Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones

Abstract

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.

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

“…The position of hydroxyl groups in the ring affects lipase inhibition; 2‐hydroxy benzoic acid or benzoyl derivatives were reported with best inhibitory activity and this possibly related to increased phenolic group acidity for such compounds through intra‐molecular H‐Bs of close ortho groups (Buchholz & Melzig, and references cited therein). Similar to our findings with FQs research, Arabiyat () and Arabiyat et al (, ) reported that 2‐hydroxy benzoic acid compounds replaced with a methoxy group are weak inhibitors of PL and the inhibitory effects of hydroxyl groups in the ortho ‐position were stronger than at the para ‐position (Buchholz & Melzig, ; Menteşe et al, ). It is concluded that loosing free acidic OH or COOH can lessen the activity and this can be explained through the loss of the intra‐molecular H‐B for both ortho related keto or carboxyl groups with hydroxyl group at position 2.…”

“…Previous work by our group on FQs has shed some light on the main SAR features of PL inhibitors derived from FQs. We can conclude at this stage that the basic requirements for a highly active antipancreatic lipase FQ derivative are as seen in Chart (Arabiyat, ; Arabiyat et al, , ): Free 4‐oxo‐pyridine‐3‐carboxylic acid is seen as esterification of COOH group led to very weak activity. Free rotating hydrogen bond groups at C‐7 and C‐8 are essential and major requirements for activity. Lipophilicity was a major feature in all active FQs, and the c log P was above 3. The rigid structure of FQs between C7‐8 decreases PL inhibitory activity. A lipophilic phenyl group substituted at C‐7 carrying methoxy or amine, such as anisidine and aniline substituents, was the most active through their capability of forming extra H‐Bs. …”

“…Accordingly, the primary aims of this study were to repurpose drugs and select acidic market drugs already in market. Many synthetic and natural compounds with acidic characteristics, including salicylate, fluoroquinolone (FQ) derivatives, curcumin, flavonoids, caffeic acids, and others (Al-Hiari et al, 2014;Arabiyat, Al-Hiari, Bustanji, Zalloum, & Kasabri, 2016;Arabiyat et al, 2017;Buchholz & Melzig, 2015;Karama c & Amarowicz, 1996;Mohammad et al, 2015;Musialik, Kuzmicz, Pawłowski, & Litwinienko, 2009) have shown diverse activities as PL inhibitors. From a chemistry point, all active natural or synthetic PL inhibitors compounds were acidic compounds (with benzoic or phenolic groups) with no clear mechanism.…”

“…From a chemistry point, all active natural or synthetic PL inhibitors compounds were acidic compounds (with benzoic or phenolic groups) with no clear mechanism. Arabiyat et al (, ) have revealed that the structure‐activity relationship (SAR) of PL activity of the FQ nucleus (Figure ) relies on the free carboxylic acid system within the basic FQ system. We assumed that ionizable acidic groups could interact/chelate/form hydrogen bonds (H‐B) with some functionalities of amino‐acids found in the catalytic site of PL such as Ser‐152, Arg‐256, and Phe‐77.…”

“…The 4‐keto group in the basic fluoroquinolone‐3‐caboxylic structure (Figure ) has also subsidized the inhibitory activity, possibly due to the chelation mechanism with the PL enzyme. The free 3‐COOH group was established as an interacting group with the receptor PL since it forms H‐B with the ser‐152‐catalytic site of the enzyme (Arabiyat et al, ). This group provided ionic (negative electrostatic) interaction, H‐Bs, and potential co‐ordination (chelation with metals).…”