Synthesis and cytotoxic activity of new indolylpyrrole derivatives

Mohamed A.A. Radwan; Osamah Al Rugaie; Waleed Al Abdulmonem; Mohammad Y. Alfaifi; Serag Eldin I. Elbehairi

doi:10.1016/j.arabjc.2021.103209

View/Download PDF

Buy Reprints

PDF

Translate this page into:

Original article

2021

:14;

202107

doi:

10.1016/j.arabjc.2021.103209

Synthesis and cytotoxic activity of new indolylpyrrole derivatives

Mohamed A.A. Radwan^{^a,^b,⁎}, Osamah Al Rugaie^{^c}, Waleed Al Abdulmonem^{^d}, Mohammad Y. Alfaifi^{^e}, Serag Eldin I. Elbehairi^{^e,^f}

a Department of Chemistry, Collage of Science, Qassim University, Buraidah, Saudi Arabia

b Applied Organic Chemistry Department, National Research Center, Dokki, Egypt

c Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia

d Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia

e King Khalid University, Faculty of Science, Biology Department, Abha 9004, Saudi Arabia

f Cell Culture Lab, Egyptian Organization for Biological Products and Vaccines (VACSERA Holding Company), 51 Wezaret El-Zeraa St., Agouza, Giza, Egypt

⁎Corresponding author at: Department of Chemistry, Collage of Science, Qassim University, Buraydah, Saudi Arabia. mrthaoan@qu.edu.sa (Mohamed A.A. Radwan),

Received: 2021-3-29, Accepted: 2021-5-4,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

The current approach described the synthesis of a new series of indolylpyrrole derivatives through multicomponent reaction of α-cyano chalcones, appropriate aldehydes, and ammonium acetate in refluxed acetic acid. The chemical structures of the designed compounds were confirmed with spectroscopic data and elemental analysis and then tested for their in vitro cytotoxic activity by SRB assay method towards three cell lines involving human Prostate adenocarcinoma; metastatic cells (PC-3), human ovary adenocarcinoma (SKOV3) and human dukes' type B, colorectal adenocarcinoma (LS 174 T). Most significant activity provided with compounds 5c, 5h and, 5j against prostate cancer cells (PC-3) with IC50s of 3.30 ± 0.20, 3.60 ± 0.10, and 3.60 ± 0.90 µg/ml, respectively. In human ovarian carcinoma (SKOV3), the compounds 5a, and 5i have stronger cytotoxicity with IC50s of 1.20 ± 0.04, 1.90 ± 0.50 µg/ml, respectively than the standard doxorubicin (IC50 = 2.20 ± 0.02 µg/ml). On the other hand, only compound 5a has the ability to diminish the viability of LS174T cells in an active manner with IC50 2.80 ± 0.10 µg/ml. Consequently, this effort offers groundwork for additional examination of nominated indolylpyrroles as antiproliferative agents.

Keywords

Indole

Pyrrole

Cytotoxicity

SRB assay

PC-3

SKOV3

LS174T

Show Related Articles from PubMed

1 Introduction

In the last two decades, one of the foremost growing patterns in the synthesis of organic compounds is in what manner to construct new heterocyclic systems as biologically active skeleton in drug finding (Lipinski, and Hopkins, 2004; Schreiber, 2000). Indole and pyrrole derivatives, both natural and synthetic, have been identified as the most effective bioactive targets among a variety of heterocyclic molecules.

The indole structure is a common unit in some natural products (especially marine alkaloids, plant or mushroom families) and medicines, characterized by a widespread range of biological properties (Kaushik et al. 2013; Hamid et al. 2017; Homer and Sperry, 2017; Wan, et al. 2019; Ciulla, et al. 2019; Netz and Opatz, 2015; Gul and Hamann, 2005 ). Moreover, indole molecule is featured extensively in a range of medicinal agents with various pharmacological behaviors, as anticancer (Cascioferro, et al., 2019; Carbone et al., 2021; Chen, et al. 1996 ), antioxidant (Suzen and Buyukbingol, 2000), antirheumatoidal (Giagoudakis and Markantonis, 2005), anti-HIV (Büyükbingöl et al., 1994; Suzen and Buyukbingol, 1998), and antimicrobial activity (Carbone et al. 2018, 2021; Parrino, et al. 2021 ). In fact, the most prominent indole structures of this group were the anticancer agent’s vinblastine and vincristine (Ferguson, et al. 1984). The intriguing reactivity of indole was dominated in several organic syntheses, and is constructed principally on its nucleophilicity (Sundberg, 1996) instead of electrophilicity (Bandini, 2013). Furthermore, there are several indole compounds with diverse pharmacological activity. Indomethacin and Etodolac are common nonsteroidal anti-inflammatory drugs owning an indole ring, and their antioxidant activity has been described (Shirinzadeh et al., 2016, 2020a, 2020b; Mukhopadhyay, et al. 2016 ). One important conclusion is that various indole derivatives have antioxidant potential (Suzen, 2007; Estevão et al. 2010). Among them, melatonin derivatives has been established to be particularly efficient (Galano, 2016) with well-known potent ROS and RNS scavenging effect (Suzen, 2015).

On the other hand, pyrrole and its derivatives are estimated during 1999 to 2008 as important unit in medical research in recent years, with a number of well-known bioactivities such as antibacterial, antioxidant, and antibiotic agents. (Biava et al. 1999; MacLean, et al. 2008; Lehuédé, et al. 1999; Cantrell et al. 1999; Hidalgo et al. 2003 ). Moreover, Natural products have enthused the synthesis of compounds for pharmaceutical application, most of which are based on N-heterocyclic ring. Among these, the pyrrole moiety is one of the most discovered heterocycles in drug finding databases for several therapeutic ranges, established by the high number of pyrrole-based drugs reaching the market. (Petri et al. 2020; Kilic-Kurt, et al. 2019; Bortolozzi, et al. 2019 ).

