Synthesis and evaluation of anticancer activity of some novel 6-aryl-2-(p-sulfamylphenyl)-pyridazin-3(2H)-ones

doi:10.1016/j.ejmech.2012.01.026

European Journal of Medicinal Chemistry

Volume 49, March 2012, Pages 304-309

https://doi.org/10.1016/j.ejmech.2012.01.026 Get rights and content

Absract

A series of novel pyridazinone derivatives bearing benzenesulfonamide moiety (2a–h) has been synthesized by the condensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Five derivatives (2a, 2b, 2d, 2g and 2h) were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute. The 2h showed remarkable activity against SR (leukemia) and NCI-H522 (non-small cell lung) with a GI₅₀ value of less than 0.1 μM. It also displayed good activity against leukemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226), non-small cell lung cancer (NCI-H460), colon (HCT-116, HCT-15, HT29, KMI2, SW-620), CNS (SF-295), melanoma (MALME-3M, M14, MDA-MB-435 SK-MEL-5), ovarian (OVCAR-3, NCI/ADR-RES) and breast (MCF7) cancer cell lines with a GI₅₀ less than 1.0 μM. The acute toxicity study of 2h indicated that it is well tolerated intra-peritoneally (400 mg/kg) by athymic nude mice. The 2h may possibly be used as lead compound for developing new anticancer agents.

Graphical abstract

Highlights

► Out of eight novel derivatives five were selected for anti-proliferative activity by NCI. ► Compound (2h) exhibited remarkable antiproliferative activity. ► 2h was referred to Biological Evaluation Committee for advance study. ► 2h is well tolerated intra-peritoneally (400 mg/kg) by athymic nude mice. ► The 2h may possibly be used as lead compound for developing new anticancer agents.

Introduction

Among all diseases that affect humanity, cancer ranks high as a major killer [1], [2]. Although major advances have been made in the chemotherapeutic management of some patients, the continued commitment to the arduous task of discovering new anticancer agents remains critically important. A large number of structurally novel sulfonamide derivatives have recently been reported to show substantial antitumor activity, both in vitro and/or in vivo. Although they have a common chemical motif of aromatic/heterocyclic sulfonamide, there are a variety of mechanisms of their antitumor action, most of them poorly understood at this moment. It is believed that carbonic anhydrase inhibition, cell cycle arrest in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition may be among such relevant mechanisms of these anticancer compounds. Some of these derivatives are currently being evaluated in clinical trials, and there is much optimism that they may lead to novel alternative anticancer drugs, devoid of the side effects of the presently available pharmacological agents [3], [4], [5].

Pyridazinone derivatives have been reported to exhibit a wide range of pharmacological activities such as antidepressant [6], antihypertensive [7], [8], antithrombotic [9], anticonvulsant [10], cardiotonic [11], antibacterial [12], diuretic [13], anti-HIV [14], aldose reductase inhibitors [15], hepatoprotective agents [16] and COX-2 inhibitors [17]. It has also been reported that pyridazinone derivative have remarkable anticancer activity [18], [19].

In continuation of an ongoing program aiming at finding new structure leads with potential chemotherapeutic activities [20], [21], [22] it was thought worthwhile to synthesize and investigate the antitumor activity of some novel pyridazinone derivatives comprising the benzenesulfonamide moiety (2a–h). The data of these synthesized compounds were submitted to National Cancer Institute (NCI), USA for antiproliferative activity. As per the protocol of NCI, only five representative compounds 2a, 2b, 2d, 2g and 2h were selected and granted NSC codes Viz; NSC 749115, NSC 749114, NSC 747557, NSC 749116 and NSC 747558 respectively and screened at NCI for antiproliferative activity at a single high dose (10⁻⁵ M) in full 60 cell panel. Compound (2h) NSC 747558 exhibited the best result at a single dose and was selected for further evaluation at five dose level screening. It showed remarkable antiproliferative activity at five dose level screening and was referred to Biological Evaluation Committee of NCI for advanced study. This paper presents the synthesis of novel compounds (2a–h) and in vitro anticancer efficacy against human cancer cell lines of 2a, 2b, 2d, 2g and 2h compounds.

