Newly Substituted Anilino-Fluoroquinolones with Proliferation Inhibition Potential against a Panel of Cancer Cell Lines.

BACKGROUND: From a chemistry point of view, we hypothesized that superlative dual cytotoxicity-radical scavenging bioefficacies of series 4 FQs correlate to their acidic groups and C8-C7 ethylene diamine Chelation Bridge. METHODOLOGY: Newly synthesized 16 lipophilic-acid chelating FQs have been screened for in vitro duality of proliferation inhibition and radical scavenging capacities. RESULTS: Substantially in LPS prompted RAW264.7 macrophages inflammation, IC50 values (µM) in the ascending order of  new FQs' NO scavenging/antiinflammation capacity were 4e<4b<3d<4f<5c0.05). In comparison to classical and robust antineoplastic agent cisplatin and unlike triazoloFQs; nitroFQs (3a, 3b and 3f) and the reduced FQs (4a, 4c, 4d and 4e) exerted antiproliferation IC50 values <50 µM in leukaemia K562. Besides nitroFQ 3, the reduced FQs (4c and 4f) exhibited antineoplastic IC50 values <50 µM in lung A549 carcinoma. NitroFQ 3c and reduced FQs 4b, 4c, and 4f in breast MCF7 and reduced 4c in pancreatic PANC1 had reduction of viability IC50 values <50 µM. NitroFQ 3e, reduced FQs 4b and, 4c and triazoloFQ 5a exerted antiproliferation IC50 values <50 µM in breast T47D cells. Also nitroFQ 3e, reduced FQ 4c and triazoloFQ 5f exhibited antineoplastic IC50 values <50 µM in PC3 prostate cancer cells. Exceptionally triazoloFQ 5a, but neither nitro- nor reduced FQs, had cytotoxicity IC50 value <50 µM in resistant melanoma A375 cells. Unequivocally 4b antineoplastic effectiveness linked with its radical scavenging and antiinflammation effects while 3d and 5c lacked matching antiproliferation potentialities to their exquisite antiinflammation capacities. Explicitly reduced 4e and 4f exerted antiinflammation-selective cytotoxicity duality in vitro. CONCLUSION: Collectively, this work reveals lipophilic-acidic chelator FQs as authentic agents for the repurposing approach in anticancer chemotherapy/prevention.

Antiproliferative Activities of Lipophililic Fluoroquinolones- Based Scaffold Against a Panel of Solid and Liquid Cancer Cell Lines.

OBJECTIVES: In this work, 9 lipophilic-acid chelating FQs (fluoroquinolones) comprising chelating groups  have been prepared, characterized and screened for in vitro cytotoxicity, radical scavenging and antiinflammation propensities. METHODS: Using sulforhodamine B colorimetric bioassay vs. cisplatin; FQs-inflicted reductions' of viability against breast T47D and MCF7, Pancreatic PANC-1, colorectal HT29, HCT116, SW620, CACO2, SW480 and Leukaemia K562 cancer cell lines were examined in quadruplicates/dose/cell line. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals' scavenging capacities -as their molecular action mechanism- in comparison to ascorbic acid and indomethacin respectively. Using Griess assay in Lipopolysaccharide (LPS) prompted RAW264.7 macrophages; mitigation of inflammation was investigated. RESULTS: nitroFQ 3b, unlike the rest of FQs in PANC1 and MCF7 cells, exhibited remarkably superior NO-radical scavenging/antiinflammation capacity to indomethacin with respective antiproliferative IC50 values (<50µM) 49 vs. cisplatin's 122 and 6 vs. cisplatin's 28 (p<0.01-0.001; n=4). Reduced FQ 4b of significantly dual DPPH-NO scavenging propensities exerted exceptionally substantial micromolar antiproliferation in colorectal cancer cells with respective antiproliferative IC50 values (<50µM) of HCT116 0.84< HT29 1.6

In vitro Antiproliferative Properties of Lipophililic-Acid Chelating Fluoroquinolones and TriazoloFluoroquinolones with 7-dihaloanilinosubstitution.

