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Journal ArticleDOI: 10.1016/J.BIOORG.2021.104803

Novel structural hybrids of quinoline and thiazole moieties: Synthesis and evaluation of antibacterial and antifungal activities with molecular modeling studies.

05 Mar 2021-Bioorganic Chemistry (Academic Press)-Vol. 110, pp 104803-104803
Abstract: One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of quinolines bearing a thiazole moiety were synthesized using thiosemicarbazones 2a-f. Cyclization of 2a-f with ethyl chloroacetate, ethyl 2-chloropropanoate or chloroacetone afforded the corresponding thiazoles 3-5. The antimicrobial activity of the new quinoline derivatives was evaluated. The most of tested compounds revealed potent both of the antibacterial and antifungal activities. Fourfold potency of amphotericin B for the inhibition the growth of the A. fumigatus was displayed by ccompound 5e. The latter compound displayed twofold potency of gentamycin for inhibition the growth of N. gonorrhoeae. Moreover, this compound showed equipotent potency of references drugs for inhibition of the growth of S. flexneri, S. pyogenes, P. vulgaris, A. clavatus, G. candidum and P. marneffei. So, quinolines bearing a thiazole moiety can be suggested as interesting scaffolds for the development both of the novel antibacterial and antifungal agents. Some new derivatives were studied as peptide deformylase enzyme inhibitors. Thiazolidin-4-one derivative 3d and 2,3-dihydrothiazole derivative 5c had shown good PDF inhibition activity, which had been supported by the docking results with highest binding affinity and lowest docking energy score. These results suggested that the most potent compounds might be possible agents as novel bacterial PDF inhibitor.

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Topics: Thiazole (57%), Docking (molecular) (54%), Peptide deformylase (51%) ... show more

20 results found

Journal ArticleDOI: 10.1016/J.BIOORG.2021.104794
Abstract: 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.

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9 Citations

Journal ArticleDOI: 10.1016/J.MOLSTRUC.2021.130317
Abstract: 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.

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Topics: Quinoxaline (51%)

8 Citations

Journal ArticleDOI: 10.1016/J.MOLSTRUC.2021.130748
Abstract: 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.

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Topics: Dihydrofolate reductase (55%), Quinoline (53%), Thiazole (51%) ... show more

7 Citations

Journal ArticleDOI: 10.1016/J.DYEPIG.2021.109504
01 Sep 2021-Dyes and Pigments
Abstract: A series of new magenta azomethine reactive disperse dyes were synthesized and applied into polyester/cotton blend fabrics. Various spectroscopic and analytical techniques characterized all the synthesized dyes. The obtained data and theoretical values of all the synthesized molecules were in good agreement with the proposed molecular structure. These dyes have proven their efficiency in dyeing blend fabrics, as they give satisfactory results in fastness properties, colorimetric data and exhaustion, fixation study. Moreover, the dyed fabrics were tested for ultraviolet protection factor and offered high ultraviolet protection. The advantage of synthesizing these dyes is quite facile, and scale-up is feasible, preferring industrial dyeing applications. The designed thiazole azomethine dyes exhibited broad-spectrum antibacterial agents against MDR Gram-positive and Gram-negative bacterial isolates, which will facilitate their rational usage in multiple therapeutic applications. Our findings also demonstrate the possibility of using gamma radiation for sterilization of dyed fabrics and the ability of radiation to intensify their antibacterial activities, thereby inhibiting any bacterial growth on the surface of textiles. The molecular docking study showed good binding as a preferred mode between the dyes and DNA gyrase's active site (2XCT).

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Topics: Dyeing (62%)

6 Citations

Journal ArticleDOI: 10.1016/J.BIOORG.2021.105339
Seham A. Ibrahim1, Eman A. Fayed2, Hala F. Rizk1, Said E. Desouky2  +1 moreInstitutions (2)
Abstract: Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. The assigned structure was characterized entirely based on elemental and spectral analyses. The antimicrobial activity represented by MIC was performed using a resazurin-based turbidimetric (TB) assay. The results exhibited good antimicrobial activity against gram-positive strains, especially S. aureus (ATCC6538) while showing poor to moderate activity against gram-negative and fungal strains. Furthermore, the most active derivatives 3, 4a, 4c, and 5b were evaluated for MIC, MBC, antibiofilm, hemolytic assay, and drug combination testing against two S. aureus (ATCC6538) and MRSA (ACL18) strains. Additionally, bis-thiazolyl pyrazole 3, 4c, and 5b exhibited more potent inhibitory activity for DHFR with IC50 values (6.34 ± 0.26, 7.49 ± 0.28, and 3.81 ± 0.16 µM), respectively, compared with Trimethoprim (8.34 ± 0.11 µM). The bis-1-(substituted-thiazol-2-yl)-1H-pyrazole-4-carbonitrile derivative 5b was the most active member with MIC values ranging from (0.12–0.25 µM) compared to Vancomycin (1–2 µM), and MBC values ranging from (0.5–1 µM) for S. aureus (ATCC6538) and MRSA (ACL18). Surprisingly, compound 5b displayed bactericidal behavior, synergistic effect with three commercial antibiotics, and inhibited DHFR with 2.1 folds higher than Trimethoprim. Finally, good findings were obtained from in silico investigations incorporating toxicity prediction and molecular docking simulation.

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Topics: Antimicrobial (56%), Pyrazole (51%)

4 Citations


40 results found

Open accessJournal ArticleDOI: 10.1038/SREP42717
03 Mar 2017-Scientific Reports
Abstract: To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.

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Topics: Cheminformatics (55%), Drug development (54%)

2,561 Citations

Journal ArticleDOI: 10.1021/JM00025A010
F W Bell1, Cantrell As, Marita Högberg, Jaskunas  +6 moreInstitutions (1)
Abstract: A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.

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416 Citations

Open accessJournal ArticleDOI: 10.1111/J.1574-6976.2010.00247.X
Abstract: Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc1 complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression.

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Topics: Autoinducer (54%), Antimicrobial (52%), Quorum sensing (51%) ... show more

415 Citations

Open accessJournal ArticleDOI: 10.1111/J.1469-0691.2005.01131.X
Abstract: Quinolones are one of the largest classes of antimicrobial agents used worldwide. This review considers the quinolones that are available currently and used widely in Europe (norfoxacin, ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin) within their historical perspective, while trying to position them in the context of recent and possible future advances based on an understanding of: (1) their chemical structures and how these impact on activity and toxicity; (2) resistance mechanisms (mutations in target genes, efflux pumps); (3) their pharmacodynamic properties (AUC/MIC and Cmax/MIC ratios; mutant prevention concentration and mutant selection window); and (4) epidemiological considerations (risk of emergence of resistance, clonal spread). Their main indications are examined in relation to their advantages and drawbacks. Overall, it is concluded that these important agents should be used in an educated fashion, based on a careful balance between their ease of use and efficacy vs. the risk of emerging resistance and toxicity. However, there is now substantial evidence to support use of the most potent drug at the appropriate dose whenever this is required.

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Topics: Antibacterial agent (51%), Drug resistance (51%)

323 Citations

Journal ArticleDOI: 10.1021/JM00092A006
William C. Patt1, Harriet W. Hamilton2, Taylor2, Michael J. Ryan2  +6 moreInstitutions (2)
Abstract: A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.

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313 Citations