Determination of Gemcitabine and Sorafenib in Spiked Human Plasma Using Multivariate Model Update Chemometric Methods.

BACKGROUND: Gemcitabine (GEM), a pyrimidine nucleoside, has been used as a first-line treatment in non-small-cell lung cancer (NSCLC). Sorafenib (SOR), a nonselective multi-kinase inhibitor, is used as a chemotherapeutic agent in different types of cancers including NSCLC in preclinical studies. Co-administration of GEM and SOR was found to be effective and well-tolerated in the treatment of NSCLC. OBJECTIVE: The aim of the present work is to determine the studied drugs in spiked human plasma simultaneously through resolving the overlapping spectra and removing the interference of the plasma matrix. METHOD: Two updated chemometric models were developed using UV absorbance of the drugs, which named principal component regression (PCR) and partial least-squares (PLS) for determination of GEM and SOR in the ranges of 5-25 and 2-22 µg/mL, respectively. RESULTS: Validation of the two updated models has been achieved in accordance with US Food and Drug Administration (FDA) guidelines, and the results were satisfactory. The two methods had the advantages of high predictive ability of the studied drugs with high precision and accuracy. Moreover, there was no significant difference obtained when statistical comparison was done between the developed and reported methods, showing good validity of the suggested methods. CONCLUSIONS: The two updated models have the advantages of being rapid, accurate, sensitive, and cost-effective for the determination of GEM and SOR in quality control laboratories without any need for initial separation procedures. HIGHLIGHTS: Two updated chemometric methods, PCR and PLS, were developed for the estimation of GEM and SOR in spiked human plasma using their UV absorbance data.

Determination of Bendamustine, Gemcitabine and Vinorelbine (BEGEV) regimen in spiked human plasma using multivariate model update chemometric methods.

Combination of bendamustine (BEN), gemcitabine (GEM), and vinorelbine (VIB), (BEGEV) regimen, has been proved to be a tolerable, safe and effective regimen in relapsed/refractory classical hodgkin lymphoma (R/R cHL). Two chemometric models named principal component regression (PCR) and partial least squares (PLS) were established for determination and quantification of BEN, GEM and VIB simultaneously in the ranges of 5-25 µg/mL for each of BEN and VIB, while in the range of 10 -30 µg/mL for GEM in pure and spiked plasma using their UV absorbance. The updated methods have been proven their ability to predict the concentrations of the studied drugs and validated according to FDA guidelines showing good results. There was no significant difference between the developed methods and the reported LC-MS/MS method upon statistical comparison was applied. Furthermore, the updated chemometric methods have advantages of being sensitive, accurate and cost effective for estimation of BEN, GEM and VIB and monitoring their concentration.

Development of certain aminoquinazoline scaffolds as potential multitarget anticancer agents with apoptotic and anti-proliferative effects: Design, synthesis and biological evaluation.

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI50 = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC50 = 0.093 ± 0.006 µM and 0.143 ± 0.008 µM, respectively) to those of lapatinib and ribociclib (IC50 = 0.03 ± 0.002 µM and 0.067 ± 0.004 µM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.

Ecofriendly LC-MS/MS and TLC-densitometric methods for simultaneous quantitative assay and monitoring of BEGEV regimen, in vivo pharmacokinetic study application.