In view of abovementioned literature surveys, and as a result of the importance of indole and pyrrole scaffolds in discovery and improvement of antitumor drugs, we represent herein a hybrid of the two molecules, indole-pyrrole derivatives, and study their anticancer potency towards three cell lines including human Prostate adenocarcinoma; metastatic cells (PC-3), human ovary adenocarcinoma (SKOV3) and human dukes' type B, colorectal adenocarcinoma (LS174T).

2 Results and discussion

2.1

2.1 Chemistry

The synthesis of variety of heterocycle compounds for biological evaluation is a part of our basic program strategy (Muhammad et al., 2019; El-Nezhawy et al., 2016; Radwan and Abbas, 2009; Ghorab et al., 2008 ). Herein, we report the synthesis of new indolylpyrrole derivatives through multicomponent reaction of the previously reported α-cyano chalcones 3 (Radwan et al., 2020; Quiroga et al., 2009; Ke et al., 2014; Li et al., 2017 ), appropriate aldehydes 4, and ammonium acetate in refluxed acetic acid as illustrated in Scheme 1.

Synthesis of new indolylpyrrole derivatives.

Moreover, a probable mechanism is suggested for the construction of new indolylpyrrole derivatives. Firstly, conjugated intermediate enimine A formed through condensation of α-cyano chalcones 3 with ammonium acetate. Which in turn react with appropriate aldehydes 4 to form enimine alcohol intermediates B. After that, intermediate B underwent intramolecular cyclization leading to the C–N bond formation followed by the loss of water then auto-oxidation leading to the formation product Molecules 5a-l, Scheme 2.

The chemical structures of the newly synthesized compounds (5a- l) were evidenced by spectral data (experimental units), e.g., the IR of compound 5a displaying bands at 3216–3318, 2214, and 1560, 1350 cm⁻¹ for the 2NH, cyano, and NO₂ groups, respectively, together with the disappearance of the C⚌O group. Moreover, ¹H NMR revealed two broad peak (exchangeable D₂O) at 11.67 and 12.27 ppm of two NH groups, and the loss of distinguishing olefinic proton of chalcone 3a. Furthermore, ¹³C NMR data and mass spectroscopy reinforced the suggested construction of compound 5a mass spectrum showed for the molecular formula C₂₅H₁₅ClN₄O₂ M⁺ at m/z 438,70% , and M⁺+2 at m/z 440,19% (see Scheme 2).

The proposed mechanism of the new indolylpyrrole derivatives.

Moreover, the structure of compound 5 h was chemically established by an alternative synthesis via a reaction of compound 1 with available 1,4-dichlorobenzoin 6 and excess ammonium acetate in refluxed H₂O/EtOH (Tamaddon and Amirpoor, 2013; Bhat and Trivedi, 2013) Scheme 3.

Alternative way for the synthesis of indolylpyrrole 5 h.

2.2

2.2 Cytotoxic activities

All the produced target compounds (5a-l) were estimated for their in vitro cytotoxic activity. The cytotoxic activity was achieved by SRB (Sulforhodamine B colorimetric) assay towards three cell lines including human Prostate adenocarcinoma; metastatic cells (PC-3), human ovary adenocarcinoma (SKOV3) and human dukes' type B, colorectal adenocarcinoma (LS174T), over a concentration range of 0.01 to 1000 μg/ml range of. Most of the compounds displayed notable cytotoxic activity. Compounds 5c, 5h and, 5j showed moderate activity against prostate cancer cells (PC-3) with IC50s of 3.30 ± 0.20, 3.60 ± 0.10 and 3.60 ± 0.90 µg/ml respectively, while the rest of the tested compounds have encouraged antiproliferative effect against (PC-3) with IC50s range of 5.40 ± 0.60 to 15.40 ± 2.20 µg/ml (Table 1 & Fig. 1).

Table 1 The IC50 (µg/ml) of new indolylpyrrole derivatives against different human adenocarcinoma.

Compounds	IC50 (µg/ml)
	PC-3	SKOV3	LS 174 T
5a	13.30 ± 1.90	1.20 ± 0.04	2.80 ± 0.10
5b	6.20 ± 0.50	4.90 ± 0.60	17.40 ± 0.70
5c	3.30 ± 0.20	6.10 ± 0.40	17.30 ± 0.40
5d	6.50 ± 0.30	8.30 ± 1.10	14.40 ± 1.10
5e	9.60 ± 0.40	5.20 ± 1.80	14.70 ± 0.30
5f	6.80 ± 0.70	3.80 ± 0.90	34.10 ± 1.30
5g	9.20 ± 0.60	9.20 ± 0.70	23.80 ± 1.30
5h	3.60 ± 0.10	8.5 ± 0.4	20.50 ± 0.60
5i	5.40 ± 0.60	1.90 ± 0.50	9.70 ± 1
5j	3.60 ± 0.90	3.60 ± 0.40	10 ± 0.90
5k	11.70 ± 1.20	9.70 ± 0.60	29.20 ± 1.10
5l	15.40 ± 2.20	12.60 ± 0.90	21.30 ± 0.90
Doxorubicin	2.10 ± 0.10	2.20 ± 0.02	2.40 ± 1.20

The IC50s of new indolylpyrrole derivatives comparison with chemotherapy (doxorubicin) after 72 hr. incubation with three human adenocarcinoma cells (PC-3, SKOV3, and LS174T) cells.

In human ovarian carcinoma (SKOV3), the compounds 5a, 5i, 5j, and 5f have strong cytotoxicity with IC50s of 1.20 ± 0.04, 1.90 ± 0.50, 3.60 ± 0.40, and 3.80 ± 0.90 µg/ml respectively, while the other compounds have moderate cytotoxicity effect with IC50s in the range of 5.40 ± 0.60 to 15.40 ± 2.20 µg/ml (Table 1& Fig. 1).

On the other hand, only compound 5a has the ability to diminish the viability of LS 174 T cells in an active manner with IC50 2.80 ± 0.10 µg/ml and the compounds 5i, and 5j have respectable effect with IC50s of 9.70 ± 1 and 10 ± 0.90 µg/ml, while the other compounds have1 weak toxicity with IC50s in the range of 14.40 ± 1.10 to 29.20 ± 1.10 µg/ml (Table 1 & Fig. 1).

