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Synthesis, cytotoxicity and mechanistic evaluation of 4-oxoquinoline-3-carboxamide derivatives: finding new potential anticancer drugs.

ABSTRACT: As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells.

SUBMITTER: Forezi Lda S

PROVIDER: S-EPMC6271384 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Synthesis, cytotoxicity and mechanistic evaluation of 4-oxoquinoline-3-carboxamide derivatives: finding new potential anticancer drugs.

Forezi Luana da S M Lda S Tolentino Nathalia M C NM de Souza Alessandra M T AM Castro Helena C HC Montenegro Raquel C RC Dantas Rafael F RF Oliveira Maria E I M ME Silva Floriano P FP Barreto Leilane H LH Burbano Rommel M R RM Abrahim-Vieira Bárbara B de Oliveira Riethe R Ferreira Vitor F VF Cunha Anna C AC Boechat Fernanda da C S Fda C de Souza Maria Cecília B V MC

Molecules (Basel, Switzerland) 20140522 5

As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active agai ...[more]

PMID: 24858098

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Project description:BackgroundIsoxazole is an important pharmacophore in medicinal chemistry with a wide range of pharmacological activities. The present study deals with the synthesis and evaluation of antinociceptive potential of nine novel 3-substituted-isoxazole-4-carboxamide derivatives.SynthesisIn the first step, respective oxime was prepared and further treated with ethylacetoacetate and anhydrous zinc chloride followed by hydrolysis of ester to furnish 3-substituted isoxazole-4-carboxylic acid. The respective carboxylic acids were converted to acid chlorides and condensed with aromatic amines to get the target carboxamide derivatives (A1-A5 and B1-B5). These compounds were characterized by FTIR, 1HNMR, 13CNMR and elemental analysis data and screened for their analgesic activity using acetic acid-induced writhing assay and hot plat test in mice and compared with the standard centrally acting analgesic, tramadol.ResultsAll the synthesized carboxamide derivatives showed low to moderate analgesic activity. Among the synthesized derivatives B2 having methoxy (OCH3) showed high analgesic activity as compared to tramadol both in acetic acid-induced writhing assay and hot plate assay at dose of 6 mg/kg. To examine the involvement of opioidergic mechanism in the mediation of analgesic effects of isoxazole derivatives animals were further treated with non-selective opioid analgesic, naloxone (0.5 mg/kg). The results showed that compounds A3 and B2 follow a non-opioid receptor pathway in the mediation of analgesic effects. Synthesized compounds A3 and B2 were docked against non-opioid receptors COX-1 (3N8X), COX-2 (1PXX) and human capsaicin receptor (HCR, 3J9J) to analyze their binding interactions. They showed binding energies in the range of - 7.5 to - 9.7 kcal/mol.ConclusionsThe results indicated that isoxazole carboxamide derivatives possess moderate analgesic potential especially compounds A3 and B2 can be considered as lead molecules and explored further for pain management with fewer side effects.

Dataset Information

Synthesis, cytotoxicity and mechanistic evaluation of 4-oxoquinoline-3-carboxamide derivatives: finding new potential anticancer drugs.

Publications

Synthesis, cytotoxicity and mechanistic evaluation of 4-oxoquinoline-3-carboxamide derivatives: finding new potential anticancer drugs.

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