To date no analytical method has been developed for the determination of the BEGEV regimen and no study has investigated the kinetic interaction between the drugs, to give us priorities for further clinical study, so two rapid, accurate, sensitive and ecofriendly chromatographic methods were developed for the simultaneous determination of bendamustine (BEN), gemcitabine (GEM) and vinorelbine (VIB) using sildenafil (SIL) as an internal standard (IS) for the purpose of an in vivo pharmacokinetics study in rats. Firstly, the LC-MS/MS method was performed using a mixture of methanol and a 0.1% aqueous solution of formic acid as the mobile phase on a ZORBAX Eclipse Plus C18 (4.6 mm × 150 mm, 5 µm) column as the stationary phase. BEN, GEM and VIB were ionized by positive ions and detected in the multi-reaction monitoring (MRM) mode using precursor → products of m/z 358.20 → 228.25 for BEN, m/z 264.05 → 112.15 for GEM, m/z 779.55 → 122.20 for VIB and m/z 475.00 → 58.35 for SIL. Secondly, TLC-densitometry was applied on TLC silica gel plates using methanol : ethyl acetate (8 : 2, v/v) as the developing system when the separated peaks were scanned at 280 nm. FDA guidelines were followed for validation of the proposed methods, which presented acceptable ranges; then they were applied for an in vivo study in rats with a quantitative determination of each drug after single or combined administration for an investigation of any suspected drug-drug interaction, and all pharmacokinetic parameters were calculated for therapeutic drug monitoring of those drugs. Green analytical chemistry principles were considered during all the procedural steps to ensure the greenness and the safety of the methods, which were evaluated using four assessment tools, eco-scale assessment, the national environmental method index (NEMI), the green analytical procedure index (GAPI) and the analytical greenness metric approach (AGREE), and the results were satisfactory.

Design, synthesis and mechanistic studies of novel imidazo[1,2-a]pyridines as anticancer agents.

Herein, the design, synthesis and mechanistic study of five series of imidazo[1,2-a]pyridines 8a-d, 9a-f, 11a-c, 12a-d and 14a-d as anticancer agents were discussed. The cytotoxicity of imidazo[1,2-a]pyridine derivatives was screened against NCI 60 cancer cell lines. The cytotoxicity of compounds 8b, 8c, 9e and 9f was then evaluated against leukemia K-562 cancer cell line and normal lung fibroblasts (WI38). The hydrazone derivatives 8b and 8c exhibited significant cytotoxic activities against the leukemia K-562 cancer cell line with good safety margins (IC50 = 2.91 µM, SI = 8.32 and IC50 = 1.09 µM, SI = 10.54, respectively). In addition, compounds 8b, 8c, 9e and 9f were tested for their EGFR and COX-2 inhibitory activities. The hydrazone derivatives 8b and 8c were the most active EGFR inhibitors with IC50 values of 0.123 and 0.072 µM, respectively. Compound 8c selectively inhibited COX-2 (IC50 = 1.09 µM, SI = 13.78). Moreover, the potential of compound 8c to induce apoptosis in leukemia K-562 cell line was determined. Compound 8c showed a pre-G1 apoptosis and a growth arrest of leukemia K-562 cell line at G1 phase of cell cycle. Also, compound 8c was able to induce caspase-3 overexpression (6.98 folds), if compared to control. Finally, molecular docking studies and physicochemical properties calculation of compounds 8b, 8c, 9e and 9f were carried out to explain the biological data and to predict bioavailability of the most active compounds.

Design, synthesis, biological assessment, and in-Silico studies of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives have been designed and synthesized as combretastatin CA-4 analogs. They were screened for anticancer and tubulin polymerization inhibition activities. The trimethoxyphenyl 1,2,4-triazolo[1,5-a]pyrimidine derivative 4c showed significant antiproliferative activity in which it exhibited IC50 = 0.53 µM against HCT-116 cancer cell line. It was further tested as a tubulin polymerization inhibitor showing an IC50 = 3.84 µM if compared to combretastatin IC50 = 1.10 µM. Further mechanism studies revealed that compound 4c could obviously inhibit the proliferation of HCT-116 cancer cells by inducing apoptosis and arresting the cell cycle at the G2/M phase. Furthermore, docking studies showed that compound 4c illustrated good fitting to the colchicine binding site of tubulin. Thus, it is considered an anticancer lead compound worthy of further development as a tubulin polymerization inhibitor.

Design, synthesis and mechanistic study of novel diarylpyrazole derivatives as anti-inflammatory agents with reduced cardiovascular side effects.