3 Conclusion

Traditional three-component method has been used to construct a new series of indolylpyrrole derivatives through multicomponent reaction of α-cyano chalcones, appropriate aldehydes, and ammonium acetate in refluxed acetic acid. The chemical structures of the prepared compounds were established with spectroscopic studies and tested for their in vitro cytotoxic activity by SRB assay counter to three cell lines involving human Prostate adenocarcinoma; metastatic cells (PC-3), human ovary adenocarcinoma (SKOV3) and human dukes' type B, colorectal adenocarcinoma (LS174T). Compounds 5c, 5 h and, 5j showed moderate activity against prostate cancer cells (PC-3) with IC50s of 3.30 ± 0.20, 3.60 ± 0.10 and 3.60 ± 0.90 µg/ml, respectively. In human ovarian carcinoma (SKOV3), the compounds 5a, and 5i have stronger cytotoxicity with IC50s of 1.20 ± 0.04, 1.90 ± 0.50 µg/ml, respectively than doxorubicin drug. On the other hand, only compound 5a has the capability to diminish the feasibility of LS 174 T cells in an active manner with IC50 2.80 ± 0.10 µg/ml.

From the structure–activity relationship (SAR), it is observed that the 4-NO₂-Phenyl and 4-Cl-Phenyl substituted as compound 5a enhance the activity against human ovarian carcinoma (SKOV3), also compound 5i 4-Cl-Phenyl and 2,4-diCl-Phenyl substituted have stronger cytotoxicity than doxorubicin drug. Consequently, this effort introduces groundwork for additional investigation of selected indolylpyrrole derivatives as antiproliferative agents.

4 Experimental

4.1

4.1 Materials and methods

All available reagents and solvents in this research were of analytical grade purity and procured by Merck, and Sigma-Aldrich. Melting point (°C) was recited by XT-5 microscopic apparatus. IR spectra proceeded on IS10 spectrometer by means of KBr disk. MS (EI) m/z was done by means of a DCQII apparatus. ¹HNMR and ¹³CNMR spectra were verified on a Varian (Inova 500 MHz) spectrometer and chemical shifts were expressed in (ppm) using tetramethylsilane (TMS) as the internal standard. The formation of the reaction was monitored by thin-layer chromatography (TLC/n-hexane:EtOAc; 3:7).

4.1.1

4.1.1 General procedure for the synthesis of indolylpyrrole derivatives (5a-l)

A mixture of α-cyano chalcones 3 (1 mmol), appropriate aldehydes 4 (1 mmol), and ammonium acetate (4 mmol) was refluxed in acetic acid at 120 °C for 16 h (controlled by TLC/n-hexane:EtOAc; 3:7). Subsequently, the reaction mixture was left to cool and then the precipitated was recrystallized from ethanol/DMF.

Method B for the synthesis of 4,5-bis(4-Chlorophenyl)-2-(indol-3-yl)pyrrole-3-carbonitrile (5h):

To a mixture of 1,4-dichlorobenzoin 6 (2 mmol), and compound 1 (2 mmol) in H₂O–EtOH (15 mL, 50:50) was added NH₄OAc (4 mmol), and the reaction was stirred under reflux. After the reaction completed (monitored by TLC/n-hexane:EtOAc; 3:7), the obtained products were separated by filtration (87%).

5-(4-Chlorophenyl)-2-(indol-3-yl)-4-(4-nitrophenyl)-pyrrole-3-carbonitrile (5a). Recrystallized using EtOH/DMF, pale brown solid (yield 83%); mp 263 °C; IR (KBr) mmax/cm⁻¹ 3216–3318 (2 NH), 2214 (CN), 1560, 1350 (NO₂); ¹H NMR (500 MHz, DMSOd₆): δ 7.27–7.29 (m, 2H, indole H5, H6), 7.50–7.52 (dd, J = 1.2, 8.6 Hz, 1H, indole H7), 7.54 (s, 2H, 4-Cl-Ph), 7.90 (m, 2H, 4-Cl-Ph), 7.92 (s, 2H, 4-NO₂-Ph), 8.18 (m, 2H, 4-NO₂-Ph), 8.20 (dd, J = 1.1, 8.4 Hz, 1H, indole H4), 8.58 (s, 1H, indole-H2), 11.67 (brs, NH, pyrrole), 12.27 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 151.08, 139.42, 136.56, 134.78, 129.82, 129.60, 129.32 (2C), 128.96 (2C), 128.84 (2C), 128.24, 124.90, 124.23 (2C), 121.64, 121.20, 119.68, 118.30, 117.12, 113.38, 111.48, 111.13, 68.90; MS-EI (m/z %): 438 [M⁺, 70%], 440 [M⁺+2, 19%]; Calcd. for C₂₅H₁₅ClN₄O₂: C, 68.42; H, 3.45; N, 12.77. Found: C, 68.47; H, 3.46; N, 12.73.

4-(4-Bromophenyl)-5-(4-chlorophenyl)-2-(indol-3-yl)-pyrrole-3-carbonitrile (5b). Recrystallized using EtOH/DMF, yellow solid (yield 81%); mp 229–230 °C; IR (KBr) mmax/cm⁻¹ 3200–3320 (2 NH), 2243 (CN); ¹H NMR (500 MHz, DMSOd₆): δ 7.26–7.28 (m, 2H, indole H5, H6), 7.52–7.54 (dd, J = 1.2, 8.5 Hz, 1H, indole H7), 7.55 (s, 2H, 4-Br-Ph), 7.57 (m, 2H, 4-Br-Ph), 7.58 (s, 2H, 4-Cl-Ph), 7.91 (m, 2H, 4-Cl-Ph), 8.11 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.60 (s, 1H, indole-H2), 11.61 (brs, NH, pyrrole), 12.32 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 138.43, 136.76, 134.12, 131.55, 130.32 (2C), 129.87 (2C), 129.12 (2C), 128.84 (2C), 123.77, 123.20, 122.13 (2C), 121.47, 121.23, 119.88, 118.54, 116.98, 113.87, 111.44, 111.29, 67.86; MS-EI (m/z %): 472 [M⁺+1, 67%]; 474 [M⁺+2, 16%]; Calcd. for C₂₅H₁₅BrClN₃: C, 63.51; H, 3.20; N, 8.89. Found: C, 63.62; H, 3.15; N, 8.85.

