Abstract
A series of 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a–j) were synthesized by condensation of the appropriate β-aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol and tested for anti-cancer, anti-inflammatory, and antimicrobial actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay, compound 2g showed high activity against HL-60 (TB) (leukemia), SR (leukemia), NCI-H522 (non-small-cell lung cancer), and BT-549 (breast cancer) with a GI50 value of less than 2 μM. Two compounds (2c and 2f) were found to have promising anti-inflammatory activity, while a fair number of compounds showed good antifungal activity.
Introduction
Though not commonly found in nature, pyridazinones have been used as scaffolds in the pharmaceutical industry for a wide range of structure–activity relationship (SAR) studiesCitation1. For example, azelastine is an antihistamine, while zardaverine exhibits phosphodiesterase (PDE) III and PDE IV inhibitory activity. The significant commercial interest in the pharmaceutical uses of pyridazinones is further illustrated by the large number of patents filed in this area that cover positive inotropic agents for the treatment of congestive heart failure, antidepressants, α1/α2 antagonists, potassium channel activators, anti-asthmatics, and othersCitation2,3. Recently, these derivatives have been reported as potent aldose reductase inhibitorsCitation4, hepatoprotective agentsCitation5, antibacterial and antifungal agentsCitation6, and cyclo-oxygenase-2 (COX-2) inhibitorsCitation7.
The benzenesulfonamide moiety has exhibited its importance by its presence in a large variety of pharmaceuticals covering a wide range of biological activities. These have been reported as carbonic anhydrase inhibitorsCitation8. They show affinities for endothelin receptors ETA and ETB in the low non-molar range and high functional antagonistic potency in vitroCitation9. Antibacterial, antifungal, and cytotoxic activities have been similarly evaluatedCitation10,11. They have also been reported as COX-2 inhibitorsCitation12. The anti-inflammatory activity of celecoxib (Celebrex), a clinically marketed drug, is attributed to the presence of SO2NH2 pharmacophore. Structure–activity studies have shown that the SO2NH2 substituent at the para position of one aryl group usually confers optimal COX-2 inhibitor potencyCitation13. Therefore, it was thought worthwhile to synthesize novel pyridazinone derivatives bearing the benzenesulfonamide moiety and screen them for their anti-cancer, anti-inflammatory, and antimicrobial activity.
Materials and methods
Chemistry
Melting points were determined using open capillary tubes and are uncorrected. All Fourier transform infrared (FTIR) spectra were recorded on a Bio-rad FTS-135 spectrophotometer using KBr pellets; νmax values are given in cm−1. 1H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Spectrospin DPX 300-MHz spectrometer using deuterated dimethylsulfoxide (DMSO) as solvent and tetramethylsilane (TMS) as internal standard. Chemical shifts are given in δ (ppm) scale and coupling constants (J values) are expressed in Hz. Mass spectra (MS) were scanned by using a fast atom bombardment (FAB) ionization Jeol JMS-DX 303 apparatus, equipped with direct inlet probe system. The m/z values of the more intense peaks are mentioned. Purity of the compounds was checked on thin layer chromatography (TLC) plates (silica gel G) which were visualized by exposing to iodine vapors. Elemental analysis was carried out on a CHNS Elementar (Vario EL III) system.
General procedure for the synthesis of aroylpropionic acids (1a–j)
To liquid aromatic hydrocarbon (30 mL), anhydrous aluminum chloride (16.6 g, 0.125 mol) was added. The mixture was stirred using a magnetic stirrer at room temperature for 30 min. To this, succinic anhydride (5 g, 0.05 mol) was added in five portions with continuous stirring. Vigorous reaction started with the evolution of HCl gas. Stirring was continued for another 6 h at room temperature. The mixture was left at room temperature for 48 h and then decomposed by adding ice-cold hydrochloric acid (50%, 100 mL). The excess solvent was removed by steam distillation. The precipitated solid was treated with saturated sodium bicarbonate solution, filtered, washed with cold water, dried, and crystallized from the appropriate solvent to give 1a–jCitation14,15.