Novel diarylpyrazole (5a-d, 6a-e, 12, 13, 14, 15a-c and 11a-g) derivatives were designed, synthesized and evaluated for their dual COX-2/sEH inhibitory activities via recombinant enzyme assays to explore their anti-inflammatory activities and cardiovascular safety profiles. Comprehensively, the structures of the synthesized compounds were established via spectral and elemental analyses, followed by the assessment of both their in vitro COX inhibitory and in vivo anti-inflammatory activities. The most active compounds as COX inhibitors were further evaluated for their in vitro 5-LOX and sEH inhibitory activities, alongside with their in vivo analgesic and ulcerogenic effects. Compounds 6d and 11f showed excellent inhibitory activities against both COX-2 and sEH (COX-2 IC50 = 0.043 and 0.048 µM; sEH IC50 = 83.58 and 83.52 µM, respectively). Moreover, the compounds demonstrated promising results as anti-inflammatory and analgesic agents with considerable ED50 values and gastric safety profiles. Remarkably, the most active COX inhibitors 6d and 11f possessed improved cardiovascular safety profiles, if compared to celecoxib, as shown by the laboratory evaluation of both essential cardiac biochemical parameters (troponin-1, prostacyclin, tumor necrosis factor-α, lactate dehydrogenase, reduced glutathione and creatine kinase-M) and histopathological studies. On the other hand, docking simulations confirmed that the newly synthesized compounds displayed sufficient structural features required for binding to the target COX-2 and sEH enzymes. Also, in silico ADME studies prediction and drug-like properties of the compounds revealed favorable oral bioavailability results. Collectively, the present work could be featured as a promising future approach towards novel selective COX-2 inhibitors with declined cardiovascular risks.

Five spectrophotometric methods for simultaneous determination of Amlodipine besylate and celecoxib in presence of its toxic impurity.

Five simple, selective and accurate spectrophotometric methods have been applied and developed for first time for simultaneous determination of amlodipine besylate (AML) and celecoxib (CEL) in presence of one harmful impurity, 4-methylacetophenone (MAP), in their ternary mixture without prior separation. Those spectrophotometric methods were developed and called: dual wave length in ratio spectra (DWRS), successive ratio-derivative spectra (SDR), modified absorption factor method (MAFM), modified amplitude center method (MACM) and first derivative -zero crossing coupled with amplitude factor method (FDAF). These methods include various steps using zero /or ratio /or derivative spectra and some mathematical techniques. Linear calibration curves were constructed over the concentration range of 2-100, 10-200 and 0.5-20 µg/mL for AML, CEL and MAP, respectively. High sensitivity with low LOD values 0.583, 3.118 and 0.147 for AML, CEL and MAP, respectively were obtained. Moreover, validation of the proposed methods was achieved according to ICH guidelines and satisfactory results were obtained indicating that the developed methods can be used for quality control analysis of AML and CEL concerning its impurity. No significant difference was observed when the obtained results of the developed methods were statistically compared with the reported HPLC method.

Validated green chromatographic methods for determination of amlodipine and celecoxib in presence of methylacetophenone.

Aim: Green, accurate and rapid methods, namely LC-MS/MS and thin layer chromatography-densitometric methods, were developed for determination of amlodipine besylate and celecoxib in presence of its process-related impurities, 4-methylacetophenone in pure and formulated tablets. Results: LC-MS/MS was achieved on ZORBAX Eclipse Plus C18 column using methanol:aqueous solution of 5 mM formic acid (95:5 v/v). High sensitivity with low limit of detection values 0.00028, 0.00027 and 0.0003 for amlodipine, celecoxib and 4-methylacetophenone, respectively were obtained. While, thin layer chromatography-densitometric was established using methanol:water:ammonia (70:25:1.5, by volume). Good linearity was obtained in the range of 0.1-10 µg/band, 1-150 µg/band and 0.01-2 µg/band for amlodipine, celecoxib and 4-methylacetophenone, respectively. Conclusion: The proposed method validation was achieved according to ICH guidelines. Those methods possess advantages of being ecofriendly methods which permit their application in quality control laboratories.

Design, synthesis and mechanistic study of new 1,2,4-triazole derivatives as antimicrobial agents.