4,5-bis(4-Bromophenyl)-2-(indol-3-yl)pyrrole-3-carbonitrile (5c). Recrystallized using EtOH/DMF, yellow solid (yield 84%); mp 225–227 °C; IR (KBr) mmax/cm⁻¹ 3230–3345 (2 NH), 2221 (CN); ¹H NMR (500 MHz, DMSOd₆): δ 7.29–7.30 (m, 2H, indole H5, H6), 7.50–7.52 (dd, J = 1.2, 8.5 Hz, 1H, indole H7), 7.53 (s, 2H, 4-Br-Ph), 7.56 (m, 2H, 4-Br-Ph), 7.57 (s, 2H, 4-Br-Ph), 7.74 (m, 2H, 4-Br-Ph), 8.16 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.61 (s, 1H, indole-H2), 11.43 (brs, NH, pyrrole), 12.44 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 137.11, 132.05 (2C), 131.32, 130.84, 130.02 (2C), 129.81, 128.72 (2C), 128.34, 124.86, 123.13, 122.21 (2C), 121.34, 121.26, 121.15, 119.83, 118.08, 116.67, 113.98, 111.41, 111.23, 67.87; MS-EI (m/z %): 514 [M+, 55%]; 516 [M+, 51%]; Calcd. for C₂₅H₁₅Br₂N₃: C, 58.06; H, 2.92; N, 8.12. Found: C, 58.19; H, 2.90; N, 8.08.

4-(4-Bromophenyl)-5-(4-cyanophenyl)-2-(indol-3-yl)pyrrole-3-carbonitrile (5d). Recrystallized using EtOH/DMF, yellow solid (yield 85%); mp 261–263 °C; IR (KBr) mmax/cm⁻¹ 3235–3350 (2 NH), 2225, 2230 (2CN); ¹H NMR (500 MHz, DMSOd₆): δ 7.30–7.32 (m, 2H, indole H5, H6), 7.53 (s, 2H, 4-Br-Ph), 7.54–7.56 (dd, J = 1.2, 8.5 Hz, 1H, indole H7), 7.57 (m, 2H, 4-Br-Ph), 7.82 (s, 2H, 4-CN-Ph), 7.95 (m, 2H, 4-CN-Ph), 8.13 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.58 (s, 1H, indole-H2), 11.65 (brs, NH, pyrrole), 12.32 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 136.98, 136.24, 132.86 (2C), 131.54, 131.33, 130.01 (2C), 129.66, 128.70, 128.50, 124.89 (2C), 123.18, 122.03 (2C), 121.41, 119.85, 118.74, 118.24, 116.62, 113.88, 112.23, 111.40, 111.31, 66.96; MS-EI (m/z %): 462 [M⁺,52%]; 464 [M⁺+2,52%]; Calcd. for C₂₆H₁₅BrN₄: C, 67.40; H, 3.26; N, 12.09. Found: C, 67.46; H, 3.23; N, 12.02.

4-(4-Bromophenyl)-5-(4-(dimethylamino)phenyl)-2-(indol-3-yl)pyrrole-3-carbonitrile(5e). Recrystallized using EtOH/DMF, yellow solid (yield 79%); mp 255–257 °C; IR (KBr) mmax/cm⁻¹ 3230–3360 (2 NH), 2220 (CN); ¹H NMR (500 MHz, DMSOd₆): δ 3.12 (2 s, 6H, N-Me₂), 7.12 (s, 2H, 4-NMe₂-Ph), 7.31–7.32 (m, 2H, indole H5, H6), 7.50 (s, 2H, 4-Br-Ph), 7.53–7.55 (dd, J = 1.2, 8.6 Hz, 1H, indole H7), 7.56 (m, 2H, 4-Br-Ph), 7.59 (m, 2H, 4-NMe₂-Ph), 8.11 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.59 (s, 1H, indole-H2), 11.63 (brs, NH, pyrrole), 12.38 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 156.07, 136.61, 131.45, 129.86 (2C), 129.54, 128.54 (2C), 128.52, 123.09, 121.80 (2C), 121.66, 121.46, 121.43, 121.21, 119. 83, 118.04, 116.74, 113.94, 112.78 (2C), 112.13, 111.65, 68.02; 42.26 (2C). MS-EI (m/z %): 480 [M⁺,51%]; 482 [M⁺+2; 49%]; Calcd. for C₂₇H₂₁BrN₄: C, 67.37; H, 4.40; N, 11.64. Found: C, 67.42; H, 4.37; N, 11.60.

4-(4-Bromophenyl)-2-(indol-3-yl)-5-(4-nitrophenyl)pyrrole-3-carbonitrile (5f). Recrystallized using EtOH/DMF, pale brown solid (86%); mp 253–255 °C; IR (KBr) mmax/cm⁻¹ 3206–3330 (2 NH), 2234 (CN), 1550, 1340 (NO₂); ¹H NMR (500 MHz, DMSOd₆): δ 7.24–7.26 (m, 2H, indole H5, H6), 7.51–7.53 (dd, J = 1.2, 8.5 Hz, 1H, indole H-7), 7.54 (s, 2H, 4-Br-Ph), 7.57 (m, 2H, 4-Br-Ph), 7.95 (s, 2H, 4-NO₂-Ph), 8.23 (m, 2H, 4-NO₂-Ph), 8.12 (dd, J = 1.2, 8.5 Hz, 1H, indole H4), 8.60 (s, 1H, indole-H2), 11.78 (brs, NH, pyrrole), 12.34 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 149.65, 137.94, 136.58, 131.08, 129.82, 129.32 (2C), 126.96 (2C), 128.84, 128.24, 124.90, 124.45 (2C), 123.60, 121.68 (2C), 121.20, 119.78, 118.33, 116.84, 113.70, 111.40, 111.14, 68.67; MS-EI (m/z %): 483 [M⁺,50%]; 485 [M⁺+2; 47%]; Calcd. for C₂₅H₁₅BrN₄O₂: C, 62.13; H, 3.13; N, 11.59. Found: C, 62.21; H, 3.10; N, 11.51.

