The emergence of strains resistant to certain antibiotics is turning into an important issue worldwide that threatens global health with the increasing incidence of carbapenemase-producing Klebsiella pneumoniae (KPC). Thus, successful doripenem–ertapenem (DOR–ERTA) combination is highly recommended in treatment of bacteremic ventilator-associated pneumonia due to Klebsiella pneumoniae. Hence, a fast and highly-sensitive HPLC-UV method was developed for the estimation of the cited drugs simultaneously in their pure form, pharmaceutical dosage forms and in simulated synthetic mixtures. The DOR–ERTA mixture was successfully separated within 6 min on a reversed-phase ODS column using an isocratic elution; a mobile phase mixture consists of 0.05 M phosphate buffer (pH 3.0 adjusted by 85% ortho-phosphoric acid) : acetonitrile : methanol (86 : 12 : 2; % v/v/v). The proposed method was optimized and validated according to ICH guidelines, where the calibration graph was constructed from 0.04 to 50 μg mL−1 and from 0.05 to 50 μg mL−1 with low detection limits reached 1.7 and 1.4 ng mL−1 for DOR and ERTA respectively. The proposed method showed higher sensitivity than several previous methods, which allowed an effective estimation of the DOR and ERTA in human plasma after a simple extraction method with high recovery results ranged from 96.30% ± 1.55 to 97.90% ± 1.45 and without any interference from plasma components.

Thioglycolic acid-capped cadmium sulphide quantum dots (TGA-CdS QDs) have been synthesized and utilized as a fluorescent probe for the estimation of doripenem (DOR). Monitoring of DOR in different biological fluids is required to estimate the efficient dose to avoid bacterial infections and resistance. The investigated method is based on the measurement of fluorescence quenching of TGA-CdS QDs after the addition of DOR. The synthesized TGA-CdS QDs were characterized using transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRD) and ZETA sizer. The TGA-CdS QDs showed unique photophysical properties with high quantum yield (0.32) using a comparison method with rhodamine B. Different experimental parameters affecting the synthesis process of the TGA-CdS QDs and their behavior with the studied drug DOR were examined and optimized. The values of the fluorescence quenching were linearly correlated to DOR concentration over the range of 10–500 ng mL−1 with a good correlation coefficient of 0.9991. The proposed method showed higher sensitivity over several reported methods, with LOD reaching 2.0 ng mL−1. The method was effectively applied for the estimation of DOR in human plasma and urine with good recovery results ranged from 95.16% to 99.51%. Furthermore, the stability of DOR in the human plasma was studied and a pharmacokinetic study of DOR in real human plasma was conducted.

Thioglycolic acid-capped cadmium sulphide quantum dots (TGA-CdS QDs) have been synthesized and utilized as a fluorescent probe for the estimation of doripenem (DOR). Monitoring of DOR in different biological fluids is required to estimate the efficient dose to avoid bacterial infections and resistance. The investigated method is based on the measurement of fluorescence quenching of TGA-CdS QDs after the addition of DOR. The synthesized TGA-CdS QDs were characterized using transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRD) and ZETA sizer. The TGA-CdS QDs showed unique photophysical properties with high quantum yield (0.32) using a comparison method with rhodamine B. Different experimental parameters affecting the synthesis process of the TGA-CdS QDs and their behavior with the studied drug DOR were examined and optimized. The values of the fluorescence quenching were linearly correlated to DOR concentration over the range of 10–500 ng mL−1 with a good correlation coefficient of 0.9991. The proposed method showed higher sensitivity over several reported methods, with LOD reaching 2.0 ng mL−1. The method was effectively applied for the estimation of DOR in human plasma and urine with good recovery results ranged from 95.16% to 99.51%. Furthermore, the stability of DOR in the human plasma was studied and a pharmacokinetic study of DOR in real human plasma was conducted.

