Anti-cancer chalcones: Structural and molecular target perspectives.

Hybrid molecules: The privileged scaffolds for various pharmaceuticals

Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489).

Advances in Chalcones with Anticancer Activities

Synthesis, biological evaluation and molecular docking of novel chalcone-coumarin hybrids as anticancer and antimalarial agents.

A comprehensive review of topoisomerase inhibitors as anticancer agents in the past decade.

Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: Synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity

Purpose Pseudomonas aeruginosa possesses a large number of resistance mechanisms to different antimicrobials with carbapenems being the most powerful in treating resistant P. aeruginosa. Hence, it is imperative to explore different mechanisms of carbapenems-resistance in P. aeruginosa to achieve successful treatment through the design of new drugs acting on this interaction to combat against antimicrobial resistance. Strains and Methods A total of 634 P. aeruginosa clinical isolates were collected from various patient sources and their MIC levels were measured. Molecular evaluation of carbapenem resistance was assessed by investigating the presence of blaIMP1, blaIMP2, blaVIM1, blaVIM2, blaSPM and blaNDM genes and the gene expression of the following multi-drug efflux pump systems: MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY-OprM and its correlation with MIC. Isolates were typed by Random Amplified Polymorphic DNA (RAPD)-typing. Results Carbapenem resistance was detected in 32 (5%) isolates, which were all imipenem resistant (of which 29 were meropenem resistant). High-level resistance (≥64mg/mL) to imipenem was found in 27 (84.3%) isolates, and to meropenem in 28 (96.5%) isolates. The carbapenemase blaVIM-1 was found in 31 isolates, while blaNDM was detected in 4 isolates. None of the isolates possessed either bla-VIM-2, blaIMP-1, blaIMP-2 or blaSPM. The majority of the isolates displayed over-expression of MexCD-OprJ (75%) followed by MexXY-OprM efflux pump (62%), while MexAB-OprM and MexEF-OprN efflux pumps were overexpressed in 21.8% and 18.7% of the isolates, respectively, with no down-regulation of oprD in any of the isolates. A strong correlation was found between CDJ efflux pump expression and meropenem, imipenem resistance (r=0.532, 0.654, p<0.001, <0.001) respectively. Four major clusters were detected by RAPD-typing: group 1(10 isolates), group 3 (9 isolates), group 2 (8 isolates) while the fourth group (4) included 4 isolates (12.5% polymorphism). Conclusion High-level carbapenem resistance reported in this study was allied to multiple mechanisms including carbapenemase production and efflux-pump over-expression. Threatening cross-infection is possible inside the hospital and stringent infection control measures are crucial.

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Molecular Epidemiology and Mechanisms of High-Level Resistance to Meropenem and Imipenem in Pseudomonas aeruginosa

Herein, natural zeolite (clinoptilolite) was functionalized by Na+ ions (G.Na+/Clino) utilizing a green tea extract prepared by a green production method as a potential carrier for the 5-fluorouracil (5-Fu) drug with enhanced physicochemical behaviors. The G.Na+/Clino-modified product showed enhanced surface area (312 m2/g) and ion-exchange capacity (387 mequiv/100 g). The loading studies reflect high and controlled loading properties of G.Na+/Clino with an actual loading capacity of 291 and 462 mg/g, respectively. The loading reactions of 5-Fu into G.Na+/Clino were of pseudo-second-order kinetics and exhibited Langmuir isotherm properties. This suggested a monolayer and homogeneous loading process by chemical complexation and ion-exchange mechanisms with a Gaussian energy value of 10.47 kJ/mol. Additionally, these reactions were of endothermic and spontaneous nature based on the determined thermodynamic parameters. The release studies demonstrated the 5-Fu release profile for about 150 h at pH 1.2 and for 80 h at pH 7.4. The release reactions had non-Fickian transport properties and were controlled by both erosion and diffusion mechanisms, considering the release kinetic findings and the values of the diffusion exponent (0.42 at pH 1.2 and 0.37 at pH 7.4). The composite showed remarkable biocompatibility based on the measured cell viability and a cytotoxic effect on normal colorectal cells (CCD-18Co). Additionally, the application of G.Na+/Clino as an inorganic carrier for the 5-Fu drug prompted the cytotoxic effect of the drug on colon cancer cell treatment (HCT-116).