4-(4-Bromophenyl)-2-(indol-3-yl)-5-(2-nitrophenyl)pyrrole-3-carbonitrile (5 g). Recrystallized using EtOH/DMF, pale brown (81%); mp 250–251 °C; IR (KBr) mmax/cm⁻¹ 3210–3340 (2 NH), 2234 (CN), 1535, 1345 (NO₂);; ¹H NMR (500 MHz, DMSOd₆): δ 7.30–7.32 (m, 2H, indole H5, H6), 7.52–7.54 (dd, J = 1.2, 8.5 Hz, 1H, indole H7), 7.55 (s, 2H, 4-Br-Ph), 7.57 (m, 2H, 4-Br-Ph), 7.76 (m, 1H, 2-NO₂-Ph), 7.94 (m, 2H, 2-NO₂-Ph), 8.07 (m, 1H, 2-NO₂-Ph), 8.13 (dd, J = 1.2, 8.5 Hz, 1H, indole H4), 8.60 (s, 1H, indole-H2), 11.84 (brs, NH, pyrrole), 12.38 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 149.23, 136.68, 135.98, 132.70, 131.88, 129.83, 129.71 (2C), 129.44, 128.50, 125.21, 124.83, 124.81, 124.48, 123.62, 121.63 (2C), 121.54 119.80, 118.21, 116.51, 113.84, 111.32, 111.12, 69.52; MS-EI (m/z %): 483 [M⁺,53%]; 485 [M⁺+2; 51%]; Calcd. for C₂₅H₁₅BrN₄O₂: C, 62.13; H, 3.13; N, 11.59. Found: C, 62.23; H, 3.09; N, 11.52.

4,5-bis(4-Chlorophenyl)-2-(indol-3-yl)pyrrole-3-carbonitrile (5 h). Recrystallized using EtOH/DMF, yellow (80%); mp 232–233 °C; IR (KBr) mmax/cm⁻¹ 3220–3340 (2 NH), 2243 (CN); ¹H NMR (500 MHz, DMSOd₆): δ 7.29–7.31 (m, 2H, indole H5, H6), 7.51–7.52 (dd, J = 1.2, 8.6 Hz, 1H, indole H7), 7.54 (s, 2H, 4-Cl-Ph), 7.64 (m, 2H, 2H, 4-Cl-Ph), 7.76 (s, 2H, 4-Cl-Ph), 7.96 (m, 2H, 4-Cl-Ph), 8.16 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.60 (s, 1H, indole-H2), 11.68 (brs, NH, pyrrole), 12.41 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 136.57, 135.08, 134.94, 131.02, 130.89, 129.97, 129.76 (2C), 129.33 (2C), 128.96 (2C), 128.50 (2C), 124.81, 123.22, 121.51, 121.45, 119.83, 118.12, 116.57, 113.81, 111.27, 111.14, 67.50; MS-EI (m/z %): 427 [M⁺, 70%], 429 [M⁺+2, 39%]; 431 [M⁺+4, 6%]; Calcd. for C₂₅H₁₅Cl₂N₃: C, 70.11; H, 3.53; N, 9.81. Found: C, 70.15; H, 3.50; N, 9.76.

4-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-(indol-3-yl)pyrrole-3-carbonitrile (5i). Recrystallized using EtOH/DMF, yellow (82%); mp 249–251 °C; IR (KBr) mmax/cm⁻¹ 3250–3310 (2 NH), 2221 (CN); ¹H NMR (500 MHz, DMSOd₆): δ 7.26–7.28 (m, 2H, indole H-5, H-6), 7.34 (s, 1H, 2,4-diCl-Ph), 7.49 (d, 1H, 2,4-diCl-Ph), 7.50–7.52 (dd, J = 1.2, 8.6 Hz, 1H, indole H7), 7.61 (m, 2H, 4-Cl-Ph), 7.96 (m, 2H, 4-Cl-Ph), 8.04 (d, 1H, 2,4-diCl-Ph), 8.18 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.60 (s, 1H, indole-H2), 11.71 (brs, NH, pyrrole), 12.43 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 136.95, 135.86, 134.66, 133.70, 131.04, 130.94, 130.56, 129.61 (2C), 129.56, 128.98 (2C), 128.52, 128.43, 127.63, 124.35, 121.78, 121.36, 119.87, 118.29, 116.89, 113.85, 111.21, 111.13, 66.87; MS-EI (m/z %): 462 [M⁺, 86%], 464 [M⁺+2, 47%]; 466 [M⁺+4, 13%]; 468 [M⁺+6, 7%]; Calcd. for C₂₅H₁₄Cl₃N₃: C, 64.89; H, 3.05; N, 9.08. Found: C, 64.93; H, 3.01; N, 9.04.