General procedure for the synthesis of pyridazinones (2a–j)
A mixture of the appropriate aroylpropionic acid (1a–j) (0.001 mol) and 4-hydrazinobenzenesulfonamide hydrochloride (0.001 mol) in absolute ethanol (20–30 mL) was refluxed for 18–24 h. The reaction mixture was concentrated to one-third of its volume and left at room temperature, when a solid separated out. The crude product was filtered off, washed with a small volume of alcohol, and stirred with 5% sodium bicarbonate solution (25 mL). It was filtered, and washed with 2% acetic acid and then with water. The product was dried and crystallized from methanol (2a–j).
6-Phenyl-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one (2a)
Yield = 63%; m.p. 178°C; IR νmax (KBr, in cm−1): 3305 and 3191 (NH2), 1662 (C=O), 1590 (C=N), 1327 and 1154 cm−1 (SO2N); 1H NMR: 2.77 and 3.17 (each t, 2 × -CH2-), 7.39 (2H, s, SO2NH2), 7.49 (3H, m, Ar-H), 7.77–7.88 (6H, m, Ar-H); FAB-MS (m/z): 329 [M+]; molecular formula C16H15N3O3S; Calculated: C = 58.53, H = 4.59, N = 12.76, S = 9.73; Found: C = 58.49, H = 4.37, N = 13.02, S = 9.61%.
6-(4-Methylphenyl)-2-(p-sulfamylphenyl)-4, 5-dihydropyridazine-3(2H)-one (2b)
Yield = 66%; m.p. 192°C; IR νmax (KBr, in cm−1): 3303 and 3195 (NH2), 1662 (C=O), 1591 (C=N), 1329 and 1155 cm−1 (SO2N); 1H NMR: 2.36 (3H, s, CH3), 2.76 and 3.14 (each t, 2 × -CH2-), 7.28 (2H, d, J = 7.5 Hz, Ar-H), 7.36 (2H, s, SO2NH2), 7.76–7.80 (4H, m, Ar-H), 7.88 (2H, d, J = 8.0 Hz, Ar-H); FAB-MS (m/z): 343 [M+], 344 [M + 1]; molecular formula C17H17N3O3S; Calculated: C = 59.46, H = 4.99, N = 12.24, S = 9.34; Found: C = 58.98, H = 5.06, N = 12.09, S = 9.51%.
6-(4-Chlorophenyl)-2-(p-sulfamylphenyl)-4, 5-dihydropyridazine-3(2H)-one (2c)
Yield = 70%; m.p. 220–222°C; IR νmax (KBr, in cm−1): 3303 and 3225 (NH2), 1644 (C=O), 1591 (C=N), 1334 and 1154 cm−1 (SO2N); 1H NMR: 2.78 and 3.16 (each t, 2 × -CH2-), 7.27 (2H, s, SO2NH2), 7.54 (2H, d, J = 8.5 Hz, Ar-H), 7.77 (2H, d, J = 8.6 Hz, Ar-H), 7.86 (2H, J = 6.2 Hz, Ar-H), and 7.89 (2H, d, J = 6.2 Hz, Ar-H); FAB-MS (m/z): 363 [M+], 364 [M + 1]; molecular formula C16H14ClN3O3S; Calculated: C = 52.82, H = 3.88, N = 11.55, S = 8.81; Found: C = 52.59, H = 3.64, N = 11.52, S = 8.76%.
6-(4-Methoxyphenyl)-2-(p-sulfamylphenyl)-4, 5-dihydropyridazine-3(2H)-one (2d)
Yield = 63%; m.p. 228°C; IR νmax (KBr, in cm−1): 3304 and 3179 (NH2), 1654 (C=O), 1599 (C=N), 1331 and 1156 (SO2N), 1032 cm−1 (OCH3); 1H NMR: 2.75 and 3.13 (each t, 2 × -CH2-), 3.82 (3H, s, OCH3), 7.03 (2H, d, J = 7.8 Hz, Ar-H), 7.36 (2H, s, SO2NH2), 7.78–7.88 (6H, m, Ar-H); FAB-MS (m/z): 359 [M+]; molecular formula C17H17N3O4S; Calculated: C = 56.81, H = 4.77, N = 11.69, S = 8.92; Found: C = 57.02, H = 4.73, N = 11.55, S = 8.96%.