https://pubs.acs.org/doi/pdf/10.1021/acsomega.1c06671

Insight into the Loading Properties of Na+ Green-Functionalized Clinoptilolite as a Potential Carrier for the 5-Fluorouracil Drug, its Release Kinetics, and Cytotoxicity

The prevalence of Enterococcus faecalis (E. faecalis) infections among Egyptians with urinary tract infection (UTI), their antimicrobial susceptibility and mechanisms of resistance are under investigated. In this study, 300 urine samples were collected from UTI patients to identify E. faecalis. Antimicrobial susceptibility to 18 antimicrobial agents was tested. The presence of aac(6)-Ie-aph(2)Ia, erm(B) and mef(A/E) genes was examined by PCR. Fifty-seven (19%) isolates were identified as E. faecalis. All isolates were sensitive to teicoplanin and were completely resistant to nalidixic acid, cefotaxime and cefadroxil. Multi-drug-resistant (MDR) was found to be 100% with 45 different antibiotypes. The aac(6)Ia-aph(2)Ia gene was found in 100 and 90% of the isolates resistant to gentamicin at concentrations of 120 and 10 μg, respectively. erm(B) and mef(A/E) genes were present in 92.5% (37/40) and 2.5% (1/40) of erythromycin-resistant isolates, respectively. We conclude that there is a high prevalence of E. faecalis in UTI cases with a 100% MDR rate indicating a serious problem in treating infections by this organism in Egypt.

Multi-drug-resistant Enterococcus faecalis among Egyptian patients with urinary tract infection

INTRODUCTION Surgical wound infection is a serious problem, especially with metallo-beta lactamases (MBLs)- producing gram-negative bacteria as Pseudomonas aeruginosa. The main objective of this work was to evaluate for the first time in Minia- Upper Egypt, the incidence of imipenem-resistant Pseudomonas aeruginosa infection of surgical wounds particularly that mediated by MBL production. METHODOLOGY P. aeruginosa was isolated from infected wounds by swabs and underwent full microbiological identification and Antibiotic Susceptibility testing. MBL production was tested by E-test and PCR was used for imipenemase (blaIMP) and Verona integron-encoded metallo-beta-lactamase (blaVIM) gene detection. RESULTS Out of 200 pus samples collected from surgical site infections, P. aeruginosa had the prevalence rate of 35%. Imipenem resistance was found in 28.57% of the isolated Pseudomonas aeruginosa. The prevalence of MBL-producing isolates among Imipenem-resistant P. aeruginosa (IRPA) was 85 % by phenotypic method with 29% of them harboring blaVIM gene. High resistance rates to other classes of antibiotics were reported among the isolates with multi-drug resistance (MDR) detected in 97.3% of the isolates. CONCLUSION To our knowledge, this is the first report in Minia, Upper Egypt describing the relatively high incidence of IRPA in infected surgical wounds with MBLs involved in the majority of isolates.

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Mohamed Sayed

Papers

Novel N-4-piperazinyl-ciprofloxacin-chalcone hybrids: Synthesis, physicochemical properties, anticancer and topoisomerase I and II inhibitory activity

Molecular Epidemiology and Mechanisms of High-Level Resistance to Meropenem and Imipenem in Pseudomonas aeruginosa

Insight into the Loading Properties of Na+ Green-Functionalized Clinoptilolite as a Potential Carrier for the 5-Fluorouracil Drug, its Release Kinetics, and Cytotoxicity

Multi-drug-resistant Enterococcus faecalis among Egyptian patients with urinary tract infection

High incidence of MBL-mediated imipenem resistance among Pseudomonas aeruginosa from surgical site infections in Egypt.