4-(4-Chlorophenyl)-5-(4-(dimethylamino)phenyl)-2-(indol-3-yl)pyrrole-3-carbonitrile (5j). Recrystallized using EtOH/DMF, yellow (83%); mp 216–217 °C; IR (KBr) mmax/cm⁻¹ 3220–3360 (2 NH), 2226 (CN); ¹H NMR (500 MHz, DMSOd₆): δ 3.15 (2 s, 6H, N-Me₂), 7.10 (s, 2H, 4-NMe₂-Ph), 7.30–7.32 (m, 2H, indole H5, H6), 7.53–7.55 (dd, J = 1.2, 8.5 Hz, 1H, indole H7), 7.60 (m, 2H, 4-Cl-Ph), 7.98 (m, 2H, 4-Cl-Ph), 7.58 (m, 2H, 4-NMe₂-Ph), 8.20 (dd, J = 1.2, 8.5 Hz, 1H, indole H4), 8.60 (s, 1H, indole-H2), 11.68 (brs, NH, pyrrole), 12.43 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 155.69, 136.63, 134.76, 130.14, 129.45 (2C), 129.54, 128.92 (2C), 128.43 (2C), 128.06, 124.47, 121.67, 121.46, 121.43, 119.83, 118.04, 116.74, 113.94, 112.79 (2C), 111.21, 111.08, 67.41; 43.32 (2C). MS-EI (m/z %): 436 [M+, 90%]; 438 [M⁺ 2, 31%]; Calcd. for C₂₇H₂₁ClN₄: C, 74.22; H, 4.84; N, 12.82. Found: C, 74.28; H, 4.80; N, 12.87.

5-(4-Bromophenyl)-2-(indol-3-yl)-4-(thiophen-2-yl)pyrrole-3-carbonitrile (5 k). Recrystallized using EtOH/DMF, pale brown (73%); mp 215 °C; IR (KBr) mmax/cm⁻¹ 3240–3312 (2 NH), 2234 (CN); ¹H NMR (500 MHz, DMSOd₆): δ 7.08 (m, 1H, thiophene H4), 7.16 (m, 1H, thiophene H3), 7.31–7.33 (m, 2H, indole H5, H6), 7.54 (s, 2H, 4-Br-Ph), 7.57–7.59 (dd, J = 1.2, 8.6 Hz, 1H, indole H7), 7.76 (m, 2H, 4-Br-Ph), 7.79 (m, 1H, thiophene H2), 8.16 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.60 (s, 1H, indole-H2), 11.80 (brs, NH, pyrrole), 12.34 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 139.08, 136.91, 132.13 (2C), 130.63, 128.94, 128.85, 128.67, 128.34 (2C), 128.21, 127.76, 124.83, 123.48, 121.72, 121.45, 119.81, 118.24, 117.52, 111.12, 111.07, 100.64, 68.47; MS-EI (m/z %): 443 [M⁺,53%]; 445 [M⁺+2; 51%]; Calcd. for C₂₃H₁₄BrN₃S: C, 62.17; H, 3.18; N, 9.46; S, 7.22. Found: C, 62.22; H, 3.15; N, 9.48; S, 7.27.

2-(Indol-3-yl)-5-(4-nitrophenyl)-4-(thiophen-2-yl)pyrrole-3-carbonitrile (5 l). Recrystallized using EtOH/DMF, pale brown (73%); mp 201 °C; IR (KBr) mmax/cm⁻¹ 3240–3325 (2 NH), 2234 (CN), 1565, 1355 (NO₂); ¹H NMR (500 MHz, DMSOd₆): δ 7.12 (m, 1H, thiophene H4), 7.34 (m, 1H, thiophene H3), 7.30–7.32 (m, 2H, indole H5, H6), 7.56–7.58 (dd, J = 1.2, 8.6 Hz, 1H, indole H7), 7.73 (m, 1H, thiophene H-2), 7.96 (s, 2H, 4-NO₂-Ph), 8.18 (dd, J = 1.2, 8.6 Hz, 1H, indole H4), 8.24 (m, 2H, 4-NO₂-Ph), 8.60 (s, 1H, indole-H2), 11.76 (brs, NH, pyrrole), 12.37 (brs, NH, indole); ¹³C NMR (500 MHz, DMSO‑d₆) δ/ppm: 148.05, 138.16, 137.97, 136.56, 129.03, 128.65, 128.46, 128.11, 127.71, 126.21 (2C), 124.79, 124.53 (2C), 121.74, 121.42, 119.83, 118.22, 117.50, 111.13, 111.09, 100.35, 69.13; MS-EI (m/z %): 410 [M+, 56%]; Calcd. for C₂₃H₁₄N₄O₂S: C, 67.30; H, 3.44; N, 13.65; O, 7.80; S, 7.81. Found: C, 67.36; H, 3.41; N, 13.62; S, 7.83.

4.2

4.2 Cytotoxicity screening

4.2.1

4.2.1 Cell culture

Three cell lines including human Prostate adenocarcinoma; metastatic cells (PC-3), human ovary adenocarcinoma (SKOV3) and human dukes' type B, colorectal adenocarcinoma (LS174T), were obtained from the American Culture Collection (ATCC). Cells were conserved in RPMI-1640 complemented with (100 µg/mL), penicillin (100parts/mL) and warmth-deactivated fetal bovine serum (10% v/v) in a moistened, 5% (v/v) CO₂ atmosphere at 37 °C.

4.2.2

4.2.2 Cytotoxicity assay

Three cells lines were preserved with six different concentrations of each complex (0.01, 0.1, 1, 10, 100 and 1000 mg); cells (control) were added. Cells were incubated with each concentration at 72 h and fixed with TCA (10% w/v) for 1 h at 4 °C. Three cells lines were washed many times and marked by 0.4% (w/v) SRB solution for 10 min in a dark room. The additional of stain was take out and removed with 1% (v/v) acetic acid. The SRB-marked cells were dry overnight, and subsequently dissolved with Tris-HCl and the color strength was studied in a micro plate reader at 540 nm. The relation between viability ratio of each growth cell line and tested molecule concentrations was examined to obtain the IC₅₀ by Sigma Plot 12.0 software (Jeong-Chae et al., 2002).