Novel 5-amino-1,2,4-triazole derivatives and their cyclized 1,2,4-triazolo[1,5-a]pyrimidine analogues were designed, synthesized and evaluated for their antimicrobial activities. They were tested against five bacterial strains (Methicillin Resistant S. aureus (MRSA), E. coli, K. pneumoniae, A. baumannii and P. aeruginosa) using ciprofloxacin as a positive control and against two fungal strains (C. albicans and C. neoformans) using fluconazole and amphotericin B as positive controls. Compounds 9, 13a and 13b showed high to moderate antifungal activities against candida albicans (MIC values = 4-32 µg/ml), with considerable safety profiles; where no cytotoxicity against human embryonic kidney or red blood cells were detected at concentrations up to 32 µg/mL. Furthermore, compound 9 showed significant inhibitory activity against lansterol 14α-demethylase (IC50 = 0.27 µM), compared to the reference drug fluconazole (IC50 = 0.25 µM). Molecular docking of compound 9 into the active site of the cytochrome P450 enzyme revealed comparable binding modes and docking scores to those of fluconazole. Finally, in silico ADME studies prediction and drug-like properties of these compounds revealed favorable oral bioavailability results.

Experimentally designed chromatographic method for the simultaneous analysis of dimenhydrinate, cinnarizine and their toxic impurities.

Recently, experimental design has beaten the traditional optimization approach (one variable at a time) by providing better quality for chromatographic separation using minimal effort and resources. Benzophenone (BZP) and [1-(diphenylmethyl)piperazine] (DPP) were reported to be the most toxic impurities for dimenhydrinate (DMH) and cinnarizine (CIN), respectively. Additionally, there is no reported HPLC method for the simultaneous determination of DMH, CIN and their toxic impurities. A custom experimental design was adopted to estimate the optimum conditions that achieved the most acceptable resolution with adequate peak symmetry within the shortest run time. Desirability function was used to define the optimum chromatographic conditions and the optimum separation was achieved using XBridge® HPLC RP-C18 (4.6 × 250 mm, 5 µm), acetonitrile: 0.1% sodium lauryl sulphate (SLS) in water (90 : 10, v/v) as a mobile phase at flow rate 2 mL min-1 and UV detection at 215 nm. Method validation was carried out according to ICH guidelines and linearity was achieved in the ranges of 2-25, 1-25, 1-12.5, and 1-12.5 µg mL-1 for DMH, CIN, BZP and DPP, respectively. By application of the proposed method to the market dosage form, no interference from excipients was observed. Moreover, the greenness of the method was evaluated using the National Environmental Method Index (NEMI), Analytical Eco-Scale and Green Analytical Procedure Index (GAPI) metrics and the results revealed the green environmental impact of the developed method.

Design, synthesis and molecular modeling studies of 2-styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers.

Herein, we report the synthesis of novel 2-substituted styrylquinazolines conjugated with aniline or sulfonamide moieties, anticipated to act as potent anticancer therapeutic agents through preferential EGFR inhibition. In doing so, all the synthesized compounds were screened for their in vitro anticancer activities (nine subpanels) at the National Cancer Institute (NCI), USA. The resulting two most active anticancer compounds (7b and 8c) were then chemically manipulated to investigate feasible derivatives (12a-e and 15a-d). MTT cytotoxicity, in vitro cell free EGFR and anti-proliferative activity against EGFR/ A549 cell line evaluation for the most active broadly spectrum candidates (7a/b, 8c/e, 12b and 15d) was conducted. Promising results were obtained for the styrylquinazoline-benzenesulfonamide derivative 8c (IC50 = 8.62 µM, 0.190 µM and = 79.25%), if compared to lapatanib (IC50 = 11.98 µM, 0.190 µM, and 79.25%), respectively. Moreover, its apoptotic induction potential was studied through cell cycle analysis, Annexin-V and caspase-3 activation assays. Results showed a clear cell arrest at G2/M phase, a late apoptotic increase (76 folds) and a fruitful caspase-3 expression change (8 folds), compared to the control. Finally, molecular docking studies of compounds 7a/b, 8c/e, 12b and 15d revealed proper fitting into the active site of EGFR with a low binding energy score for compound 8c (-13.19 Kcal/mole), compared to lapatanib (-14.54 Kcal/mole).

