Synthesis of 1H-1,2,3-Triazole-Linked Quinoline–Isatin Molecular Hybrids as Anti-Breast Cancer and Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents

2020 ◽  
Vol 20 ◽  
Author(s):  
Paul Awolade ◽  
Nosipho Cele ◽  
Oluwakemi Ebenezer ◽  
Nagaraju Kerru ◽  
Lalitha Gummidi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Staphylococcus Aureus ◽  
In Silico ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Dilution Method ◽  
Methicillin Resistant ◽  
Relationship Analysis ◽  
In Silico Studies ◽  
Molecular Hybrids ◽  
Mcf 7

Background: The persistence of breast cancer as the leading cause of mortality among women, coupled with drug resistance to tamoxifen, the standard endocrine therapy for the disease, exacts fixated attention. To this effect, molecular hybridisation offers an attractive route to drugs with improved bioactivity profile. Objective: The primary goal of this study was to examine the potentials of 1H-1,2,3-triazole linked quinoline-isatin molecular hybrids as drug candidates against breast cancer and methicillin-resistant Staphylococcus aureus (MRSA) cells. Methods: The quinoline-isatin hybrids were synthesised via click chemistry-mediated molecular hybridisation strategy. Anti-breast cancer activity was determined in 3-(4,5-dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using estrogen-responsive (ER+) MCF-7 and MDA-MB-231 (triple-negative breast cancer -TNBC) cells while antimicrobial efficacy was established via the broth dilution method. Also, the toxicity profile of potent compounds to non-cancerous cells was determined using human embryonic kidney cells (HEK293) and human red blood cells (hRBCs). In silico techniques were employed to predict the drug-like properties of potent compounds and understand their binding modes with estrogen receptor alpha (ERα). Results: Compounds 7g-i exhibited the strongest cytotoxicity to MCF-7 cells with IC50 values of 23.54, 23.66, and 32.50 μM, respectively. Interestingly, compound 7h also emerged as the best drug candidate against MDA-MB-231 and MRSA cells with IC50 = 71.40 μM and MIC80 = 27.34 μM, respectively. Structure-activity relationship analysis revealed that quinoline-2-carbaldehyde and 5,7- disubstituted isatin moieties confer desirable potency. These compounds showed no significant cytotoxic or haemolytic effects on HEK293 or hRBCs in vitro at their active concentrations; hence, eliciting their selectivity for cancer cells. In silico studies also presented the drugability of potent compounds and the likely structural features interacting with amino acid residues at the ligand-binding domain of ERα. Conclusion: These results suggest that the identified 1H-1,2,3-triazole-linked quinoline-isatin hybrids are viable chemotypes that can be adopted as templates for the development of new anti-breast cancer and anti-MRSA agents.

scholarly journals Antibacterial Alkaloids from Chelidonium Majus Linn (Papaveraceae) Against Clinical Isolates of Methicillin-Resistant Staphylococcus Aureus

2009 ◽  
Vol 11 (4) ◽  
pp. 90 ◽  
Author(s):  
Guo Ying Zuo ◽  
Fan Yan Meng ◽  
Xiao Yan Hao ◽  
Yun Ling Zhang ◽  
Gen Chun Wang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Antibacterial Effect ◽  
Dilution Method ◽  
Chelidonium Majus ◽  
Methicillin Resistant ◽  
Aerial Parts ◽  
Bioassay Guided Fractionation ◽  
Mrsa Strains

Purpose. This study describes the antibacterial effect of extracts and compounds isolated from the aerial part of Chelidonium majus Linn. (Papaveraceae) acting against clinical strains of methicillin-resistant Staphylococcus aureus (MRSA). Methods. The activities were evaluated by using the macrobroth dilution method and reported as the MICs/MBCs. Results. Bioassay-guided fractionation of the most active extract from the aerial parts (EtOAc) led to the isolation of benzo[c]phenanthridine-type alkaloids 8-hydroxydihydrosanguinarine (hhS), 8-hydroxydihydrochelerythrine (hhC), which were potently active against MRSA strains. Conclusions. The selective antibacterial activity reported in this paper for 8-hydroxylated benzo[c]phenanthridine-type alkaloids isolated from C.majus opens the possibility that they could be helpful for the developing of new antibacterial agents for treating the infection of MRSA which has created nosocomial problem worldwide.