6-(4-Ethylphenyl)-2-(p-sulfamylphenyl)-4, 5-dihydropyridazine-3(2H)-one (2e)
Yield = 68%; m.p. 148°C; IR νmax (KBr, in cm−1): 3300 and 3186 (NH2), 1660 (C=O), 1591 (C=N), 1331 and 1154 cm−1 (SO2N); 1H NMR: 1.20 (3H, t, -CH2-CH3), 2.65 (2H, q, -CH2-CH3), 2.76 and 3.15 (each t, 2 × -CH2-), 7.32 (2H, d, J = 7.8 Hz, Ar-H), 7.37 (2H, s, SO2NH2), 7.77–7.89 (6H, m, Ar-H); FAB-MS (m/z): 357 [M+]; molecular formula C18H19N3O3S; Calculated: C = 60.49, H = 5.36, N = 11.76, S = 8.97; Found: C = 60.27, H = 5.31, N = 11.57, S = 9.09%.
6-(2-Hydroxy-5-methylphenyl)-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one (2f)
Yield = 59%; m.p. 228°C; IR νmax (KBr, in cm−1): 3291, 1654 (C=O), 1592 (C=N), 1311 and 1152 cm−1 (SO2N); 1H NMR: 2.17 (3H, s, CH3), 2.72 and 3.11 (each t, 2 × -CH2-), 6.85 (1H, d, J = 8.3 Hz, Ar-H), 7.36 (2H, s, SO2NH2), 7.55 (1H, d, J = 8.3 Hz, Ar-H), 7.62 (1H, s, Ar-H), 7.77 (2H, d, J = 8.3 Hz, Ar-H), 7.86 (2H, d, J = 8.5 Hz, Ar-H), 9.82 (1H, s, OH); FAB-MS (m/z): 359 [M+]; molecular formula C17H17N3O4S; Calculated: C = 56.81, H = 4.77, N = 11.69, S = 8.92; Found: C = 57.11, H = 4.59, N = 11.96, S = 9.15%.
6-(4-Hydroxy-2-Methylphenyl)-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one (2g)
Yield = 57%; m.p. 290°C; IR νmax (KBr, in cm−1): 3307 and 3204 (NH2), 1665 (C=O), 1600 (C=N), 1334 and 1157 cm−1 (SO2N); 1H NMR: 2.29 (3H, s, CH3), 2.56 and 3.01 (each t, 2 × -CH2-), 6.56 (2H, m, Ar-H), 7.18 (2H, s, SO2NH2), 7.31 (1H, d, J = 7.6 Hz, Ar-H), 7.50 (2H, d, J = 8.3 Hz, Ar-H), 7.69 (2H, d, J = 8.3 Hz, Ar-H), 10.93 (1H, s, OH); FAB-MS (m/z): 359 [M+]; molecular formula C17H17N3O4S; Calculated: C = 56.81, H = 4.77, N = 11.69, S = 8.92; Found: C = 56.26, H = 4.48, N = 11.38, S = 8.80%.
6-(4-Hydroxy-3-Methylphenyl)-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one (2h)
Yield = 54%; m.p. 240°C; IR νmax (KBr, in cm−1): 3395 and 3292 (NH2), 1654 (C=O), 1592 (C=N), 1314 and 1152 cm−1 (SO2N); 1H NMR: 2.17 (3H, s, CH3), 2.72 and 3.09 (each t, 2 × -CH2-), 6.85 (1H, d, J = 8.4 Hz, Ar-H), 7.36 (2H, s, SO2NH2), 7.55 (1H, d, J = 7.8 Hz, Ar-H), 7.62 (1H, s, Ar-H), 7.78 (2H, d, J = 8.5 Hz, Ar-H), 7.87 (2H, d, J = 8.5 Hz, Ar-H), 9.82 (1H, s, OH); FAB-MS (m/z): 359 [M+]; molecular formula C17H17N3O4S; Calculated: C = 56.81, H = 4.77, N = 11.69, S = 8.92; Found: C = 56.62, H = 4.61, N = 11.65, S = 8.98%.