Acknowledgment

The authors extends their gratefulness to Department of chemistry, College of Science, Qassim University and to the Deanship of Scientific Research at King Khalid University for funding this effort over Project under funding number (Cos-2019-2-2-1-5669).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

Bandini M., . Electrophilicity: the “dark-side” of indole chemistry. Org. Biomol. Chem.. 2013;11(32):5206-5212.
[CrossRef] [Google Scholar]
Bhat S.I., Trivedi D.R., . A catalyst-and solvent-free three-component reaction for the regioselective one-pot access to polyfunctionalized pyrroles. Tet. Lett.. 2013;54(41):5577-5582.
[CrossRef] [Google Scholar]
Biava M., Fioravanti R., Porretta G.C., Deidda D., Maullu C., Pompei R., . New pyrrole derivatives as antimycobacterial agents analogs of BM212. Bioorg. Med. Chem.. 1999;9(20):2983-2988.
[CrossRef] [Google Scholar]
Bortolozzi R., Carta D., Prà M.D., Antoniazzi G., Mattiuzzo E., Sturlese M., Di Paolo V., Calderan L., Moro S., Hamel E., Quintieri L., Ronca R., Viola G., Ferlin M.G., . Evaluating the effects of fluorine on biological properties and metabolic stability of some antitubulin 3-substituted 7-phenyl-pyrroloquinolinones. Eur. J. Med. Chem.. 2019;178:297-314.
[CrossRef] [Google Scholar]
Büyükbingöl, E., Süzen, S., Klopman, G., 1994. Studies on the synthesis and structure-activity relationships of 5-(3'-indolal)-2-thiohydantoin derivatives as aldose reductase enzyme inhibitors. Farmaco (Societa chimica italiana: 1989, 49(6), 443-447. PMID: 8074787.
Cantrell C.L., Groweiss A., Gustafson K.R., Boyd M.R., . A new staurosporine analog from the prosobranch mollusk Coriocella nigra. Nat. Prod. Lett.. 1999;14(1):39-46.
[CrossRef] [Google Scholar]
Carbone A., Parrino B., Cusimano M.G., Spanò V., Montalbano A., Barraja P., Cascioferro S., . New thiazole nortopsentin analogues inhibit bacterial biofilm formation. Marine drugs. 2018;16(8):274.
[CrossRef] [Google Scholar]
Carbone D., Parrino B., Cascioferro S., Pecoraro C., Giovannetti E., Di Sarno V., Diana P., . 1, 2, 4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells, Targeting GSK3β Kinase. ChemMedChem. 2021;16(3):537-554.
[CrossRef] [Google Scholar]
Cascioferro S., Attanzio A., Di Sarno V., Musella S., Tesoriere L., Cirrincione G., Parrino B., . New 1, 2, 4-oxadiazole nortopsentin derivatives with cytotoxic activity. Marine drugs. 2019;17(1):35.
[CrossRef] [Google Scholar]
Chen I., Safe S., Bjeldanes L., . Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem. Pharm.. 1996;51(8):1069-1076.
[CrossRef] [Google Scholar]
Ciulla M.G., Zimmermann S., Kumar K., . Cascade reaction based synthetic strategies targeting biologically intriguing indole polycycles. Org. Biomol. Chem.. 2019;17(3):413-431.
[CrossRef] [Google Scholar]
El-Nezhawy A.O., Eweas A.F., Radwan M.A., El-Naggar T.B., . Synthesis and Molecular Docking Studies of Novel 2-Phenyl-4-Substituted Oxazole Derivatives as Potential Anti-cancer Agents. J. Het. Chem.. 2016;53(1):271-279.
[CrossRef] [Google Scholar]
Estevão M.S., Carvalho L.C., Ribeiro D., Couto D., Freitas M., Gomes A., Ferreira L.M., Fernandes E., Marques M.M.B., . Antioxidant activity of unexplored indole derivatives: synthesis and screening. Europ. J. Med. Chem.. 2010;45:4869-4878.
[Google Scholar]
Ferguson P.J., Phillips J.R., Selner M., Cass C.E., . Differential activity of vincristine and vinblastine against cultured cells. Cancer research.. 1984;44(8):3307-3312. PMID: 6744266
[Google Scholar]
Galano A., . Computational-aided design of melatonin analogues with outstanding multifunctional antioxidant capacity. RSC Adv.. 2016;6:22951-22963.
[CrossRef] [Google Scholar]
Giagoudakis G., Markantonis S.L., . Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen. Pharmacotherapy: The Journal of Human Pharmacology and Drug. Therapy.. 2005;25(1):18-25.
[CrossRef] [Google Scholar]
Ghorab M., Taha N.M., Radwan M.A.A., Amin N.E., Shehab M.A., Faker I.M., . Dapson in Heterocyclic Chemistry, Part I: Novel Synthesis of Sulfone Biscompounds for Antimicrobial and Antitumor Activities. Phosphorus, Sulfur, and Silicon.. 2008;183(12):2891-2905.
[CrossRef] [Google Scholar]
Gul W., Hamann M.T., . Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases. Life sciences.. 2005;78(5):442-453.
[CrossRef] [Google Scholar]
Hamid H.A., Ramli A.N., Yusoff M.M., . Indole alkaloids from plants as potential leads for antidepressant drugs: A mini review. Front. Pharmacol.. 2017;8:96.
[CrossRef] [Google Scholar]
Hidalgo F.J., Nogales F., Zamora R., . Effect of the pyrrole polymerization mechanism on the antioxidative activity of nonenzymatic browning reactions. J. Agric. Food Chem.. 2003;51(19):5703-5708.
[CrossRef] [Google Scholar]
Homer J.A., Sperry J., . Mushroom-derived indole alkaloids. J. Nat. Prod.. 2017;80(7):2178-2187.
[CrossRef] [Google Scholar]
Jeong-Chae L., Hak-Ryul K., Ju K., Yong-Suk J., . Antioxidant property of an ethanol extract of the stem of Opuntia ficusindica var. saboten. J. Agr. Food Chem.. 2002;50:6490-6496.