scholarly journals Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study

Molecules ◽  
2014 ◽  
Vol 19 (4) ◽  
pp. 4491-4509 ◽  
Author(s):  
Claudia Avitia-Domínguez ◽  
Erick Sierra-Campos ◽  
José Salas-Pacheco ◽  
Hugo Nájera ◽  
Arturo Rojo-Domínguez ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Kinetic Study ◽  
In Silico ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Biochemical Characterization ◽  
Shikimate Dehydrogenase ◽  
Methicillin Resistant

Synthesis and In Vitro Evaluation of Tetrahydroquinoline Derivatives as Antiproliferative Compounds of Breast Cancer via Targeting the GPER

2019 ◽  
Vol 19 (6) ◽  
pp. 760-771 ◽  
Author(s):  
Oscar J. Zacarías-Lara ◽  
David Méndez-Luna ◽  
Gustavo Martínez-Ruíz ◽  
José R. García-Sanchéz ◽  
Manuel J. Fragoso-Vázquez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
In Silico ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
In Silico Studies ◽  
Mcf 7

Background: Some reports have demonstrated the role of the G Protein-coupled Estrogen Receptor (GPER) in growth and proliferation of breast cancer cells. Objective: In an effort to develop new therapeutic strategies against breast cancer, we employed an in silico study to explore the binding modes of tetrahydroquinoline 2 and 4 to be compared with the reported ligands G1 and G1PABA. Methods: This study aimed to design and filter ligands by in silico studies determining their Lipinski's rule, toxicity and binding properties with GPER to achieve experimental assays as anti-proliferative compounds of breast cancer cell lines. Results: In silico studies suggest as promissory two tetrahydroquinoline 2 and 4 which contain a carboxyl group instead of the acetyl group (as is needed for G1 synthesis), which add low (2) and high hindrance (4) chemical moieties to explore the polar, hydrophobic and hindrance effects. Docking and molecular dynamics simulations of the target compounds were performed with GPER to explore their binding mode and free energy values. In addition, the target small molecules were synthesized and assayed in vitro using breast cancer cells (MCF-7 and MDA-MB-231). Experimental assays showed that compound 2 decreased cell proliferation, showing IC50 values of 50µM and 25µM after 72h of treatment of MCF-7 and MDA-MB-231 cell lines, respectively. Importantly, compound 2 showed a similar inhibitory effect on proliferation as G1 compound in MDA-MB-231 cells, suggesting that both ligands reach the GPER-binding site in a similar way, as was demonstrated through in silico studies. Conclusion: A concentration-dependent inhibition of cell proliferation occurred with compound 2 in the two cell lines regardless of GPER.

scholarly journals Non-β-Lactam Allosteric Inhibitors Target Methicillin-Resistant Staphylococcus aureus: An In Silico Drug Discovery Study

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 934
Author(s):  
Mahmoud A. A. Ibrahim ◽  
Khlood A. A. Abdeljawaad ◽  
Alaa H. M. Abdelrahman ◽  
Othman R. Alzahrani ◽  
Fahad M. Alshabrmi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
In Silico ◽  
Acidic Medium ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Binding Affinities ◽  
Allosteric Site ◽  
Allosteric Inhibitors ◽  
Methicillin Resistant ◽  
In Silico Admet

Penicillin-binding proteins (PBPs) catalyze the final stages for peptidoglycan cell-wall bio-synthesis. Mutations in the PBP2a subunit can attenuate β-lactam antibiotic activity, resulting in unimpeded cell-wall formation and methicillin-resistant Staphylococcus aureus (MRSA). A double mutation in PBP2a (i.e., N146K and E150K) is resistant to β-lactam inhibitors; however, (E)-3-(2-(4-cyanostyryl)-4-oxoquinazolin-3(4H)-yl) benzoic acid (QNZ), a heterocyclic antibiotic devoid of a β-lactam ring, interacts non-covalently with PBP2a allosteric site and inhibits PBP enzymatic activity. In the search for novel inhibitors that target this PBP2a allosteric site in acidic medium, an in silico screening was performed. Chemical databases including eMolecules, ChEMBL, and ChEBI were virtually screened for candidate inhibitors with a physicochemical similarity to QNZ. PBP2a binding affinities from the screening were calculated based on molecular docking with co-crystallized ligand QNZ serving as a reference. Molecular minimization calculations were performed for inhibitors with docking scores lower than QNZ (calc. −8.3 kcal/mol) followed by combined MD simulations and MM-GBSA binding energy calculations. Compounds eMol26313223 and eMol26314565 exhibited promising inhibitor activities based on binding affinities (ΔGbinding) that were twice that of QNZ (−38.5, −34.5, and −15.4 kcal/mol, respectively). Structural and energetic analyses over a 50 ns MD simulation revealed high stability for the inhibitors when complexed with the double mutated PBP2a. The pharmacokinetic properties of the two inhibitors were predicted using an in silico ADMET analysis. Calculated binding affinities hold promise for eMol26313223 and eMol26314565 as allosteric inhibitors of PBP2a in acidic medium and establish that further in vitro and in vivo inhibition experimentation is warranted.