Glyoxylic acid (GA) is the intermediate metabolite in various mammalian metabolic pathways. GA showed high reactivity towards formation of advanced glycation end-products (AGEs); the main cause of pathogenesis and complications of many diseases. The presented study aimed to detect GA in healthy and cardiovascular patients' (CV) sera; however analysis of GA in biological fluid is a challenge and requires chemical derivatization. Hence, a new, highly sensitive, time saving and reproducible pre-column fluorescence derivatization procedure coupled with high performance liquid chromatography (HPLC) method was developed. The derivatization method was based on reaction of 2-aminobenzenthiol (2-ABT), a fluorogenic reagent, with GA in acidic medium to form highly fluorescent thiazine derivative (290 and 390 nm for excitation and emission wavelengths respectively). The fluorescent derivative was separated within 6 min on a reversed-phase ODS column using an isocratic elution with a mixture of methanol-water (70:30, v/v%). The proposed method parameters were optimized and the method was validated. A good linearity in the concentration range (0.05-5.0 µM) was obtained with detection limit (LOD) of 10 nM (200 fmol/injection), which is more sensitive than several previous methods. Moreover, the recovery results were within the range of 85.0-95.5 % and the intra- and inter-day precision results were ≤3.5%. It should be emphasized that this method is the first one for monitoring of GA in CV patients; to investigate its role for diagnosis and monitoring the severity and complications of this disease in clinical laboratory.

In continuation of our efforts to develop new antiproliferative agents that could be effective and selective in treatment of cancer, we designed and synthesized new hybrid structures containing an arylsulfonamide scaffold linked to a steroidal skeleton through a 1,2,3-triazole ring. Both in vitro cytotoxicity on breast MCF-7 cancer cells and human placental aromatase enzyme (pAROM) inhibition assays were performed on new hybrids. All new hybrids showed marked cytotoxic activity against breast MCF-7 cancer cells (IC50 = 3.56–43.76 μM) in comparison to staurosporine (IC50 = 4.06 μM). Tumor selectivity index was higher for some of the new hybrids on normal fibroblast (F-180) cells (TS = 1.5–25) in comparison to staurosporine (TS = 2.5). The p-nitro derivative exhibited the best inhibitory activity on the pAROM with an IC50 of 64.6 ng/cm3, compared to hybrids unsubstituted derivative, p-bromo derivative, and letrozole (IC50 = 375.14, 269.86, and 132.86 ng/cm3, respectively). Furthermore, the p-nitro hybrid arrested the cell cycle selectively at the G2/M phase, in addition to inducing both early and late apoptotic processes of breast MCF-7 cancer cells. Molecular docking studies were performed within pAROM to explore the binding modes of the new hybrids. Collectively, the antiproliferative profile of new hybrids indicates how good they are as promising leads for developing tumor-specific cytotoxins, and deserve further studies to optimize their structure and in vivo activity.

A novel series of urea-linked ciprofloxacin (CP)-chalcone hybrids 3a-j were synthesized and screened by NCI-60 cancer cell lines as potential cytotoxic agents. Interestingly, compounds 3c and 3j showed remarkable antiproliferative activities against both colon HCT-116 and leukemia SR cancer cells compared to camptothecin, topotecan and staurosporine with IC50 = 2.53, 2.01, 17.36, 12.23 and 3.1 μM for HCT-116 cells, respectively and IC50 = 0.73, 0.64, 3.32, 13.72 and 1.17 μM for leukemia SR cells, respectively. Also, compounds 3c and 3j exhibited inhibitory activities against Topoisomerase (Topo) I with % inhibition = 51.19% and 56.72%, respectively, compared to camptothecin (% inhibition = 60.05%) and Topo IIβ with % inhibition = 60.81% and 60.06%, respectively, compared to topotecan (% inhibition = 71.09%). Furthermore, compound 3j arrested the cell cycle of leukemia SR cells at G2/M phase. It induced apoptosis both intrinsically and extrinsically via activation of proteolytic caspases cascade (caspases-3,

A novel series of urea-linked ciprofloxacin (CP)-chalcone hybrids 3a-j were synthesized and screened by NCI-60 cancer cell lines as potential cytotoxic agents. Interestingly, compounds 3c and 3j showed remarkable antiproliferative activities against both colon HCT-116 and leukemia SR cancer cells compared to camptothecin, topotecan and staurosporine with IC50 = 2.53, 2.01, 17.36, 12.23 and 3.1 μM for HCT-116 cells, respectively and IC50 = 0.73, 0.64, 3.32, 13.72 and 1.17 μM for leukemia SR cells, respectively. Also, compounds 3c and 3j exhibited inhibitory activities against Topoisomerase (Topo) I with % inhibition = 51.19% and 56.72%, respectively, compared to camptothecin (% inhibition = 60.05%) and Topo IIβ with % inhibition = 60.81% and 60.06%, respectively, compared to topotecan (% inhibition = 71.09%). Furthermore, compound 3j arrested the cell cycle of leukemia SR cells at G2/M phase. It induced apoptosis both intrinsically and extrinsically via activation of proteolytic caspases cascade (caspases-3,