Discovery of novel urea-diarylpyrazole hybrids as dual COX-2/sEH inhibitors with improved anti-inflammatory activity and highly reduced cardiovascular risks.

Herein we describe our efforts to develop novel anti-inflammatory/analgesic agents devoid of known cardiovascular drawbacks. In doing so, two 1,5-diarylpyrazole series of urea linked (9a-f) and amide linked (11a-f) compounds were synthesized and evaluated in vitro as dual COX-2/sEH inhibitors using recombinant enzyme assays. The in vivo anti-inflammatory and analgesic activities were then examined using reported animal models. Compounds 9b and 9c showed the highest inhibitory activities against both COX-2 and sEH (IC50 of COX-2 = 1.85 and 1.24 µM; sEH = 0.55 and 0.40 nM, respectively), besides showing the best activity as anti-inflammatory agents. Interestingly, the cardiovascular profile of the two compounds 9b and 9c was evaluated through measuring some biochemical parameters such as prostacyclin (PGI2), lactate dehydrogenase (LDH), troponin-1 (Tn-1), tumor necrosis factor- α (TNF-α), creatine kinase-M (CK-M) and reduced glutathione (GSH) in addition to a histo-pathological study to investigate the changes in the heart muscle. The results confirmed that compounds 9b and 9c have a more favorable cardio-profile than celecoxib with much less cardiovascular risks associated with the common selective COX-2 inhibitors. Finally, the current work provided a promising approach that can be optimized to serve as a lead project to overcome the cardiovascular toxicity related to the traditional selective COX-2 inhibitors.

Design, synthesis, molecular docking and antiproliferative activity of some novel benzothiazole derivatives targeting EGFR/HER2 and TS.

Multi-targeted anticancer drugs are in focus as a promising research topic. A new series of benzothiazoles hybridized with pyrimidine moiety was designed and synthesized using the lead compound 4a. Various chemical modifications on the pyrimidine ring of 4a at four different positions were done in a trial to get new multi-targeted anticancer agents. The structures of the newly synthesized compounds were established on their elemental analyses and spectral data. All final synthesized derivatives were submitted to the National Cancer Institute (NCI), USA, to be screened for their in vitro anticancer activity. Further evaluation for the cytotoxic activity of the most active compounds was performed using the MTT assay method. Compounds 4d, 8d, 8h, 8i and 17 were then selected for examining their in vitro enzyme inhibitory activities against EGFR, HER2 and TS enzymes using lapatinib and 5FU as standards. Furthermore, cell cycle analysis and apoptosis induction detection were also evaluated. Finally, molecular docking studies were carried out for compounds 4d, 8d, 8h, 8i and 17 to interpret their observed enzymatic activities based on the ligand-protein interactions.

Simultaneous estimation of dimenhydrinate, cinnarizine and their toxic impurities benzophenone and diphenylmethylpiperazine; in silico toxicity profiling of impurities.

The British Pharmacopeia (BP) reported that the carcinogenic and hepatotoxic, benzophenone (BZP) is a dimenhydrinate (DMH) impurity. On the other hand, cinnarizine (CIN) is reported to have five impurities (A-E). The toxicity profile of CIN impurities was studied and the in silico data revealed that impurity A [1-(diphenylmethyl)piperazine] (DPP) was the most toxic CIN impurity, and hence it was selected during this work. TLC-densitometric method was developed for separation and simultaneous quantitation of DMH, CIN and their toxic impurities. In the proposed method hexane : ethanol : acetone : glacial acetic acid (7 : 3 : 0.7 : 0.5, by volume) with UV scanning at 225 nm were used. Method validation was carried out according to ICH guidelines and linearity was achieved in the range 0.2-4, 0.5-5, 0.1-2.0, and 0.05-2.2 µg per band for DMH, CIN, BZP and DPP, respectively. On the application of the method to pharmaceutical formulation, no interference from additives was observed. The greenness of the method was evaluated using the analytical eco-scale and the results revealed the low negative environmental impact of the developed method.