scholarly journals Susceptibility of community associated methicillin resistant Staphylococcus aureus isolated from faeces to antiseptics

2011 ◽  
Vol 6 (04) ◽  
pp. 317-323 ◽  
Author(s):  
Ezekiel Olugbenga Akinkunmi ◽  
Adebayo Lamikanra
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Property A ◽  
Biochemical Tests ◽  
Methicillin Resistant ◽  
Diffusion Technique ◽  
Significant Difference ◽  
Agar Dilution

Introduction: The study aimed to investigate the resistance of methicillin resistant Staphylococcus aureus (MRSA), an indicator used in hospitals but isolated from faecal samples of children in the community, to commonly used antibiotics and antiseptic agents. Methodology: S. aureus isolates were identified by phenotypic and genotypic techniques such as biochemical tests and polymerase chain reaction. Antibiotic susceptibility was investigated using the disc diffusion technique while the agar dilution method was used to determine the minimum inhibitory concentration (MIC) of antiseptics. Results: MRSA showed considerably higher resistance to other antibiotics than methicillin sensitive Staphylococcus aureus (MSSA). Twelve percent of the MSSA were susceptible to all the antibiotics studied while none of the MRSA had this property. A significant difference in susceptibility between MRSA and MSSA to the three antiseptic agents was observed as 68.8%, 75.0% and 100% of MRSA were less susceptible to benzalkonium chloride, chlorhexidine and cetrimide respectively, while 32.0%, 28.0% and 56.0% of MSSA respectively were less susceptible to these agents compared with S. aureus NCTC 6571. Overall, the MICs for the antiseptics were 2-3 times greater in the MRSA than in the MSSA (p < 0.001). Conclusion: Results show that the concentration of antiseptics used in the prevention of the transmission of infectious agents may have to be raised to cope with the possible presence of MRSA in patients coming into hospital.

scholarly journals In Vitro Antimicrobial Activity of Tigecycline

2015 ◽  
Vol 13 (2) ◽  
pp. 35-38
Author(s):  
Sabita Bhatta ◽  
Babli Basu ◽  
Chandrasekhar Narharrao Chaudhary ◽  
Ashok Kumar Praharaj
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Susceptibility ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Diffusion Method ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Klebsiella Pneumonia ◽  
Methicillin Resistant ◽  
Agar Dilution ◽  
Vancomycin Resistant

Introduction: Tigecycline is a novel glycylcycline  derivative of the tetracycline with activity against a wide range of  organisms including Methicillin resistant Staphylococcus aureus, Vancomycin  resistant  Enterococcus , Extended spectrum beta lactamase   producing  (Escherichia coli , Klebsiella  pneumonia)  and Acinetobacter species.  The aim of the study was to assess effectiveness of the drug against methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE), ESBL producers and carbapenem resistant Acinetobacter baumannii and to compare the efficacy of different methods of antimicrobial susceptibility testing for Tigecycline.Methods: A total of 250 clinical isolates were processed and identified by conventional methods. In all the 250 isolates, antimicrobial susceptibility was carried out by disc diffusion method , Minimum inhibitory test by agar dilution method (MIC) and in 30 isolates of A baumannii  MIC was also done by E test.Results: Out of 250 isolates, 236 isolates were sensitive to tigecycline by agar dilution method while only 159 were sensitive by disk diffusion method.Conclusion: Marked discordance was observed between the results of two different methods (DDT & Agar dilution method) for E coli, Klebsiella spp and A baumannii, where significant number of isolates were resistant to tigecycline by DDT as compared to AD method. But results of MIC by agar dilution method & E test were in concordance for A. baumannii.

scholarly journals Phytochemical analysis, antibacterial activity of hydromethanol extracts from stems of Ximenia americana, Côte d’Ivoire species on methicillin-resistant Staphylococcus aureus

2021 ◽  
Vol 14 (9) ◽  
pp. 3429-3440
Author(s):  
Baudelaire Affi Kakou ◽  
Anoubile Benie ◽  
Alain Hugues N’Guessan ◽  
Konan K. Fernique ◽  
N.K. Guessennd ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Public Health Problem ◽  
Antibacterial Activities ◽  
Dilution Method ◽  
Phytochemical Analysis ◽  
Methicillin Resistant ◽  
Ximenia Americana