New azidosulfonamide–chalcone derivatives were designed and synthesized. Their structures were elucidated by 1H and 13CNMR spectral analyses, in addition to elemental analyses. The synthesized derivatives were tested for their antimicrobial activity against a wide variety of Gram-positive, Gram-negative, and fungal strains. Three azidosulfonamide–chalcones showed relatively broad activity against tested strains. Two compounds exhibited eminent antibacterial activity toward S. aureus, M. luteus, and S. marcens (better than ampicillin trihydrate). The synthesized compounds exhibited moderate activity against K. pneumonia and a lower ability to inhibit E. coli growth. Among six tested fungal species, the most potent derivatives demonstrated strong activity toward only two of the fungal strains (T. rubrum and G. candidum). Assessment of drug-likeness, bioavailability, and promiscuity indicated that the compounds are viable drug candidates. In silico molecular docking analysis revealed that the synthesized azidosulfonamide–chalcones successfully occupied pterin-binding site of the dihydropteroate synthase (DHPS), implying that the prepared compounds could exert their activity by the inhibition of the microbial DHPS enzyme. These results provided essential information for the prospective design of more effective antimicrobial compounds.

A facile and convenient synthesis of new pyridazines suitable for use as antimicrobial agents was reported. The hydrazide intermediate was coupled with various benzaldehydes and/or acetophenones and cyclized instantaneously to afford target pyridazine derivatives. The structures of new pyridazines were confirmed by IR, 1H- and 13C-NMR, elemental analysis in addition to representative LC/MS. Antimicrobial activity was screened against 10 bacterial and fungal strains. The new pyridazines showed strong to very strong antibacterial activity against Gram-negative (GNB) bacteria, while none of them showed significant antifungal activity at the same concentration range. Chloro derivatives exhibited the highest antibacterial activity with MICs (0.892–3.744 μg/mL) lower than that of chloramphenicol (2.019–8.078 μg/mL) against E. coli, P. aeruginosa, and S. marcescens. Prediction of ADME parameters, pharmacokinetics, and substrate promiscuity revealed that these new pyridazines could be promising drug candidates. Cytotoxic studies on rat hepatocytes showed how much safe these new pyridazines on living organisms (IC50>64 μg/mL). MOE docking studies showed a good overlay of these new pyridazines with co-crystallized ligand within an E. coli DNA gyrase subunit B active sites (4KFG).

A new series of antiproliferative casein kinase 2a (CK2a) inhibitors were synthesized incorporating either a hydrophilic group (carboxylic or hydrazide) or a hydrophobic group (ester) at N1 or N2 of 4,5,6,7-tetrabromobenzotriazole (TBBt). New compounds were prepared via N-alkylation of TBBt followed by base-catalysed hydrolysis or hydrazinolysis. All the compounds demonstrated low sub-micromolar inhibition of CK2a and antiproliferative activity against both breast and lung cancer cell lines (MCF-7, and A549, respectively), at low micromolar concentrations with N2-regioisomers exhibiting higher activity than their corresponding N1-isomers. The most active compound incorporates an acetic acid hydrazide moiety at the N2 of the TBBt triazole nucleus with IC50 at 0.131 mM (CK2a), 9.1 mM (MCF-7) and 6.3 mM (A549). It induced apoptosis in the MCF-7 cell line through upregulation of bax (pro-apoptotic gene) four to five times higher than the corresponding ester or acid analogues. Molecular docking suggests that the hydrophilic group at N2 of the TBBt triazole nucleus provides binding with important residues (Asp175, Lys68 and Trp176) in the ATP binding site of the CK2a enzyme. We are the first to experimentally estimate the lipophilicity of TBBt derivatives. Our study demonstrated that TBBt hydrazides are more lipophilic than their corresponding acids in contrast to the contradicting calculated lipophilicity using four well-known software programs. This may explain the higher anticancer activity of the most active hydrazide over its corresponding acid despite their nearly equipotent enzyme inhibition.