Fluoroquinolones: novel class of gastrointestinal dietary lipid digestion and absorption inhibitors

Al‐Hiari, Yusuf; Kasabri, Violet; Shakya, Ashok K.; Alzweiri, Muhammed; Afifi, Fatma U.; Bustanji, Yasser; Almasri, Ihab M.

doi:10.1007/s00044-014-0913-4

Cited by 17 publications

(21 citation statements)

References 20 publications

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“…In effect, FQs, mostly popular as potent and effective antibacterials, have been proven recently to act as potential PL inhibitors. TFQs exhibit similar structural scaffold to previously reported tetracyclic FQ derivatives as benzodiazepines and have been reported as PL inhibitors [5] with appreciable anticancer propensities. TFQs exhibit similar structural scaffold to previously reported tetracyclic FQ derivatives as benzodiazepines and have been reported as PL inhibitors [5] with appreciable anticancer propensities.…”

Section: Introductionsupporting

confidence: 58%

“…[5] Synthesis of compound 2 was carried out following a previously reported procedure (Scheme 1). [5] Synthesis of compound 2 was carried out following a previously reported procedure (Scheme 1).…”

Section: Synthesis Of Novel Compoundsmentioning

confidence: 99%

“…[13] The 12 designed compounds were estimated by simulated docking to bind within the active site of PL. [5] Our previous experience in PL-inhibitors docking simulations [5,[17][18][19] guided us toward two essential binding requirements for PL inhibition activity: (i) strong network of hydrogen bonding (HB) (Figures 1b and 2a) with the cocrystallized ligand within the binding site of PL (Figures 1a and 2c), capable of binding with the catalytic triad, especially Ser-152; (ii) a lipophilic moiety that mimics the hydrophobic fatty acid moiety of a triglyceride substrate. The lipolytic active site of PL contains three key amino acids forming the catalytic triad: His-263, Asp-176, and Ser-152.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…[4] Scaffold similarities in the structures of reported PL inhibitors based on isoquinoline and quinolone structures were the basis to investigate the anti-PL activities of the synthetic fluoroquinolones (FQs). [5] In this present work, novel FQs as well as a trihybrid structure, triazolofluroquinolones (TFQs), are prepared. [5] In this present work, novel FQs as well as a trihybrid structure, triazolofluroquinolones (TFQs), are prepared.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, there is now considerably incremental evidence that obesity has pathophysiological effects that extend beyond well-known comorbidities to include a number of organ-specific cancers. [5] 2.2.2 | Synthesis of ethyl 7-chloro- [8,9] This study has intended to prepare FQs and TFQs that are substituted at C-7 with cyclohexylamine and aniline.…”

Section: Introductionmentioning

confidence: 99%

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Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones

et al. 2017

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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-IC 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 IC 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.

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Section: Introductionsupporting

confidence: 58%

Section: Synthesis Of Novel Compoundsmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones

et al. 2017

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Evaluation of selected commercial pharmacotherapeutic drugs as potential pancreatic lipase inhibitors and antiproliferative compounds

Mamdooh

Kasabri

Al‐Hiari

et al. 2018

Drug Development Research

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In this study, 15 commercial acidic drugs have been evaluated for pancreatic lipase (PL) inhibitory activity using an in vitro spectrophotometric method. The acidity was the basis of selection, since most PL inhibitors exhibit acidic groups and high lipophilicity. Orlistat was the robust reference agent for potency and efficacy determinations. In comparison to the cisplatin, the evaluation of the antineoplastic activities of selected drugs in a panel of colorectal cancer cell lines (HT‐29, HCT‐116, SW620, CACO‐2, and SW480) and normal periodontal ligament fibroblasts for safety examination was performed by using a sulforhodamine procuring ascorbic acid as a reference in diphenyl‐2‐picryl‐hydrazyl assay of radical scavenging properties was performed. This research revealed three highly acidic pharmacological classes with reasonable PL inhibitory activity in comparison to orlistat out of 15 selected drugs, namely sulfonylureas, fluoroquinolones, and proton pump inhibitors. Docking studies supported the hypothesis of a selection based on acidity, since it showed that the sulfonamide acid group (glyburide) is a remarkably potent interacting group with the enzyme. Failing to fulfill other structure‐activity relationship requirements (lipophilicity) led to weak activity. Since the drugs are of different chemical classes with unknown mechanisms, they showed diverse antiproliferative activity. Some drugs such as atorvastatin and gemifloxacin showed higher antiproliferative activity than cisplatin with high‐safety profiles against SW620 and SW480 cell lines, respectively, whereas lansoprazole and clopidogrel revealed comparable activity to cisplatin against HCT‐116 and SW480, respectively. Unfortunately, selected tested drugs exhibited negligible radical scavenging activity versus ascorbic acid. Hit, Lead & Candidate Discovery

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Dual anti‐inflammatory and antiglycation propensities of a potentially novel class of functionalized fluoroquinolones

Hamdan

Kasabri

Al‐Hiari

et al. 2019

Journal of Heterocyclic Chem

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Promoted by elevated blood glucose concentrations in diabetes, glycation involves the nonenzymatic addition of reducing sugars and/or their reactive degradation products to amine groups on proteins. New synthetic approaches to 18 fluoroquinolones (FQs) have been developed on the basis of a promising antiglycation activity using 400μM methylglyoxal as the choice glucocytotoxicity concentration. Their anti-inflammatory and radical scavenging properties were elucidated in vitro. Intriguingly, FQs could exhibit an exceedingly more superior than or substantially comparable cytoprotection against methylglyoxal-induced carbonyl toxicity in RAW264.7 macrophages and antiglycation activity to aminoguanidine, as the reference compound. This kind of activity can suggestively be associated with the chelating properties possessed by the synthesized FQs as their DPPH radical scavenging activities proved to be significantly inferior to those of the reference compound, the ascorbic acid. The inhibitory bioactivities using the Griess assay were examined of the compounds against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Selectively, compounds R-2TCBA, R-4FACBA, R-3TCBA, and R-4CLACBA exerted an exceedingly remarkable and superior anti-inflammatory effects (P < .001 vs indomethacin IC 50 value of 101.07 ± 2.2 μM) while R-4TCBA and T-4BrACBA were moderately more efficacious than indomethacin. Compounds T-4CLACBA and R-4BrACBA displayed comparable activity with indomethacin. None of the tested compounds and indomethacin exerted any cytotoxicity against RAW 264.7 mouse macrophages. FQs possess potent duality of antiglycation-anti-inflammatory capacities and are devoid of undesirable side effects. FQs can, therefore, serve as scaffolds for the development and designing of new clinical deglycation and antiglycation therapeutic agents.

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Fluoroquinolones: novel class of gastrointestinal dietary lipid digestion and absorption inhibitors

Cited by 17 publications

References 20 publications

Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones

Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones

Evaluation of selected commercial pharmacotherapeutic drugs as potential pancreatic lipase inhibitors and antiproliferative compounds

Dual anti‐inflammatory and antiglycation propensities of a potentially novel class of functionalized fluoroquinolones

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