The emergence of bacteria resistant to several families of antibiotics is nowadays a public health problem in the world. To overcome this, it appeared necessary to explore sources of active molecules from natural substances. Thus, the objective of this study was to carry out the phytochemical sorting of hydromethanol extracts from Ximenia americana stems and to evaluate their antibacterial activities on the in-vitro growth of methicillin-resistant Staphylococcus aureus. The phytochemical screening performed allowed us to identify saponins, sterols and polyterpenes, polyphenols, tannins and flavonoids. HPLC-MS/MS analysis lead to the identification of a variety of flavan-3ol, quercetin and derivatives. The study of antibacterial activity carried out on 5 multi-resistant clinical strains and on a reference strain by the Muller-Hinton agar medium diffusion and dilution method showed that the extracts were active on all the strains with MICs ranging from 6.25 to 100 mg and MBCs ranging from 12.5 to 100 mg. The antibacterial potential of these extracts highlighted in this study could make this plant a candidate for in-depth investigations that could lead to the discovery of new antibacterial molecules. L’apparition de bactéries résistantes à plusieurs familles d’antibiotiques constitue, de nos jours, un problème de santé publique dans le monde. Pour y remédier, l’exploration de sources de molécules actives à partir des substances naturelles s’est avérée nécessaire. Ainsi, l’objectif de cette étude était de réaliser le tri phytochimique des extraits hydrométhanoliques de tiges de Ximenia americana et d’évaluer leurs activités antibactériennes sur la croissance in-vitro des Staphylococcus aureus résistant à la méticilline. Le screening phytochimique réalisé a permis d’identifier des saponines, des stérols et polyterpènes, des polyphénols, des tanins et des flavonoïdes. L’analyse à la HPLC-MS/MS a permis d’identifier une variété de flavan-3ol, de la quercétine et dérivées. L’étude de l’activité antibactérienne réalisée sur 5 souches cliniques multirésistantes et sur une souche de référence par la méthode de diffusion et de dilution en milieu gélosé Muller-Hinton a montré que les extraits étaient actifs sur toutes les souches avec des CMI variant de 6,25 à 100 mg et des CMB variant de 12,5 à 100 mg. Le potentiel antibactérien de ces extraits mis en évidence dans cette étude pourrait faire de cette plante une candidate à des investigations approfondies pouvant aboutir à la découverte de nouvelles molécules antibactériennes.

scholarly journals NONANTIBIOTICS ENHANCE THE ANTIBACTERIAL ACTIVITY OF CEFTRIAXONE AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

2018 ◽  
Vol 11 (11) ◽  
pp. 134
Author(s):  
Akilandeswari Krishnan ◽  
Ruckmani Kandasamy
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Inhibitory Concentration ◽  
Dilution Method ◽  
Methicillin Resistant ◽  
Therapeutic Procedures ◽  
Mebeverine Hydrochloride ◽  
Lactam Antibiotic ◽  
Antiulcer Drugs

Objectives: Antibiotic resistance is one of the most persistent issues worldwide nowadays, and methicillin-resistant Staphylococcus aureus (MRSA) infection is one such issue where the standard therapeutic procedures involving powerful antibiotics have failed in controlling the infection.Methods: In the present study, the antibacterial potency of the nonantibiotics troxipide (TR), mebeverine hydrochloride (Hcl), and their combinations with ceftriaxone (CEF) against MRSA has been investigated using microbiological assays of microplate dilution method and combination index interpretations of the nonantibiotics with β-lactam antibiotic CEF and the zone of inhibition method.Results: The nonantibiotics ME and TR inhibited resistant strain tested in vitro in the checkerboard assay, where the results showed that CEF and TR exhibited minimum inhibitory concentration (MIC) at concentrations of 50 μg/ml and 318 μg/ml, respectively. Interestingly, CEF when combined with TR reduced the MIC to 8 μg/ml and 78 μg/ml. According to the results, CEF with TR exhibited synergistic interactions at the fractional inhibitory concentration of 0.36–1.4. ME and TR and its combinations, CEF with ME, and CEF with TR have considerable anti-MRSA efficacy, with synergism though at 36 h of incubation.Conclusion: ME and TR being antispasmodic and antiulcer drugs can also be used against MRSA infections, which could prove to be favorable in the reduction of dosage of antibiotics such as CEF, and cutting down the need for additional administration of antibiotics to the patients affected with multiple complications such as gastrointestinal ulcer, spasm difficulties, and infection.

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