6-(3-Chloro-4-hydroxyphenyl)-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one (2i)
Yield = 53%; m.p. 248°C; IR νmax (KBr, in cm−1): 3279, 1641 (C=O), 1590 (C=N), 1335 and 1147 cm−1 (SO2N); 1H NMR: 2.74 and 3.10 (each t, 2 × -CH2-), 7.05 (1H, d, J = 8.5 Hz, Ar-H), 7.37 (2H, s, SO2NH2), 7.69 (1H, d, J = 8.4 Hz, Ar-H), 7.76–7.88 (5H, m, Ar-H), 10.71 (1H, s, OH); FAB-MS (m/z): 379 [M+]; molecular formula C16H14ClN3O4S; Calculated: C = 50.60, H = 3.72, N = 11.06, S = 8.44; Found: C = 50.31, H = 4.02, N = 10.92, S = 8.22%.
6-(2,5-Dimethylphenyl)-2-(p-sulfamylphenyl)-4, 5-dihydropyridazine-3(2H)-one (2j)
Yield = 61%; m.p. 156–158°C; IR νmax (KBr, in cm−1): 3314, 1654 (C=O), 1591 (C=N), 1327 and 1154 cm−1 (SO2N); 1H NMR: 2.31 (3H, s, CH3), 2.38 (3H, s, CH3), 2.78 and 3.04 (each t, 2 × -CH2-), 7.15 (2H, m, Ar-H), 7.29 (1H, s, Ar-H), 7.36 (2H, s, SO2NH2), 7.73 (1H, d, J = 8.5 Hz, Ar-H), 7.85 (2H, d, J = 8.5 Hz, Ar-H); FAB-MS (m/z): 379 [M+]; molecular formula C18H19N3O3S; Calculated: C = 60.49, H = 5.36, N = 11.76, S = 8.97; Found: C = 60.87, H = 4.98, N = 12.02, S = 9.13%.
Biological evaluation
Evaluation of in vitro anti-cancer activity
An in vitro anti-cancer assay was performed using a full panel of about 60 human tumor cell lines derived from nine different cancer types: leukemia, melanoma, lung, colon, central nervous system (CNS), ovarian, renal, prostate, and breast cancers, in accordance with the protocol of the Drug Evaluation Branch, National Cancer Institute (NCI), Bethesda, and described elsewhereCitation16–18. Two standard drugs, meaning that their activities against the cell lines are well documented, were tested against each cell line: NSC 19893 (5-fluorouracil, 5-FU) and NSC 123127 (Adriamycin).
Anti-inflammatory activity
The carrageenan-induced hind paw edema method was used for evaluating anti-inflammatory activityCitation19. Wistar rats (either sex) weighing 150–175 g were procured from the Central Animal House facility of Jamia Hamdard, New Delhi (Registration no. 173/CPCSEA). The experiments were performed in accordance with the guidelines for the care and use of laboratory animals laid down by the Committee for the Purpose of Control and Supervision of Experiments in Animals (CPCSEA), Ministry of Social Justice and Empowerment, Government of India, January 2000. Overnight-fasted rats (16 h) were divided into groups of six animals each. One group of rats, which served as control, was given vehicle (1% carboxymethyl cellulose (CMC) in water in a volume of 10 mL/kg) only. Test compounds (20 mg/kg body weight (b.w.)) and celecoxib (20 mg/kg b.w.) suspended in vehicle (10 mL/kg) were administered orally to respective groups. After 30 min, all animals were injected with 0.1 mL of 1% carrageenan solution (prepared in normal saline) in the subplantar aponeurosis of the left hind paw to induce inflammation, and the volume of the injected paw was measured immediately (at 0 h) using a plethysmometer. The paw volume was measured again after 3 h and 5 h. The average paw volume in a group of treated rats was compared with vehicle (control group) and the percentage inhibition of edema was calculated using the formula:
where Vt is the mean paw volume of the test drug-treated rats and Vc is the mean paw volume of the controls.
The results were analyzed for statistical significance using one-way analysis of variance (ANOVA) followed by Dunnett’s test. A value p < 0.05 was considered significant.
