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The work reported herein describes the synthesis of a new series of anti-inflammatory pyrazolyl thiazolones. In addition to COX-2/15-LOX inhibition, these hybrids exerted their anti-inflammatory actions through novel mechanisms. The most active compounds possessed COX-2 inhibitory activities comparable to celecoxib (IC 50 values of 0.09–0.14 µM) with significant 15-LOX inhibitory activities (IC 50 s 1.96 to 3.52 µM). Upon investigation of their in vivo anti-inflammatory activities and ulcerogenic profiles, these compounds showed activity patterns equivalent or more superior to diclofenac and/or celecoxib. Intriguingly, the most active compounds were more effective than diclofenac in suppressing monocyte-to-macrophage differentiation and inflammatory cytokine production by activated macrophages, as well as their ability to induce macrophage apoptosis. The latter finding potentially adds a new dimension to the previously reported anti-inflammatory mechanisms of similar compounds. These compounds were effectively docked into COX-2 and 15-LOX active sites. Also, in silico predictions confirmed the appropriateness of these compounds as drug-like candidates.

Three green (eco-friendly), inexpensive and simple spectrophotometric methods for quetiapine fumarate (QTF) analysis have been developed and validated. Method I is based on the measurement of the oxidation product of QTF at 610 nm after the reaction with potassium permanganate. Potassium permanganate was used as oxidant. Method II depends on oxidation of the cited drug with ceric ammonium sulfate where the decrease in absorption intensity at 315 nm was measured quantitively. Method III involves complexation of the studied analyte with 2´,7´-bis (acetoxymercury) fluorescein leading to a quantitative decrease in the absorption intensity of the complexing reagent at 502 nm. Different reaction conditions affecting intensity of measurement were carefully studied, optimized and validated. In all proposed methods, no need for extraction procedures and there were linear relationships between the absorbance readings and concentrations of QTF in the range of 5-35, 1-6 and 30-100 μg/mL with LOD values 1.11, 0.12 and 2.68 μg/mL for methods I, II and III respectively. The suggested methods were successfully applied to QTF analysis in pure form and in drug tablets.

The present study represents validated simple, rapid and reliable chromatographic methods for analysis of the antidepressant drug agomelatine (AGO) in bulk powder and tablets. Method I involved application of RP-HPLC with diode array detection where Agilent Zorbax Eclipse-C18 column (4.6 × 150 mm, 5 μm) was used as stationary phase at ambient temperature (25±5). The mobile phase was composed of phosphate buffer (0.05 M, pH 3) and acetonitrile in the ratio 60:40 (v/v) and was pumped isocratically at 1 mL/min. In method II, HPTLC plates (20 × 10 cm, aluminum plates with 200-μm thickness precoated with silica gel 60 F254) was used as stationary phase with mobile phase composed of chloroform: methanol (9.3: 0.7, v/v). Detection was carried out at 230 nm in both methods. The structurally related melatonin was used as internal standard (IS) in both methods. The developed methods were validated according to International Council for Harmonization (ICH) guidelines with respect to linearity, ranges, accuracy, precision, robustness and limits of detection and quantitation. Linearity ranges were 0.5-3 μg/mL and 25-200 ng/spot in method I and method II respectively. Limits of detection and quantitation were 0.081 and 0.25 μg/mL for method I and 4.65 and 14.11 ng/spot for method II, respectively. Intra and interday precision were verified by the RSD% values which were less than 2%. The methods were implemented for assay of AGO tablet dosage form with no observable interferences.

Potent muscle relaxant (thiocolchicoside, TCC) and nonsteroidal anti-inflammatory drug (etoricoxib, ETXB) fixed-dose combination is formulated at relatively high 1:15 and 1:7.5 ratios for TCC and ETXB, respectively. Since the minor component (TCC) has lower absorptivity, assay of TCC/ETXB tablets presents an analytical challenge. The current study presents two novel methods: first is a micellar electrokinetic capillary chromatography (MEKC). Background electrolyte is borate buffer (40 mM, pH 9.2) containing 30 mM sodium dodecyl sulfate and methanol (ratio 80:20%, v/v), measured at 210 nm. Second is a direct double A max spectrophotometric method; minor component, TCC, is measured directly at its distant λ max (373 nm), at zero absorption of ETXB. Then, a ten-fold dilution step is carried out to eliminate TCC spectral interference and ETXB is determined at its λ max (282 nm). Both drugs’ concentrations disclose obedient linearities at 2–100 μg·mL−1 in MEKC, versus 3–25 and 40–350 μg·mL−1 for TCC and ETXB, respectively, in spectrophotometry. All ICH validation elements have been fulfilled for the developed methods. MEKC and spectrophotometric assays achieve accuracy, precision, selectivity, and robustness to be recommended for industrial quality control routine analysis of TCC/ETXB pills formulated at cited ratios or even higher.

Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53–MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.