Section snippets

Chemistry

The synthetic route used to synthesize title compounds (2a–h) is outlined in Scheme 1. The β-aroylacrylic acids (1a–h) required for the synthesis of pyridazinones were obtained by a Friedel Craft’s acylation through reported methods [23], [24]. The cyclization to pyridazinone derivatives bearing a benzenesulfonamide moiety was afforded by the condensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol in 9.1–16.2% yield. The purity of the compounds

Conclusion

Cyclocondensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide hydrochloride yielded pyridazinone derivatives bearing a benzenesulfonamide moiety (2a–h). The structures proposed to the synthesized compounds are well supported by spectroscopic data and elemental analyses. One of these derivatives (2h) had excellent in vitro anticancer activity and can be used as lead compound for developing new anticancer agents.

Chemistry

Melting points were determined by open capillary tubes and are uncorrected. All the Fourier Transform Infra Red (FTIR) spectra were recorded on a Bio-rad FTS-135 spectrophotometer using KBr pellets; ν_max values are given in cm⁻¹. ¹H NMR spectra were recorded on a Bruker Spectrospin DPX 300-MHz spectrometer using deuterated DMSO as solvent and tetramethyl silane (TMS) as an internal standard. Chemical shifts are given in δ (ppm) scale and coupling constants (J values) are expressed in Hz. Mass

Acknowledgment

This work was supported by Grant No. 32-228/2006 (SR) from the University Grants Commission, New Delhi, India. One of the authors, I. G. Rathish is thankful to UGC for fellowship. We thank the Antitumor Evaluation Branch of the National Cancer Institute for performing biological evaluations.

References (31)

C.W. Lee et al.
Biochem.Pharmacol.
(2002)
S.A.F. Rostom
Bioorg. Med. Chem.
(2006)
A. Coelho et al.
Tetrahedron
(2003)
S. Demirayak et al.
Eur. J. Med. Chem.
(2004)
A.A. Siddiqui et al.
Eur. J. Med. Chem.
(2010)
L.G. Costantino et al.
Il Farmaco
(2000)
W. Malinka et al.
Il Farmaco
(2004)
R. Bashir et al.
Bioorg. Med. Chem. Lett.
(2011)
S. Bano et al.
Eur. J. Med.Chem.
(2011)
M.G. Hollingshead et al.
Life Sci.
(1995)

S. Eckhardt

Curr. Med. Chem.

(2002)

A. Casini et al.

Curr. Cancer Drug Targets

(2002)

C.T. Supuran

Nature Rev. Drug Discov.

(2008)

A. Monge et al.

J. Med. Chem.

(1987)

C. Rubat et al.

Chem. Pharm. Bull.

(1990)

Cited by (66)