The acute gastric ulcerogenic effect of compounds 2c and 2f was evaluated in Wistar ratsCitation20. Albino rats of the Wistar strain (160–220g) fasted over 24 h were randomly allotted into three groups of six animals each. The animals of one group were given vehicle, 10 mL/kg (CMC 1%, w/v, in distilled water), orally. Compounds 2c (60 mg/kg) and 2f (60 mg/kg) suspended in vehicle were administered orally in a volume of 10 mL/kg to the animals of two different groups, respectively. They were scarified under deep ether anesthesia after 6 h of treatment at a dose of 60 mg/kg (three times). Their stomachs were removed and opened through the greater curvature for examining lesions or bleeding.
Antimicrobial activity
Antifungal and antibacterial activities were evaluated using the cup and plate methodCitation21. Sabouraud dextrose agar (Hi Media, Mumbai, India) and nutrient agar medium (peptone, beef extract, NaCl, and agar-agar) were used for antifungal and antibacterial screening, respectively. Inocula of different fungi and bacteria were spread over the agar medium using the garden culture method. Test drug (100 μL; 500 μg/mL in DMSO) was poured in each cavity of 6 mm diameter. Standard drug, ciprofloxacin (25 μg/disk) or fluconazole (10 μg/disk), was placed aseptically in a separate Petri dish. The plates were kept at room temperature for 1 h to diffuse the drug in the surrounding medium and then incubated at 37°C for 24 h for bacterial organisms and 32°C for 4 days for fungal organisms. The diameter of the zone of inhibition was measured in mm and compared with that of the standard drug (ciprofloxacin or fluconazole).
Results and discussion
Synthesis of compounds
The synthetic route used to synthesize title compounds (2a–j) is outlined in . The aroylpropionic acids (1a–j) required for the synthesis of pyridazinones were obtained by Friedel–Crafts acylation through reported methodsCitation14,15. The cyclization to pyridazinone derivatives bearing a benzene sulfonamide moiety was afforded by condensation of the appropriate aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol in 53–70% yield. A literature survey revealed that 2a was registered in SciFinder Scholar with number 930847-74-8, but no reference was available for work on its method of synthesis and biological study. The structures of the pyridazinone derivatives (2a–j) were determined on the basis of elemental analysis and various spectroscopic methods such as IR, 1H-NMR, and MS. Elemental analyses (C, H, N, and S) data were within ±0.4% of the theoretical values. Support for the structure was evidenced by the presence of prominent bands in the IR spectra for NH2 (3395–3294 cm−1 and 3292–3158 cm−1), cyclic carbonyl (1665–1641 cm−1), C=N (1600–1579 cm−1), and SO2N (1343–1314 cm−1 and 1166–1147 cm−1). The structures were further established by 1H-NMR spectral data. The singlet for SO2NH2 was observed at δ 7.18–7.53. Two triplets at δ 2.56–2.80 and δ 3.01–3.17, each integrating two protons, can be ascribed to -CH2-CH2- of the dihydropyridazinone ring.
Scheme 1. Synthetic route for the preparation of pyridazinones.
Biological studies
Evaluation of anti-cancer activity in vitro
A primary in vitro one-dose (10−5 M) anticancer assay was performed using a full panel of about 60 human tumor cell lines in accordance with the protocol of the Drug Evaluation Branch, National Cancer Institute (NCI), Bethesda, and described elsewhereCitation16–18. The human tumor cell lines were derived from nine different cancer types: leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers. Two standard drugs, meaning that their activities against the cell lines are well documented, were tested against each cell line: NSC 19893 (5-FU) and NSC 123127 (Adriamycin). From the synthesized compounds (2a–j), four compounds, namely 2a, 2c, 2d, and 2g, were selected by the NCI. The compounds 2a, 2c, and 2d displayed mild sensitivity toward some leukemia cell lines (). Compound 2g possessed considerable activity, and was selected for an advanced assay against a full panel (approximately 60 cell lines) at five concentrations (100, 10, 1, 0.1, and 0.001 μM). Based on the cytotoxicity assays, three antitumor activity dose–response parameters were calculated for each experimental agent against each cell line: GI50, molar concentration of the compound that inhibits 50% net cell growth; TGI, molar concentration of the compound leading to total inhibition; and LC50, molar concentration of the compound leading to 50% net cell death. Values were calculated for each of these parameters if the level of activity was reached; however, if the effect was not reached or was exceeded, the value was expressed as greater or less than the maximum or minimum concentration tested. Furthermore, mean graph midpoints (MG_MID) were calculated for each of the parameters, giving an average activity parameter over all cell lines for each compound. For calculation of the MG_MID, insensitive cell lines were included with the highest concentration tested. In the present study, 2g exhibited remarkable antitumor activities against most of the tested subpanel tumor cell lines (GI50, TGI, and LC50 values less than 100 μM) (). It showed high activity against HL-60 (TB) (leukemia), SR (leukemia), NCI-H522 (non-small-cell lung), and BT-549 (breast cancer) with a GI50 value of less than 2 μM. It also displayed good activity against leukemia (K-562, MOLT-4, RPMI-8226), colon (HCT-15, HT29, KMI2, SW-620), CNS (SF-295, SNB-75), melanoma (MALME-3M, M14, SK-MEL-5, UACC-62), ovarian (OVCAR-3, NCI/ADR-RES), and breast (MCF7) cancer cell lines with a GI50 range of 2.01–3.00 μM ().
