivatives, especially compound 7a that showed comparable antibacterial activity (MIC 4.91–9.82 μM) with Norfloxacin (MIC 2.44–9.80 µM). Furthermore, these compounds were evaluated as DNA Gyrase inhibitors and the obtained results were in the range of 15.69–23.72 µM. Immunomodulatory effect was also investigated and compounds 7a, 11c, 10f, 10c, 10a and 9b showed high immunostimulatory action with ratio (142.6 ± 0.4, 135.7 ± 0.5, 117.8 ± 0. 39, 112.5 ± 0. 83, 86.4 ± 0. 47, 72.8 ± 0. 77) respectively. Molecular docking studies of the promising derivatives into DNA Gyrase binding site proved the usefulness of hybridizing quinoxaline scaffold with SO2 and morpholine moieties as a hopeful strategy in designing new DNA Gyrase binding molecules.
Bioorganic Chemistry, Volume 96; https://doi.org/10.1016/j.bioorg.2020.103619
A series of Schiff bases 3, 5, 7 and hydrazones 9 were achieved via reaction of 5-(morpholinosulfonyl)indol-2,3-dione (1) with appropriate amines and/or hydrazide derivatives. Representative compounds of the synthesized products were tested and evaluated as antimicrobial agents. According to MIC and MBC results from compounds 9a, 9c, 7a, 3b, 3c, and 5b were able to exhibit significant antibacterial activity against both Gram-positive and Gram-negative bacteria together with moderate antifungal activities. Also, a multi-drug resistance study (MDRS) was carried out to evaluate the activity of most potent compounds, and these compounds showed considerable results compared with Norfloxacin and Tetracycline which observed no results against strains used in this study. The inhibitory activity of most potent compounds (3b, 3c, 5b, 7a, 9a, and 9c) against DNA gyrase isolated from S. aureus was examined. The results indicated that all of these derivatives inhibiting DNA gyrase and therefore lead to separate bacterial DNA and inhibit cell division. Compounds 3b, 9c showed to be very potent inhibitors towards S. aureus DNA gyrase with IC50 values (18.75 ± 1.2 and 19.32 ± 0.99 µM) respectively, compared with Ciprofloxacin (26.43 ± 0.64 µM). Molecular docking studies indicated that the synthesized compounds observed good binding with the enzyme and showed lower binding energy of the most promising compounds than a standard drug used, and enabled a better understanding of their structural features.
Synthetic Communications, Volume 50, pp 621-648; https://doi.org/10.1080/00397911.2019.1700524
When, cyanothioformamide derivatives are reacted with certain electrophiles, they produce imidazole, oxazole, thiazole, 2,5-thiadiazole, bis-imidazole and bis-oxazole derivatives; while the reaction with certain nucleophiles furnish benzoxazole, quinaolinone, triazole, bis-triazole, benzoxazinethione and 1,3,4-thiadiazole derivatives. Imidazolidineiminothione derivatives were obtained by ring closure reaction of cyanothioformamide derivatives with isocyanates. These reactions give rise to imidazole derivatives that contain adjacent thione and imino functional groups in the positions 4 and 5 which are reactive in numbers of subsequent ring closure reactions. These compounds find applications as medicinal and pharmacological agents.
European Journal of Medicinal Chemistry, Volume 188; https://doi.org/10.1016/j.ejmech.2019.111977
A series of 2-oxospiro[indoline-3,4′-pyran]derivatives 4 and 7 were obtained in good yield under mild conditions from the one-pot reaction of indole-2,3-dione derivatives 1, appropriate methylene active nitriles 2 and β-dicarbonyl compound 3 or 6. The newly synthesized compounds were characterized and evaluated for their in vitro antibacterial, antifungal as well as immunomodulatory activity. According to MIC values, the most potent compounds 4f, 4h, 7a, 7c, 7e, 7f, 7g, 8a, and 8c were evaluated for MBC and displayed high activity to killing pathogens with a good MBC value against norfloxacin as well as investigated against an extended panel of multidrug resistance bacteria (MDRB) and exhibited promising to moderate multidrug resistance activities, compounds 7f showed the much better than norfloxacin with higher potency results. Furthermore, the most potent compounds showed an increase in the intracellular killing activity of neutrophils which confirmed the immunostimulatory power. Eight of the nine active compounds exhibited inhibitory activities with IC50 ranged between (18.07 ± 0.18) to (27.03 ± 0.24) μM stronger than ciprofloxacin (26.43 ± 0.64 μM) for S. aureus DNA gyrase. Molecular docking was performed inside the active site of S. aureus DNA gyrase to predict the binding mode.
Bioorganic Chemistry, Volume 87, pp 679-687; https://doi.org/10.1016/j.bioorg.2019.03.075
A series of 5-imino-4-thioxo-2-imidazolidinone derivatives with different substituents at N1 and N3 was synthesized with high yield and excellent purity by the reaction of different N-arylcyanothioformamide derivatives with isocyanate derivatives. Treatment 5-imino-4-thioxo-2-imidazolidinone derivatives with acidic medium afforded 4-thioxoimidazolidin-2,5-dione derivatives. The structures of the obtained products were established based on spectroscopic IR, 1H NMR, 13C NMR, 1H, 1H-COSY, HSQC and elemental analyses. The anti-inflammatory activity of the synthesized compounds through the carrageenan-paw edema model as well as in vitro COX-1 and COX-2 inhibition assay were evaluated where most of the synthesized compounds showed significant anti-inflammatory activity. Mostly, all of our synthesized compounds have greater activity more than celecoxib toward both cyclooxygenase enzymes. All of the tested compounds (except one compound) exhibited IC50 valves for COX-2 ranged from 0.001 × 10−3 to 0.827 × 10−3 µM while the reference drug has IC50 40.0 × 10−3 µM. Furthermore, the analgesic activity of such compounds was also determined. Molecular modeling study was also conducted to rationalize the potential as anti-inflammatory agents of our synthesized compounds by predicting their binding modes, binding affinities and optimal orientation at the active site of the COX enzymes.
Journal of Physics: Conference Series, Volume 1032; https://doi.org/10.1088/1742-6596/1032/1/012058
Diazotization of 2-aminobenzothiazole 1 through using sulfuric acid and sodium nitrite resulted in the formation of diazonium salt which reacted with alkaline solution of salicylaldehyde to produce azo-aldehyde derivative of benzothiazole 2. The resulting aldehyde 2 was condensed with the primary aromatic amines involving (4-nitroaniline, 3-nitroaniline, 4-hydroxyaniline, 4-methoxyaniline, 2-methoxyaniline, 4-bromoaniline, 4-chloroaniline and 2,4- dichloroaniline) using microwave irradiation method in absolute ethanol to produce eight imines of benzothiazole 3a-h, respectively. The imine compounds 3a-h have been treated with L-alanine using microwave irradiation in tetrahydrofuran afforded eight new imidazolidines 4a-h containing benzothiazole moiety, respectively. Preliminary antibacterial activity of the target compounds was investigated in vitro using two kinds of bacteria, Escherichia coli (Gram-negative) and Staphylococcus aurous (Gram-positive). The results showed that the newly prepared imidazolidines (compounds 4c, 4d, 4f, 4g, and 4h) exhibited greater activities than gentamycin against Gram-positive bacteria. On the other hand, compounds 4c and 4f were also showed better activities against Gram-negative bacteria when compared with that of the control drug.