Pyridazinones: A versatile scaffold in the development of potential target-based novel anticancer agents
2023, Journal of Heterocyclic Chemistry
Pyridazinones are important nitrogen‐rich heterocyclic core that has been driving the substantial medicinal interest due to their wide range of biological activities. This privileged scaffold forms a central core in numerous potent compounds, which results in the development of novel anticancer drugs with fruitful biological activities. The current review article summarizes the progressive development of novel pyridazinone derivatives that are targets for numerous receptors such as C‐met kinase inhibitors, PARP inhibitors, Tubulin polymerization inhibitors, Dihydro folate reductase inhibitors, B‐Raf inhibitors, Bruton tyrosine kinase inhibitors, FER tyrosine kinase inhibitors, and fibroblast growth factors receptors. It features the various simple techniques for the synthesis of pyridazinones and also highlights the mechanistic insights into the anticancer properties of pyridazinone derivatives.
A comprehensive review on pyrazoline based heterocyclic hybrids as potent anticancer agents
2022, European Journal of Medicinal Chemistry Reports
Cancer is one of the leading causes of death globally, around 10 million deaths are reported every year due to cancer. Some clinically approved anticancer drugs play a riveting role in its treatment. Still, due to the severe emergence of drug resistance, side effects, and multidrug-resistant cancers due to mutations, it creates a significant demand for novel, potent, and safe candidates as an anticancer agent with diverse mechanisms of action. In medicinal chemistry, several heterocyclic derivatives and hybrids are studied and reported as potent anticancer agents; Pyrazoline is one of the versatile and ubiquitous scaffolds for developing novel anticancer agents. Many pyrazoline scaffolds bearing drugs are used clinically for the treatment of cancer. Few are in the late phase of the clinical trial for treating various cancers, for example, Indibulin, a novel microtubule inhibitor and AT9283. The hybridization strategy of a pyrazoline scaffold with various heterocyclic rings is very promising to minimize the side effects and drug resistance. In light of this pyrazoline containing hybrids monopolize an important place in developing potent, safe and novel anticancer agents. The presented review outlined recent advances studied and reported towards developing pyrazoline-containing hybrids as potent anticancer agents. The review covers synthetic strategy, structure-activity relationship and anticancer activities of pyrazoline hybrid derivatives. The sole purpose is to shed light on the design and development of pyrazoline hybrids compounds with high efficacy and reduced toxicity.
Green, Practical and Scalable Multicomponent Reaction for the Synthesis of Amides and Pyridazinones from Arenes Using L-Proline Functionalized Silicapropyl Modified Nanomagnetic as a Heterogeneous Bronsted Acid Catalyst
2022, Polycyclic Aromatic Compounds
A practical and scalable synthetic method for the synthesis of new amides and pyridazinones was established starting from the readily accessible materials as arenes, cyclic anhydrides, and 2-aminobenzimidazole or phenylhydrazine. This synthetic method includes a scalable reaction using L-proline functionalized propyl modified nanomagnetic in aqueous media without using any other harmful organic reagents or inorganic as AlCl₃. The synthetic method enables to synthesize new amides and pyridazinone derivatives in manufacturing scale, with low reaction steps and high purity. The catalyst could easily be separated from the reaction mixture by using an external magnetic field and it was reusable and green.
Studies on the relationship between the structure of pyrimidinecarboxylic, pyridazinecarboxylic and pyrazinecarboxylic acids and their antimicrobial and cytotoxic activity
2021, Journal of Molecular Structure
Diazinecarboxylic acids (pyridazine-3-carboxylic, pyridazine-4-carboxylic, pyrimidine-2-carboxylic, pyrimidine-4-carboxylic, pyrimidine-5-carboxylic and pyrazine-2-carboxylic acids) were characterized by means of spectroscopic (FT-Raman, FTIR, UV, ¹HNMR, ¹³CNMR) and thermogravimetric analysis as well as antimicrobial and cytotoxic tests. The structures of diazinecarboxylic acids were calculated by the DFT method (B3LYP/6-311G(d, p). For the most stable conformers, the energy of HOMO and LUMO molecular orbitals, the geometric (HOMA, GEO, EN, I6) and magnetic (NICS) aromaticity indices, NBO electronic charge distribution, sEDA and pEDA indexes, Wiberg Bond Order, Wiberg Index and theoretical IR and NMR spectra have been calculated. The energies of protonating