Table 1. Anticancer screening data for 2a, 2c, and 2d at concentration of 10−5 M.
Table 2. Full panel (60) human tumor cell line anticancer screening data for 2g (NSC: 747556).
With regard to the SAR, we observed that the introduction of an electron withdrawing group at the para position of the 6-phenyl unit of 2a (2a was sensitive to a certain leukemia cell line only) made the molecules sensitive to more leukemia cell lines (2a vs. 2c, 2a vs. 2d). When two electron donating groups were introduced, one at the ortho and the other at the para position of the 6-phenyl unit of 2a, these not only enhanced the remarkable activity against leukemia cell lines but also made the molecule sensitive to the other cancer cell lines, viz. colon, melanoma, ovarian, and breast (2a vs. 2g).
Anti-inflammatory activity
In the present study, all compounds (2a–j) were tested for anti-inflammatory activity by using the carrageenan-induced rat hind paw edema methodCitation19. Two compounds, namely 2c and 2f, exhibited maximum activity.
Structure–activity relationship studies showed that the introduction of lipophilic groups such as methyl and ethyl at the para position of the phenyl group attached at C-6 of dihydropyridazinone led to a significant decrease in the activity (2a vs. 2b, 2a vs. 2e), while the introduction of a chlorine atom at the same position enhanced the anti-inflammatory activity (2a vs. 2c; ).
Table 3. Effect of pyridazinones (2a–j, 20 mg/kg) and celecoxib (20 mg/kg) on carrageenan-induced hind paw edema in rats.
The acute gastric ulcerogenic effect of compounds 2c and 2f was evaluated in Wistar ratsCitation20. Six hours after treatment at a dose of 60 mg/kg (three times) they were scarified under deep ether anesthesia and their stomachs removed and opened through the greater curvature for the examination of lesions or bleeding. These compounds did not cause any gastric ulceration.
Antimicrobial activity
All of the compounds at a concentration of 500 μg/mL were screened for their in vitro antifungal activity against Candida albicans, Aspergillus fumigatus, Aspergillus versicolor, and Aspergillus flavus, and for in vitro antibacterial activity against gram-negative Escherichia coli and gram-positive Staphylococcus aureus, using the cup–plate agar diffusion method by measuring the zone of inhibition in mm21. Ciprofloxacin (25 μg/disk) was used as standard drug for antibacterial activity while fluconazole (10 μg/disk) was used for antifungal activity.
Although it seems impossible to extract an obvious structure–activity relationship from the data shown in , it may be concluded these derivatives exhibited moderate to strong activity against the fungus and weak activity against bacteria.
Table 4. Antimicrobial activity of pyridazinone derivatives (500 μg/mL).
Conclusion
The structures proposed for the synthesized compounds (2a–j) are well supported by spectroscopic data and elemental analysis. One compound, 2g, showed promising broad-spectrum antitumor activity. Two compounds (2c and 2f) were found to have promising anti-inflammatory activity, while a fair number of compounds showed good antifungal activity.
Acknowledgments
We thank the staff members of the National Cancer Institute (NCI) at Bethesda, USA, for carrying out anticancer screening tests on our compounds.
Declaration of interest
Authors are also thankful to Jamia Hamdard for providing funds for this research work. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Coates WJ. In: Katritzky AR, Rees CW, Scriven EFV, eds. Comprehensive Heterocyclic Chemistry (Vol. 2): Pyridazines and their benzo derivatives, Exeter, UK: Elsevier, 1996:1–91.
- Tisler M, Stanovnik B, eds. Advances in Heterocyclic Chemistry, Vol. 49. London, Academic Press, 1990:385–472.
- Kuroda S, Akahane A, Itani H, Nishimura S, Durkin K, Kinoshita T, et al. Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist. Bioorg Med Chem Lett 1999;9:1979–84.
- Costantino L, Rastelli G, Cignarella G, Barlocco D. Synthesis and aldose reductase inhibitory activity of a new series of benz[h]cinnolinone derivatives. Farmaco 2000;55:544–52.
- Kwon SK, Moon A. Synthesis of 3-alkylthio-6-allylthiopyridazine derivatives and their antihepatocarcinoma activity. Arch Pharm Res 2005;28:391–4.
- Sönmez M, Berber İ, Akbaş E. Synthesis, antibacterial and antifungal activity of some new pyridazinone metal complexes. Eur J Med Chem 2006;41:101–5.
- Harris RR, Black L, Surapaneni S, Kolasa T, Majest S, Namovic MT, et al. ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy) 5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor. J Pharmacol Exp Ther 2004;311:904–12.
- Krungkrai J, Supuran CT. The alpha-carbonic anhydrase from the malaria parasite and its inhibition. Curr Pharm Des 2008;14:631–40.
- Scozzafava A, Briganti F, Ilies MA, Supuran CT. Carbonic anhydrase inhibitors: synthesis of membrane-impermeant low molecular weight sulfonamides possessing in vivo selectivity for the membrane-bound versus cytosolic isozymes. J Med Chem 2000;43:292–300.
- Chohan ZH, Shaikh AU, Rauf A, Supuran CT. Antibacterial, antifungal and cytotoxic properties of novel N-substituted sulfonamides from 4-hydroxycoumarin. J Enzyme Inhib Med Chem 2006;21:741–8.
- Chohan ZH, Metal-based sulfonamides: their preparation, characterization,and in-vitro antibacterial, antifungalcytotoxic properties. X-ray structure of 4-[(2-hydroxybenzylidene) amino]benzenesulfonamide. J Enzyme Inhib Med Chem 2008;3:120–30.
- Kim SJ, Jeong HJ, Choi IY, Lee KM, Park RK, Hong SH, et al. Cyclooxygenase-2 inhibitor SC-236 [4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1-pyrazol-1-l]benzenesulfonamide] suppresses nuclear factor-kappaB activation and phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase in human mast cell line cells. J Pharmacol Exp Ther 2005;314:27–34.
- Khanna IK, Weier RM, Yu Y, Collins PW, Miyashiro JM, Koboldt CM, et al. 1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase-2. J Med Chem 1997;40:1619–33.
- Khan MSY, Siddiqui AA. Syntheses and anti-inflammatory activity of some 6-aryl-2,3,4,5-tetrahydro-3-pyridazinones. Ind J Chem 2000;39B:614–19.
- Khan MSY, Hussain A, Sharma S. Studies on butenolides: 2-arylidene-4-(substituted aryl)but-3-en-4-olides—synthesis, reactions and biological activity. Indian J Chem 2002;41B:2160–71.
- Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst 1991;83:757–66.
- Boyd MR, Paull KD. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev Res 1995;34:91–109.
- Boyd MR. In: Teicher BA, ed. Cancer Drug Discovery and Development: Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval. Totowa, NJ: Humana Press, 1997:23–43.
- Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med 1962;111:544–7.
- Rathish IG, Kalim Javed, Ahmad S, Bano S, Alam MS, Pillai KK, et al. Synthesis and antiinflammatory activity of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide. Bioorg Med Chem Lett 2009;19:255–8.
- Bisen PS, Verma K, eds. Handbook of Microbiology. Shahdara, Delhi, India: CBS Publishers and Distributors, 1994.