BACKGROUND: Incidence rates and prevalence of cancer are substantially high globally. New safe therapeutic drugs are endorsed to overcome the high toxicity and poor safety profile of clinical anticancer agents. OBJECTIVE: As antineoplastic Vosaroxin is a commercial fluoroquinolone (FQ), we hypothesize that superlative antiproliferation activity of lipophilic FQs/TFQs series correlates to their acidic groups and C8-C7 ethylene diamine Chelation Bridge along with bulky dual halogenations. METHODS: We tested dual lipophilic- acidic chelating FQs with a genuine potential of antiproliferative propensities based on their dual DPPH- and NO- radicals scavenging biocapacities using cell based - and colorimetric assays vs. respective reference agents as their molecular action mechanism. RESULTS: In this work, 9 lipophilic-acid chelating FQs and their cyclized TriazoloFQs (TFQs) designed to bear 7- dihaloanilino substituents with a special focus on dichlorosubstitutions have been prepared, characterized and screened against breast T47D and MCF7, Pancreatic PANC1, colorectal HT29, cervical HELA, lung A375, skin A549, and Leukaemia K562 cancer cell lines using sulforhodamine B colorimetric bioassay. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals' scavenging propensities - as their molecular action mechanism- in comparison to ascorbic acid and indomethacin, respectively. Using Griess assay in lipopolysaccharide (LPS) prompted RAW264.7 macrophages inflammation, IC50 values (µM) in the ascending order of new FQs' NO scavenging/antiinflammation capacity were 4a < 3a < 4c < indomethacin (23.8 < 33.4 < 36 vs. indomethacin's 124, respectively). Exceptionally unlike the rest, reduced FQ, 4b exhibited remarkably superior DPPH radical scavenging capacity to ascorbic acid (IC50 values (µM) 19.9 vs. 123.9, p < 0.001). In comparison to cisplatin; nitroFQs (3a, 3b and 3c), the reduced FQs (4a, 4b, and 4c) and the TFQs (5a, 5b and 5c) exerted substantial micromolar antiproliferation IC50 values < 50 µM in cervical Hela cancer cells but lacked comparable bioactivity in leukaemia K562. In both breast MCF7 and T47D cancer cell lines, FQs/TFQs 4a < 3a < 5b (respective IC50 values (µM) 0.52 < 22.7 < 24 vs. cisplatin's 41.8 and 0.03 < 4.8 < 27 vs. cisplatin's 509), and in both GI system colorectal HT29 and pancreatic PANC1 cancer cells FQs/TFQs 4a < 3a < 5b and 4a< 3a (respective IC50 values (µM) 0.12 < 3.5 < 15.9 vs. cisplatin's 148 and 1.5 < 10.4 vs. cisplatin's 25.5), exerted nanomolar-micromolar affinities of antiproliferation potencies < 50µM. Besides in lung A375 cancer cells FQs/TFQs 4c < 4a < 3a and in skin A549 cancer cells 5c < 3c < 4a < 3a < 4c (respective IC50 values (µM) 0.07 < 3.2 < 10.3 vs. cisplatin's 390 and 0.5 < 2.3 < 3.8 < 8.8 < 17.3 vs. cisplatin's 107) exhibited nanomolar-micromolar antineoplastic capacities < 50 µM. Their spectrum of selectivity indices for safety in fibroblasts PDL-based 72h incubations was reported. Unequivocally 4b reduction of viability effectiveness linked with its DPPH radical scavenging effects (without a matching antiinflammation effect). Explicitly 4a, 3a and 4c exerted exquisite antiinflammation-selective cytotoxicity duality in vitro. CONCLUSION: Such a new potential chelation mechanism can explain the pronounced difference in antineoplastic activity of new FQs/TFQs.

Antiproliferative Properties of 7,8-Ethylene Diamine Chelator-Lipophilic Fluoroquinolone Derivatives Against Colorectal Cancer Cell Lines.

BACKGROUND: Cancer is one of the most overwhelming diseases nowadays. It is considered the second cause of death after cardiovascular diseases. Due to the diversity of its types, stages and genetic origin, there is no available drug to treat all cancers. Serious side effects and resistance of existing drugs are other problems in the struggle against cancer. In such quest, fluoroquinolones (FQs) promising as antiproliferative compounds due to safety, low cost and lack of resistance. OBJECTIVES: Therefore, this work aims at developing lipophilic FQs and screening their antiproliferative activity against colorectal cancer. METHODS: Nine prepared FQs were investigated for antiproliferative activity utilizing in vitro SRB method. In comparison to the antiproliferative agent cisplatin; the assessment of antiproliferative activities of these novel FQs in a panel of Colorectal Cancer Cell (CRC) lines (HT29, HCT116, SW620, CACO2, SW480) and normal periodontal ligament fibroblasts for safety examination was performed. Antibacterial activity (MIC) was conducted against Staphylococcus aureus and Escherichia coli standard strains using the broth double dilution method. Antioxidant properties were suspected as the mechanism of antiproliferative activity; thus, a DPPH test was performed to analyze radical scavenging potency of FQs compared to ascorbic acid as reference agent. FQs compounds 3-5(a-c) were prepared, characterized and their structure was confirmed using spectroscopy techniques. RESULTS: All compounds manifested good to excellent antiproliferative activity on HT29, HCT116, and SW620 with high safety index. The reduced series 4a, 4b and 4c exerted excellent micro to nano -molar antiproliferative activities on HT29, HCT116, and SW620 which were stronger than the reference cisplatin against all cells. The reduced group of compounds 4(a-c) revealed higher potency vs. both nitro and triazolo groups. On cell lines HT29, HCT116, and SW620, reduced 4a with 7,8-ethylene diamine,the substitution revealed the highest antiproliferative efficacy (IC50 value) approaching nano molar affinity with higher safety vs. cisplatin. The most active compound, 4a, exhibited significant potency against HCT116, and SW620 with IC50 0.6 and 0.16 µM respectively. Novel FQs (4a, 4b and 4c) also showed strong radical scavenging activity with IC50 values (µM) 0.06, 23, and 7.99, respectively. Exquisitely 4a revealed a similar pattern of activity to doxorubicin, indicating a similar mechanism of action. Strong antiproliferative and weak antibacterial activities of series 4 endorse that their mechanism involves eukaryotic topoisomerase II inhibition. This work has revealed novel FQs with excellent anticancer activity against 5 colorectal cancer (HT29, HCT116, SW620, CACO2, SW480) cell lines with a potential chelation mechanism due to 7,8-ethylene diamine chelator bridge. CONCLUSION: The new FQs have confirmed that more lipophilic compounds could be more active as hypothesized. The p-halogenated aniline, N1-Butyl group in addition to 3-COOH, 8-NH2 are all essential requirements for strong antiproliferative FQ of our FQ scaffold. This work emphasizes the role of C-8 amino as part of ethylene diamine group as an essential requirement for antiproliferative FQs for the first time in the literature, entailing its role toward potential antineoplastic FQs.

Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti-Hyperlipidemic and Antioxidant Agents.

Hyperlipidemia and oxidative stress have been implicated as contributing factors to the development of atherosclerosis and cardiovascular diseases (CVDs). Currently, a large number of antihyperlipidemic medications are conveniently available in the market. Nonetheless, the majority of antihyperlipidemics lack the desired safety and efficacy. Thus, the present study was undertaken to evaluate the potential effect of novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives in controlling hyperlipidemia and oxidative stress using the Triton WR-1339-induced hyperlipidemic rat model for antihyperlipidemic activity and the DPPH radical scavenging assay for antioxidant activity. This study revealed the antihyperlipidemic activities of some of the newly synthesized, novel carboxamide derivatives, mainly C4 and C12 (p < 0.05). The majority of the compounds displayed a relatively low or no DPPH radical scavenging effect, with C20 possessing the best radical scavenging effect (22%) among all. This research opens the door for new potential antihyperlipidemic compounds derived from isonicotinic acid. N-(3-Benzoylphenyl)pyridine-4-carboxamide (C4) was found to have promising lipid-lowering and antioxidant effects, which may create a protective effect against CVDs, by reducing the LDL-C levels and diminishing the generation of reactive oxygen species.

Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones.

Fluoroquinolones (FQs) have been identified recently as potent inhibitors of pancreatic lipase (PL). The aim of this study was to synthesize novel FQs and triazolofluoroquinolones (TFQs) and to evaluate them in vitro with respect to their antilipolytic efficacy and potency properties. The PL-IC50 values of 12 FQs and TFQs (3 (a-c)-6 (a-c)) were in the range of 12.5-189.1 µm. These values are further supported by docking studies. The suggested association between obesity and colorectal cancer initiated the evaluation of antiproliferative activity of the new FQs and TFQs against a panel of obesity-related colorectal cells (HT29, HCT116, SW620 CACO2, and SW480). Sulforodamine B colorimetric assay revealed that some derivatives exhibited unselective cytotoxicity against HT29, HCT116, SW620 CACO2, and SW480. Remarkably, FQ 4a's selective cytotoxicity against HCT116 was found valuable with IC50 value of 4.2 µm which exceeds that of cisplatin with a substantial selective cytotoxicity in periodontal ligament fibroblasts. In conclusion, FQ and TFQ derivatives may unveil new antiobesity and anticancer agents in the future.

Lipid lowering activity of novel N-(benzoylphenyl)pyridine-3-carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats.

CONTEXT: Dyslipidemia is a major risk factor for the development of cardiovascular diseases. Many dyslipidemic patients do not achieve their target lipid levels with the currently available medications, and most of them may experience many side effects. OBJECTIVE: The present work aimed toward identifying a new class of novel nicotinic acid-carboxamide derivatives as promising antihyperlipidemic compounds. MATERIALS AND METHODS: Six novel N-(benzoylphenyl)pyridine-3-carboxamide derivatives were synthesized using acid chloride pathways. All structures were confirmed using 1H-NMR, 13C-NMR, IR, and HRMS. The evaluation of biological activity was conducted using Triton WR-1339-induced hyperlipidemic rats model. RESULTS: This study revealed that some of the newly synthesized novel N-(benzoylphenyl)pyridine-3-carboxamide derivatives mainly C4 and C6 possessed significant antihyperlipidemic activities on lipid components TG and TC (p value <0.05). DISCUSSION AND CONCLUSION: This research opens the door for new potential antihyperlipidemic compounds derived from nicotinic acid that need further optimization of their biological activities.

Design synthesis and antibacterial activity studies of new thiadiazoloquinolone compounds.

Abstract New 9-(alkyl/aryl)-4-fluoro-6-oxo[1,2,5]thiadiazolo[3,4-h]quinoline-5-carboxylic acids and their esters were designed and synthesized. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported. All the newly synthesized compounds were fully characterized using all the physico-chemical means needed. All the intermediates and the final esters and acids were tested against bacterial and fungal strains. The acids 25a and 25c proved to be very active against Gram positive and Gram negative bacteria with MIC 0.15-3 µg/mL. The structure-activity relationship of antibacterial thiadiazoloquinolones shows that compounds 25a and 25c are twice less potent than the corresponding cyclopropyl derivative 16. Therefore, the cyclopropyl moiety on N-9 seems to be the most suitable substituent.