and deprotonating acids were also calculated. The effect of the nitrogen heteroatom position in the aromatic ring in relation to the position of the carboxyl group on the electronic charge distribution, thermal stability, antimicrobial and cytotoxicity activities of the examined acids was determined. Antimicrobial activity of tested acids against of Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosaand Candida albicanswas calculated based on MTT colorimetric assay (MCA). The cytotocic effect of diazynecarboxylic acids was examined in A375 melanoma cell line and DLD-1 cell line. A biplot analysis was performed in order to determine the correlations between selected parameters of the tested compounds and relative cell viability of E. coli, B. subtilis, P. aeruginosa, C. albicans, A375 and DLD-1 cell lines. Thermal behaviour of all investigated carboxylic acids was investigated using thermogravimetry (TG) and differential scanning calorimetry (DSC) techniques in flowing air atmosphere. All compounds are stable in room temperature.
Synthesis and anticancer activity of thiourea derivatives bearing a benzodioxole moiety with EGFR inhibitory activity, apoptosis assay and molecular docking study
2020, European Journal of Medicinal Chemistry
Citation Excerpt :
So, the antitumor studies focused on optimizing the activity against EGFR [21]. Study the mechanisms of anticancer agents provide significant information for chemotherapeutic drugs design [22,23]. One of the main strategies for the discovery of new drugs is combining two or more pharmacophoric moieties in a single molecule to obtain the synergistic effect or to obtain antitumor agents that have a novel mode of action.
New thiourea derivatives bearing a benzodioxole moiety were synthesized via the reaction of 5-isothiocyanatobenzodioxole with amino compounds such as aromatic amines, sulfa drugs, heterocyclic amines, hydrazines and hydrazides. The anticancer activity of the synthesized thiourea derivatives was examined against HCT116, HepG2 and MCF-7 cancer cell lines. Most of thiourea derivatives revealed significant cytotoxic effect, in some cases greater than the doxorubicin. As example, IC₅₀ values of N¹,N³-disubstituted-thiosemicarbazone 7 were 1.11, 1.74 and 7.0 μM for HCT116, HepG2 and MCF7, respectively; IC₅₀ values of doxorubicin were 8.29, 7.46 and 4.56 μM, respectively. The anticancer mechanisms were studied via EGFR inhibition and apoptosis assessments, as well as molecular docking.
One-pot synthesis and molecular docking of some new spiropyranindol-2-one derivatives as immunomodulatory agents and in vitro antimicrobial potential with DNA gyrase inhibitor
2020, European Journal of Medicinal Chemistry
a series of 2-oxospiro[indoline-3,4′-pyran]derivatives 4 and 7 were obtained in good yield under mild conditions from the one-pot reaction of indole-2,3-dione derivatives 1, appropriate methylene active nitriles 2 and β-dicarbonyl compound 3 or 6. The newly synthesized compounds were characterized and evaluated for their in vitro antibacterial, antifungal as well as immunomodulatory activity. According to MIC values, the most potent compounds 4f, 4h, 7a, 7c, 7e, 7f, 7g, 8a, and 8c were evaluated for MBC and displayed high activity to killing pathogens with a good MBC value against norfloxacin as well as investigated against an extended panel of multidrug resistance bacteria (MDRB) and exhibited promising to moderate multidrug resistance activities, compounds 7f showed the much better than norfloxacin with higher potency results. Furthermore, the most potent compounds showed an increase in the intracellular killing activity of neutrophils which confirmed the immunostimulatory power. Eight of the nine active compounds exhibited inhibitory activities with IC₅₀ ranged between (18.07 ± 0.18) to (27.03 ± 0.24) μM stronger than ciprofloxacin (26.43 ± 0.64 μM) for S. aureus DNA gyrase. Molecular docking was performed inside the active site of S. aureus DNA gyrase to predict the binding mode.

View all citing articles on Scopus

View full text

Original articleSynthesis and evaluation of anticancer activity of some novel 6-aryl-2-(p-sulfamylphenyl)-pyridazin-3(2H)-ones

Absract

Graphical abstract

Highlights

Introduction

Section snippets

Chemistry

Conclusion

Chemistry

Acknowledgment

Biochem.Pharmacol.

Bioorg. Med. Chem.

Tetrahedron

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Il Farmaco

Il Farmaco

Bioorg. Med. Chem. Lett.

Eur. J. Med.Chem.

Life Sci.

Curr. Med. Chem.

Curr. Cancer Drug Targets

Nature Rev. Drug Discov.

J. Med. Chem.

Chem. Pharm. Bull.

Original article
Synthesis and evaluation of anticancer activity of some novel 6-aryl-2-(p-sulfamylphenyl)-pyridazin-3(2H)-ones