New substituted pyrazole derivatives targeting COXs as potential safe anti-inflammatory agents.

Aim: Everyday studies prove the increasing need for newer and safer agents to control cellular inflammatory response, an underlying cause for the pathophysiology of many other clinical cases. Results: Two newly designed sets of schiff 5a-h and chlacone 6a-f substituted pyrazoles were synthesized and evaluated for their in vivo/vitro anti-inflammatory activities. Most potent representatives were chosen for investigation of ulcerogenic and molecular docking properties. Conclusion: The synthesized compounds showed considerable edema inhibition percentage range if compared with celecoxib (13-93% and 58-93%, respectively) at different time intervals. Compound 6e showed the best screening results if compared with celecoxib (inhibition % = 93.62 and 93.51% at 5 h, COX-1/COX-2 selectivity index SI = 215.44 and 308.16 and ulcer index = 7.25 and 8, respectively).

Anti-inflammatory indomethacin analogs endowed with preferential COX-2 inhibitory activity.

Aim: The undeniable indomethacin potency has always suffered serious obstacles such as gastric damage. Continuous attempts to develop potent yet safe indomethacin analogs have never ceased. Results: Herein are new indole derivatives 4a-h and 5a-c, which were synthesized via Fisher indole reaction, evaluated for both their in vivo anti-inflammatory activities using rat paw edema method and their in vitro cyclooxygenase inhibitory activities. Then ulcerogenic liability, physicochemical parameters and molecular docking modeling were performed for the most potent ones. Conclusion: Promising results were obtained, where compound 4f was the best anti-inflammatory agent and preferential COX-2/COX-1 inhibitor (90.5% edema inhibition, selective index = 65.71, ulcer index = 7.3), if compared with indomethacin (86.7% edema inhibition, selective index = 0.079, ulcer index = 20.20).

Design, synthesis and anticancer evaluation of novel spirobenzo[h]chromene and spirochromane derivatives with dual EGFR and B-RAF inhibitory activities.

A novel series of spirobenzo[h]chromene and spirochromane derivatives was designed, synthesized and evaluated as potential anticancer agents against MCF-7 (human breast carcinoma), HT-29 (human colorectal adenocarcinoma) and A549 (human lung carcinoma) cell lines using MTT assay. Eight compounds 7, 8e, 13a-e and 16 showed a better anticancer activity than that of sorafenib, the multi-kinase inhibitor with IC50 values between 1.78 and 5.47 µM or erlotinib with IC50 values over 20 µM. Representative compounds 8e, 13c and 16 were selected for further mechanistic investigation via EGFR, B-RAF and tubulin polymerization assays. Compound 16 was the most potent EGFR inhibitor (IC50 = 1.2 µM), yet compounds 8e, 13c and 16 displayed moderate tubulin polymerization inhibition effects. Molecular docking studies of those compounds revealed their possible binding modes into the active sites of both EGFR and B-RAF kinases. The newly developed compounds represent a therapeutically promising approach for the treatment of different types of cancer.

Novel 4-methylsulfonylphenyl derivatives as NSAIDS with preferential COX-2 inhibition.

AIM: There has been an enormous commercial development following the introduction of selective COX-2 inhibitors. Efforts are continuously done to discover efficient and safe COX-2 inhibitors. RESULTS: A series of 4-methylsulfonylphenyl derivatives was designed, synthesized and screened for preferential inhibition of COX-2 over COX-1 isoforms and in vivo anti-inflammatory activity using the rat paw edema method. The most active ones were investigated via ulcerogenic liability and molecular docking. Physicochemical parameters were calculated for all the newly synthesized compounds. CONCLUSION: The new compounds showed clear preferential COX-2 over COX-1 inhibition. Selective indices for compounds 4, 6b and 6e were 124, 131 and 119, respectively. Compound 4 reached 71% in vivo anti-inflammatory inhibition. The compounds obeyed 'Lipinski's rule of five'.

Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines.

A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702nM against hCA I, of 0.41-288nM against hCA II and of 5.6-29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines.