Skip to main content
NCBI home page
Saudi Pharmaceutical Journal : SPJ logoLink to Saudi Pharmaceutical Journal : SPJ
. 2011 Mar 11;19(3):153–158. doi: 10.1016/j.jsps.2011.03.002

Synthesis, characterization and anticancer activity of certain 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}indolin-2-one derivatives

Rajyalakshmi Gudipati 1, Rama Narsimha Reddy Anreddy 1, Sarangapani Manda 1,⁎
PMCID: PMC3744961  PMID: 23960753

Abstract

A series of 5- or 7-substituted 3-{4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenylimino}-indolin-2-one derivatives were synthesized by treating 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, 1H NMR, MS) analyses. All the synthesized derivatives were screened for anticancer activity against HeLa cancer cell lines using MTT assay. All the synthetic compounds produced a dose dependant inhibition of growth of the cells. The IC50 values of all the synthetic test compounds were found between 10.64 and 33.62 μM. The potency (IC50 values) of anticancer activity of compounds VIb–d was comparable with that of known anticancer agent, Cisplatin. Among the synthesized 2-indolinones, compounds VIb–d with halogen atom (electron withdrawing groups) at C5 position showed the most potent activity. These results indicate that C5 substituted derivatives may be useful leads for anticancer drug development in the future.

Keywords: Schiff bases; Isatin; 1,3,4-Oxadiazole; Indole; Anticancer activity; MTT

1. Introduction

The development of new anticancer therapeutic agents is one of the fundamental goals in medicinal chemistry. Cytotoxicity and genotoxicity of anticancer drugs to the normal cells are major problems in cancer therapy and engender the risk of inducing secondary malignancy (Aydemir and Bilaloglu, 2003). A dose of anticancer drug sufficient to kill tumor cells is often toxic to the normal tissue and leads to many side effects, which in turn, limits its treatment efficacy. In recent years, there has been a concerned search for the discovery and development of novel selective anticancer agents, devoid of many of the unpleasant side effects of conventional anticancer agents. The synthesis of a newer class of anticancer agents is in need of time.

Literature survey revealed that isatin (1H-indole-2,3-dione) possesses diverse chemotherapeutic activities, such as anticancer (Gursoy and Karal, 2003), antiviral (Debra et al., 2006), anti-HIV (Pandeya et al., 1999a), anti-mycobacterial (Karal et al., 2007), antibacterial (Pandeya et al., 1999b), anti-inflammatory (Sridhar and Ramesh, 2001) and anticonvulsant (Verma et al., 2004). Among these properties, cytotoxic and antineoplastic activities of this moiety have been found to be interesting. It has been reported in the literature that compounds bearing 1,3,4-oxadiazole ring possess significant biological properties such as anticancer (Aboraia et al., 2006), anti-inflammatory (Nargund et al., 1994), hypoglycemic (Ladduwahetty et al., 1996), antifungal, antibacterial (Khanum et al., 2005), antitubercular (Mamolo et al., 2005), analgesic (Bhandari et al., 2008), antiviral (Kucukguzel et al., 2007) activities.

In view of the biological importance of these isatin and 1,3,4-oxadiazole moieties, it was planned to synthesize a new series of isatin derivatives containing 1,3,4-oxadiazole i.e. 5- or 7-substituted 3-{4-(5-mercapto-1,3,4-oxadiazol-2-yl) phenylimino}indolin-2-ones and were evaluated for in vitro anticancer activity against HeLa (cervical), IMR-32 (neuroblastoma) & MCF-7 (breast) cancer cell lines using MTT assay.

2. Materials and methods

2.1. General

Melting points (mp) were determined in open capillaries, using Toshniwal melting point apparatus, expressed in °C and are uncorrected. The IR spectra of the compounds were recorded on thermo Nicolet Nexus 670S series, FT-IR spectrometer using KBr disc. 1H NMR was scanned on Avance-400 MHz instrument. Chemical shifts are expressed in δ (ppm) relative to TMS as an internal standard using DMSO-d6 as solvent. Mass spectra were recorded on a LC-MSD-Trap-SL. The purity of the compounds was checked on silica gel-coated aluminum sheets (Merck, 1.005554, silica gel HF254–361, Type 60, 0.25 mm, Darmstadt, Germany) by thin-layer chromatography (TLC). TLC was performed on silica gel G for TLC (Merck) and spots were visualized by iodine vapor or by irradiation with ultraviolet light (short wave length, 254 nm). Column chromatography was performed by using Qualigen’s silica gel for column chromatography (60–120 mesh).

2.2. Chemicals

All the solvents, reagents and catalysts used are of AR grade. Isatin, fetal bovine serum (FBS), Dulbecco’s modified eagle’s medium (DMEM), penicillin, amphotericin B, and streptomycin were purchase from Himedia (Mumbai, India). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was purchased from Sigma Chemical Company (St. Louis, MO, USA). Substituted isatins were prepared by the procedures reported in the literature (Bahl, 2004).

2.3. Cell cultures

The cell cultures like HeLa (cervical), IMR-32 (neuroblastoma) & MCF-7 (breast) cancer cell lines were purchased from the National Centre for Cell sciences (NCCS), Pune, India. These cell lines were grown and maintained using suitable (DMEM) media and were grown in culture medium supplemented with 10% fetal bovine serum, 1% l-glutamine and 1% penicillin-streptomycin-amphotericin B antibiotic solution. Cells were seeded in 25 cm2 tissue culture flasks (tarsons, India), at 250,000 cells/flask in a total volume of 9 ml. When confluent, all the cells were trypsinized (using Trypsin-EDTA, HiMedia, Mumbai, India), and seeded in 96-well plates (tarsons, India).

2.4. Chemistry

2.4.1. Synthesis of isatin derivatives

The different (5- or 7-substituted) isatin derivatives were prepared as reported in the literature (Henry and Blatt, 1964).

2.4.2. Synthesis of N-(4-[hydrazinecarbonyl] phenyl) acetamide (IV)

N-(4-[Hydrazinecarbonyl] phenyl) acetamide (IV) was prepared from ethyl-p-acetamido benzoate (III) as reported in the literature (Varma and Chauhan, 1988).

2.4.3. Synthesis of 5-{4-(aminophenyl)-1,3,4-oxadiazol}-2-thiol (V)

5-{4-(Aminophenyl)-1,3,4-oxadiazol}-2-thiol (V) was synthesized from N-(4-[hydrazinecarbonyl] phenyl) acetamide (IV) by adopting the procedure mentioned by Khanum et al. (2005).

2.4.4. Synthesis of 3-{4-(5-mercapto-1,3,4-oxadiazol-2-yl) phenylimino}-5 or 7-substituted-indolin-2-one (VI)

5-{4-(Aminophenyl)-1,3,4-oxadiazol}-2-thiol (compound V; 1.93 g, 0.01 mol) and Isatin (1.47 g, 0.01 mol) were refluxed in 20 ml of ethanol in the presence of a catalytic amount of glacial acetic acid (2–3 drops) for 5–6 h and cooled. The solid separated was filtered and washed with cold alcohol and the product obtained was recrystallized from methanol (yield: 2.41 g, 75%), m.p. 268–270 °C)

2.4.5. Spectral data of synthesized compounds (VIa–k)

2.4.5.1. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-indolin-2-one (VIa)

IR υ (cm−1): 1264 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 1676 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 3432 (N–H of amide), 1533 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N) and 1184 (ether, C–O–C); 1H NMR (DMSO-d6) δ ppm: 7.45–7.62 (m, 4H, Ar–H), 7.75–7.85 (m, 4H, Ar–H), 7.81 (s, 1H, SH), 10.27 (s, 1H, indole NH), ESI: m/z value 323.2.

2.4.5.2. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-5-flouro-indolin-2-one (VIb)

IR υ (cm−1): 1261 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 1667 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 3220 (N–H of amide), 1547 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N), 1165 (ether, C–O–C) and 759 (C–F); 1H NMR (DMSO-d6) δ ppm: 6.99 (d, 1H, Ar–H), 7.3–7.6 (m, 5H, Ar–H), 7.65 (s, 1H, Ar–H), 7.89 (s, 1H, SH), 10.21 (s, 1H, indole NH), ESI: m/z value 341.0.

2.4.5.3. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-5-bromo-indolin-2-one (VId)

IR υ (cm−1): 1271 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 1682 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 3177 (N–H of amide), 1534 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N), 1151 (C–N), 1151 (ether, C–O–C) and 662 (C-Br); 1H NMR (DMSO-d6) δ ppm: 7.10 (d, 1H, Ar–H), 7.16–7.43 (m, 5H, Ar–H),7.52 (s, 1H, Ar–H), 7.88 (s, 1H, SH), 10.3 (s, 1H, indole NH), ESI: m/z value 411.1.

2.4.5.4. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-5-methyl-indolin-2-one (VIe)

IR υ (cm−1): 1261 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 2918 (C–H of CH3), 1682 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 3330 (N–H of amide), 1534 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N), 1151 (ether, C–O–C); 1H NMR (DMSO-d6) δ ppm: 2.25 (s, 3H, CH3), 6.45–6.55 (d, 1H, Ar–H), 6.8–7.1 (m, 5H, Ar–H), 7.15 (s, 1H, Ar–H), 7.30 (s, 1H, SH), 10.13 (s, 1H, indole NH), ESI: m/z value 337.0.

2.4.5.5. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-5-nitro-indolin-2-one (VIf)

IR υ (cm−1): 1250 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 1670 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 3201 (N–H of amide), 1527 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N), 1148 (ether, C–O–C), 1405 (N Created by potrace 1.16, written by Peter Selinger 2001-2019 O str, asy), 1345 (N Created by potrace 1.16, written by Peter Selinger 2001-2019 O str, sym); 1H NMR (DMSO-d6) δ ppm: 7.01 (d, 1H, Ar–H), 7.2–7.5 (m, 5H, Ar–H), 7.58 (s, 1H, Ar–H), 7.58 (s, 1H, SH), 10.15 (s, 1H, indole NH), ESI: m/z value 368.0.

2.4.5.6. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-5-carboxylic acid-indolin-2-one (VIg)

IR υ (cm−1): 1241 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 1700 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O of COOH), 1318 (CO str of COOH), 3316 (N–H of amide),1600 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 1525 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N), and 1178 (ether, C–O–C); 1H NMR (DMSO-d6) δ ppm: 6.5–6.52 (d, 1H, Ar–H), 6.7–7.0 (m, 5H, Ar–H), 7.14 (s, 1H, Ar–H), 7.59 (s, 1H, SH), 10.10 (s, 1H, indole NH), 12.5 (s, 1H, COOH), ESI: m/z value 367.1.

2.4.5.7. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-7-chloro-indolin-2-one (VIh)

IR υ (cm−1): 1180 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 1618 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 3315 (N–H of amide), 1525 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N), 1024 (ether, C–O–C) and 731 (C–Cl); 1H NMR (DMSO-d6) δ ppm: 7.0–7.4 (m, 5H, Ar–H),7.4–7.6 (t, 1H, Ar–H), 7.6 (d, 1H, Ar–H), 7.7 (s, 1H, SH), 11.09 (s, 1H, indole NH), ESI: m/z value 358.

2.4.5.8. 3-(4-[5-Mercapto-1,3,4-oxadiazole-2-yl] phenylimino)-7-carboxylic acid-indolin-2-one (VIk)

IR υ (cm−1): 1268 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 S), 3313 (OH of COOH), 1609 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O), 1710 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 O of COOH), 3200 (N–H of amide), 1498 (C Created by potrace 1.16, written by Peter Selinger 2001-2019 N), and 1027 (ether, C–O–C); 1H NMR (DMSO-d6) δ ppm: 7.1–7.4 (m, 5H, Ar–H), 7.2–7.4 (t, 1H, Ar–H), 7.6 (d, 1H, Ar–H), 7.8 (s, 1H, SH), 12.7 (s, 1H, COOH), 11.18 (s, 1H, indole NH), ESI: m/z value 367.

3. Biological activity

3.1. Evaluation of in vitro anticancer activity against HeLa, IMR-32 & MCF-7 cancer cell lines

In vitro anticancer activity against HeLa, IMR-32 & MCF-7 cancer cell lines was determined (Monks et al., 1991, Skehan et al., 1990) using 96-well tissue culture plates. The cell suspension of 1 × 105 cells/ml was prepared in complete growth medium. Stock solutions of compounds (14) were prepared in DMSO. The stock solutions were serially diluted with complete growth medium containing 50 mg/ml of gentamycin to obtain working test solution of required concentrations (having <1% DMSO). The 100 μL of cell suspension was added to each well of the 96-well tissue culture plates. The cells were allowed to grow in CO2 incubator (37 °C, 5% CO2, 90% relative humidity) for 24 h. The test materials in complete growth medium (100 μL) were added after 24 h incubation to the wells containing cell suspension. After 48 h of treatment with different concentrations of test compounds, the cells were incubated with MTT (2.5 mg/ml) for 2 h. The medium was then removed and 100 μl of DMSO were added into each well to dissolve formazan crystals, the metabolite of MTT. After thoroughly mixing, the plate was read at 490 nm for optical density that is directly correlated with cell quantity.

4. Results and discussion

4.1. Chemistry

In the present study, the compounds were synthesized as depicted in Scheme 1. Twelve different novel 3-{4-(5-mercapto-1,3,4-oxadiazol-2-yl) phenylimino}-5 or 7-substituted-indolin-2-one derivatives (VIa–l) were prepared by treating 5-(4-[aminophenyl)-1,3,4-oxadiazole-2-thiol with different isatin derivatives. The preparation of the title derivatives is outlined in Scheme 1. The physical data of the all synthesized compounds were shown in Table 1. All the synthesized compounds were purified by column chromatography using ethyl acetate, chloroform and methanol as solvent and the reactions were monitored by TLC. The chemical structures of the synthesized compounds (Table 1) were confirmed by means of their IR, 1H NMR and MS spectral analysis.

Scheme 1.

Scheme 1

Open in a new tab

Synthesis of 3-{4-(5-mercapto-1,3,4-oxadiazol-2-yl) phenylimino}-5 or 7-substituted indolin-2-one derivatives.

Table 1.

Physical data of all synthesized test compounds (VIa–l).

graphic file with name fx1.jpg

Open in a new tab
S. No. Compound Mol. formula R1 R2 Mol. wt % Yield m.p. (°C)
1 VIa C16H10O2N4S H H 322 61 268–270
2 VIb C16H9O2N4SF F H 340 70 288–289
3 VIc C16H9O2N4SCl Cl H 356 72 262–264
4 VId C16H9O2N4SBr Br H 401 70 198–202
5 VIe C17H12O2N4S CH3 H 336 71 280–282
6 VIf C16H9O4N5S NO2 H 367 63 292–293
7 VIg C17H10O4N4S COOH H 366 64 220–224
8 VIh C16H9O2N4SCl H Cl 357 72 160-162
9 VIi C16H9O4N5S H NO2 367 69 264–265
10 VIj C17H12O2N4S H CH3 336 68 210–212
11 VIk C17H10O4N4S H COOH 366 67 198–199
12 VIl C18H12O4N4S H COOCH3 380 62 238–240
Open in a new tab

4.2. In vitro anticancer activity

The anticancer activity of all the synthesized compounds (VIa–l) was evaluated against HeLa, IMR-32 & MCF-7 cancer cell lines using MTT method and the IC50 values of all the compounds including the intermediate were shown in Table 2. All the synthetic compounds produced a dose dependant inhibition of growth of the cells. The IC50 values of all the synthetic test compounds were found between 10.64 and 33.62 μM. The IC50 of these compounds were comparable with known anticancer agent, Cisplatin (IC50 value between 13.54 and 14.08). The present study reveals that among the human cancer cell lines tested, HeLa cells are slightly more sensitive to all the tested compounds than IMR-32 & MCF-7 cells. Many anticancer drugs are effective against HeLa, IMR-32 & MCF-7 cells by causing apoptosis through the expression of caspase-3, generating reactive oxygen species (ROS) and damaging DNA (Leong et al., 2003). Cisplatin causes cytotoxicity in MCF-7 and HeLa cells by a similar mechanism (Osbild et al. 2006).

Table 2.

Anticancer activity of synthesized compounds against HeLa, IMR-32 & MCF-7 cancer cells using MTT assay.

graphic file with name fx2.jpg

Open in a new tab
S. No. Compound R1 R2 IC50 (μM)∗ (HeLa) IC50 (μM)∗ (IMR-32) IC50 (μM)∗ (MCF-7)
1 Isatin 521.9 352.74 410.95
2 V (Intermediate) 309.59 176.85 206.95
3 VIa H H 25.47 30.65 33.62
4 VIb F H 11.99 13.48 15.57
5 VIc Cl H 12.84 15.84 16.68
6 VId Br H 10.64 12.68 16.06
7 VIe CH3 H 22.59 27.25 29.38
8 VIf NO2 H 18.60 22.51 24.48
9 VIg COOH H 17.25 20.85 22.95
10 VIh H Cl 18.69 22.51 24.92
11 VIi H NO2 16.20 19.35 20.38
12 VIj H CH3 15.12 18.32 20.95
13 VIk H COOH 20.36 24.28 25.98
14 VIl H COOCH3 19.32 23.85 25.18
15 Cisplatin 14.08 13.64 13.54
Open in a new tab

Values are expressed as means (n = 4).

Results indicate that the anticancer or cytotoxicity of derivatives varied with structural modification. Among the synthesized 2-indolinones, compounds VIb–d with halogen atom (electron withdrawing groups) at C5 position showed the most potent activity than other synthesized compounds. This is not surprising, as C5 substitution has previously been associated with increased biological activity for a range of indole-based compounds (Cane et al., 2000, Lee et al., 2001). Previous studies have shown that strong electronegative atom substitution such as chloro/bromo at the C5 position of the aromatic ring increases the lipophilicity of molecules and is responsible for enhanced cytotoxicity in MTT model (Hari et al., 2008). Similar substitutions are present in the compounds VIb–d. We have also observed enhanced cytotoxicity in these molecules.

5. Conclusions

A new series of 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino)-5 or 7-substituted indolin-2-one derivatives were synthesized. The synthesized compounds were active as growth inhibitors of the test HeLa, IMR-32 & MCF-7 cancer cell lines. Among all the synthesized compounds, 5-halo substituted compounds (VIb–d) were found to be the most potent anticancer agents in our study. These results indicate that C5 substituted derivatives may be useful leads for anticancer drug development in the future.

Acknowledgments

The first author is thankful to the University Grants Commission (UGC), New Delhi, India for providing the RGNF (Rajiv Gandhi National Fellowship) Junior Research Fellowship. The authors are thankful to central instrumentation centre, Kakatiya University, Warangal and IICT, Hyderabad, India for providing the spectral data.

References

  1. Aboraia A., Rahman H.M.A., Mahfuz N., Mohmoud A., Gendy E.L. Novel 5-(2-hydroxyphenyl)-3-substituted-2, 3-dihydro-1,3,4-oxadiazole-2-thione derivatives: promising anticancer agents. Bioorg. Med. Chem. 2006;14:1236–1246. doi: 10.1016/j.bmc.2005.09.053. [DOI] [PubMed] [Google Scholar]
  2. Aydemir N., Bilaloglu R. Genotoxicity of two anticancer drugs, gemcitabine and topotecan, in mouse bone marrow in vivo. Mutat. Res. 2003;537:43–51. doi: 10.1016/s1383-5718(03)00049-4. [DOI] [PubMed] [Google Scholar]
  3. Bahl, A.A., 2004. Textbook of Organic Chemistry, 5th ed., S Chand and Company Ltd., New Delhi, p. 364
  4. Bhandari S., Bothara K., Raut M., Patil A., Sarkate A., Mokale V. Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives. Bioorg. Med. Chem. 2008;16:1822–1831. doi: 10.1016/j.bmc.2007.11.014. [DOI] [PubMed] [Google Scholar]
  5. Cane A., Tournaire M.C., Barritault D., Crumeyrolle-Arias M. The Endogenous Oxindoles 5-Hydroxyoxindole and Isatin are Antiproliferative and Proapoptotic. Biochem. Biophys. Res. Commun. 2000;276:379–384. doi: 10.1006/bbrc.2000.3477. [DOI] [PubMed] [Google Scholar]
  6. Debra C.Q., Kathy A.K., Kern E.R. In vitro and in vivo evaluation of isatin-beta-thiosemicarbazone and marboran against vaccinia and cowpox virus infections. Antiviral Res. 2006;71:24–30. doi: 10.1016/j.antiviral.2006.02.010. [DOI] [PubMed] [Google Scholar]
  7. Gursoy A., Karal N. Synthesis and primary cytotoxicity evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]hydrazono]-1H-2-indolinones. Eur. J. Med. Chem. 2003;38:633–643. doi: 10.1016/s0223-5234(03)00085-0. [DOI] [PubMed] [Google Scholar]
  8. Hari H.P., Umashankar D., Wilson J.Q., Masami K., Hiroshi S., Jonathan R.D. Cytotoxic 3, 5-bis(benzylidene)piperidin-4-ones and N-acyl analogs displaying selective toxicity for malignant cells. Eur. J. Med. Chem. 2008;43:1–7. doi: 10.1016/j.ejmech.2007.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Henry, G., Blatt, A.H., 1964. Organic synthesis collective, vol. I, 2nd ed. John Wiley and Sons, New York, pp. 327–334.
  10. Karal N., Gursoy A., Kandemirli F., Shvets N., Kaynak F.B., Ozbey S., Kovalishyne V., Dimoglo A. Synthesis and structure–antituberculosis activity relationship of 1H-indole-2, 3-dione derivatives. Bioorg. Med. Chem. 2007;15:5888–5904. doi: 10.1016/j.bmc.2007.05.063. [DOI] [PubMed] [Google Scholar]
  11. Khanum S.A., Shashikanth S., Umesh S., Kavitha R. Synthesis and antimicrobial study of novel heterocyclic compounds from hydroxybenzophenones. Eur. J. Med. Chem. 2005;40:1156–1162. doi: 10.1016/j.ejmech.2005.04.005. [DOI] [PubMed] [Google Scholar]
  12. Kucukguzel S.G., Kucukguzel I.K., Tatar E., Rollas S., Sahin F., Gulluce M., Clercq E.D., Kabasakal L. Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents. Eur. J. Med. Chem. 2007;42:893–901. doi: 10.1016/j.ejmech.2006.12.038. [DOI] [PubMed] [Google Scholar]
  13. Ladduwahetty T., Baker R., Cascieri M.A., Chamber J.M., Haworth K., Keown L.E., MacIntyre E., Metzger J.M., Owen S., Ryeroft W., Sadowski S., Seward E., Shepheard S.L., Swain C.L., Tattersall F.D., Watt A.P., Willianmson D.W., Hargreaves R.J. N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists. J. Med. Chem. 1996;39:2907–2913. doi: 10.1021/jm9506534. [DOI] [PubMed] [Google Scholar]
  14. Lee D., Long S.A., Murray J.H., Adams J.L., Nuttall M.E., Nadeau D.P., Kikly K., Winkler J.D., Sung C.M., Ryan M.D., Levy M.A., Keller P.M., DeWolf W.E. Potent and selective nonpeptide inhibitors of caspases 3 and 7. J. Med. Chem. 2001;44:2015–2020. doi: 10.1021/jm0100537. [DOI] [PubMed] [Google Scholar]
  15. Leong C.O., Gaskell M., Martin E.A., Heydon R.T., Farmer P.B., Bibby M.C., Cooper P.A., Double J.A., Bradshaw T.D., Stevens M.F. Antitumour 2-(4-aminophenyl)benzothiazoles generate DNA adducts in sensitive tumour cells in vitro and in vivo. Br. J. Cancer. 2003;88:470–477. doi: 10.1038/sj.bjc.6600719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mamolo M.G., Zampieri D., Voi L., Fermeglia M., Ferrone M., Pricl S., Scialinoc G., Banfi E. Antimycobacterial activity of new 3-substituted 5-(pyridin-4-yl)-3H-1,3,4-oxadiazol-2-one and 2-thione derivatives. Preliminary molecular modeling investigations. Bioorg. Med. Chem. 2005;13:3797–3808. doi: 10.1016/j.bmc.2005.03.013. [DOI] [PubMed] [Google Scholar]
  17. Monks A., Scudiero D., Skehan P., Shoemaker R., Paull K., Vistica D., Hose C., Langley J., Cronise P. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst. 1991;83:757–766. doi: 10.1093/jnci/83.11.757. [DOI] [PubMed] [Google Scholar]
  18. Nargund L.V.G., Reddy G.R.N., Hariprasad V. Anti-inflammatory activity of substituted 1,3,4-oxadiazoles. J. Pharm. Sci. 1994;83:246–248. doi: 10.1002/jps.2600830226. [DOI] [PubMed] [Google Scholar]
  19. Osbild S., Brault L., Battaglia E., Bagrel D. Resistance to cisplatin and adriamycin is associated with the inhibition of glutathione efflux in MCF-7-derived cells. Anticancer Res. 2006;26:3595–3600. [PubMed] [Google Scholar]
  20. Pandeya S.N., Sriram D., Nath G., Clercq E.D. Synthesis, antibacterial, antifungal and anti-HIV evaluation of Schiff and Mannich bases of isatin derivatives with 3-amino-2-methylmercapto quinazolin-4(3H)-one. Pharm. Acta Helv. 1999;74:11–17. doi: 10.1016/s0031-6865(99)00010-2. [DOI] [PubMed] [Google Scholar]
  21. Pandeya S.N., Sriram D., Nath G., Clercq E.D. Synthesis and antimicrobial activity of Schiff and Mannich bases of isatin and its derivatives with pyrimidine. Il Farmaco. 1999;54:624–628. doi: 10.1016/s0014-827x(99)00075-0. [DOI] [PubMed] [Google Scholar]
  22. Skehan P., Storeng R., Scudiero D., Monks A., McMohan J., Vistica D., Warren J.T., Bokesch H., Kenney S., Boyd M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 1990;82:1107–1112. doi: 10.1093/jnci/82.13.1107. [DOI] [PubMed] [Google Scholar]
  23. Sridhar S.K., Ramesh A. Synthesis and pharmacological activities of hydrazones, Schiff and Mannich bases of isatin derivatives. Biol. Pharm. Bull. 2001;24(10):1149–1152. doi: 10.1248/bpb.24.1149. [DOI] [PubMed] [Google Scholar]
  24. Varma R.S., Chauhan S. Synthesis of substituted 2-phenylbenzothiazoles and 5(6)-nitro-1,3-disubsituted-benzimidazoline-2-thiones as CNS active agents. Ind. J. Chem. 1988;27B:438–442. [Google Scholar]
  25. Verma M., Pandeya S.N., Singh K., Stable J.P. Anticonvulsant activity of Schiff bases of isatin derivatives. Acta Pharm. 2004;54:49–56. [PubMed] [Google Scholar]

Articles from Saudi Pharmaceutical Journal : SPJ are provided here courtesy of Springer

RESOURCES