Functionalised Triazoloquinolones as a Potentially Novel Class of Antidiabesity and Antiproliferative compounds: Synthesis and Pharmacological Appraisal

Abstract

Nine newly prepared triazoloquinolones (TQs) and their precursor’s fluoroquinolones (FQs) are investigated for pancreatic lipase (PL) inhibitory activity utilizing in vitro spectrophotometric method. Registered antiobesity orlistat was the reference agent for potency and efficacy determinations. In comparison to the antiproliferative agent cisplatin; the assessment of antineoplastic activities of these novel TQs/ FQs in a panel of colorectal carcinoma (CRC) cell lines (HT29, HCT116, SW620, CACO2, SW480) and normal periodontal ligament fibroblasts for safety examination was performed. DPPH radical scavenging capacity of TQs/ FQs as antiproliferative action mechanism was analyzed in comparison to ascorbic acid as reference agent. Unlike orlistat (0.2 μM) antilipolytic properties, TQs/ FQs compounds 3a and 5a manifested moderate PL inhibition (IC50 value (μM): 39.15 and 34.19 respectively). The nitro-groups of compounds revealed higher potency vs. triazolo- and reduced groups. The ortho substituted compounds were more potent vs. meta- and para-substituted TQs/ FQs. On cell line HT29; TQ 5a, revealed significantly higher antiproliferative efficacy (IC50 value 4.09 μM) with appreciable safety vs. cisplatin (6.9 μM). Compounds 4a, 4b and 4c exerted excellent antiproliferative activities on SW620, CACO2 and SW480 with high safety index. The most active compound, 4b, exhibited significant potency against SW620, CACO2 and SW480 with IC50 0.42 μM, 1.12 μM and 1.69 μM respectively. Novel FQs (4a, 4b and 4c) also showed strong radical scavenging activity with IC50 values (μM) (90.5, 22.4, and 31 respectively). In effect the proven antilipolytic activity coupled to the antioxidative-chemopreventive efficacies of these novel TQs/ FQs are delineated.