[CrossRef] [Google Scholar]
Kaushik N.K., Kaushik N., Attri P., Kumar N., Kim C.H., Verma A.K., Choi E.H., . Biomedical importance of indoles. Molecules.. 2013;18(6):6620-6662.
[CrossRef] [Google Scholar]
Ke S., Yang Z., Zhang Z., Liang Y., Wang K., Liu M., Shi L., . Multisubstituted indole–acrylonitrile hybrids as potential cytotoxic agents. Bioorg. Med. Chem. Lett.. 2014;24(8):1907-1911.
[CrossRef] [Google Scholar]
Kilic-Kurt Z., Bakar-Ates F., Aka Y., Kutuk O., . Design, synthesis and in vitro apoptotic mechanism of novel pyrrolopyrimidine derivatives. Bioorg. Chem.. 2019;83:511-519.
[CrossRef] [Google Scholar]
Lehuédé J., Fauconneau B., Barrier L., Ourakow M., Piriou A., Vierfond J.M., . Synthesis and antioxidant activity of new tetraarylpyrroles. Eur. J. Medicinal Chem.. 1999;34(11):991-996.
[CrossRef] [Google Scholar]
Li L., Xu H., Dai L., Xi J., Gao L., Rong L., . An efficient metal-free cascade process for the synthesis of 4-arylpyrimido [1, 2-b] indazole-3-carbonitrile derivatives. Tetrahedron. 2017;73(36):5358-5365.
[CrossRef] [Google Scholar]
Lipinski C., Hopkins A., . Navigating chemical space for biology and medicine. Nature.. 2004;432:855-861.
[CrossRef] [Google Scholar]
MacLean P.D., Chapman E.E., Dobrowolski S.L., Thompson A., Barclay L.R.C., . Pyrroles as antioxidants: solvent effects and the nature of the attacking radical on antioxidant activities and mechanisms of pyrroles, dipyrrinones, and bile pigments. J. Organic Chem.. 2008;73(17):6623-6635.
[CrossRef] [Google Scholar]
Muhammad Z.A., Radwan M.A., Farghaly T.A., Gaber H.M., Elaasser M.M., . Synthesis and antitumor activity of novel [1, 2, 4, 5]-tetrazepino [6, 7-b] indole derivatives: marine natural product Hyrtioreticuline C and D analogues. Mini Rev. Medicinal Chem.. 2019;19(1):79-86.
[CrossRef] [Google Scholar]
Mukhopadhyay D., Dasgupta P., Roy D.S., Palchoudhuri S., Chatterjee I., Ali S., Dastidar S.G., . A Sensitive In vitro Spectrophotometric Hydrogen Peroxide Scavenging Assay using 1,10-Phenanthroline. Free Rad Antiox. 2016;6:124-132.
[Google Scholar]
Netz N., Opatz T., . Marine indole alkaloids. Marine drugs.. 2015;13(8):4814-4914.
[CrossRef] [Google Scholar]
Parrino B., Carbone D., Cascioferro S., Pecoraro C., Giovannetti E., Deng D., Diana P., . 1, 2, 4-Oxadiazole topsentin analogs as staphylococcal biofilm inhibitors targeting the bacterial transpeptidase sortase A. Eur. J. Med. Chem.. 2021;209:112892
[CrossRef] [Google Scholar]
Petri G.L., Spanò V., Spatola R., Holl R., Raimondi M.V., Barraja P., Montalbano A., . Bioactive pyrrole-based compounds with target selectivity. Eur. Med. Chem.. 2020;112783
[CrossRef] [Google Scholar]
Quiroga J., Trilleras J., Sanchez A.I., Insuasty B., Abonia R., Nogueras M., Cobo J., . Regioselective three-component synthesis of indolylpyrazolo [3, 4-b] pyridines induced by microwave and under solvent-free conditions. Lett. Org. Chem.. 2009;6(5):381-383.
[CrossRef] [Google Scholar]
Radwan M.A., Abbas E.M., . Synthesis of some pyridine, thiopyrimidine, and isoxazoline derivatives based on the pyrrole moiety. Monatshefte für Chemie-Chemical Monthly.. 2009;140(2):229-233.
[CrossRef] [Google Scholar]
Radwan M.A., Alminderej F.M., Awad H.M., . One-pot multicomponent synthesis and cytotoxic evaluation of novel 7-substituted-5-(1H-indol-3-yl) tetrazolo [1, 5-a] pyrimidine-6-carbonitrile. Molecules.. 2020;25(2):255.
[CrossRef] [Google Scholar]
Schreiber S.L., . Target-oriented and diversity-oriented organic synthesis in drug discovery. Science.. 2000;287:1964-1969.
[CrossRef] [Google Scholar]
Shirinzadeh H., Ghalia M., Tascioglu A., Adjali F.I., Gunesacar G., Gurer-Orhan H., Suzen S., . Bioisosteric modification on melatonin: synthesis of new naphthalene derivatives, in vitro antioxidant activity and cytotoxicity studies. Brazilian J. Pharmaceut. Sci.. 2020;56
[CrossRef] [Google Scholar]
Shirinzadeh H., Ince E., Westwell A.D., Gurer-Orhan H., Suzen S., . Novel indole-based melatonin analogues substituted with triazole, thiadiazole and carbothioamides: studies on their antioxidant, chemopreventive and cytotoxic activities. J. Enzyme Inhibition Medicinal Chem.. 2016;31(6):1312-1321.
[CrossRef] [Google Scholar]
Shirinzadeh H., Neuhaus E., Erguc E.I., Aliyev A.T., Gurer-Orhan H., Suzen S., . New indole-7-aldehyde derivatives as melatonin analogues; synthesis and screening their antioxidant and anticancer potential. Bioorg. Chem.. 2020;104:104219
[CrossRef] [Google Scholar]
Sundberg R.J., . Indoles Academic Press. San Diego. 1996;113
[Google Scholar]
Suzen, S., 2007. Antioxidant Activities of Synthetic Indole Derivatives and Possible Activity Mechanisms. In: V. Khan, M.T.H. (Ed.) Topics in Heterocyclic Chemistry, Bioactive Heterocycles. Spinger-Verlag Berlin Heidelberg, 11, 145-178. doi.org/10.1007/7081_2007_074.
Suzen, S., 2015. Evaluation of synthetic melatonin analog antioxidant compounds. Srinivasan, V., Gobbi, G., Shillcutt, S.D., Suzen, S. (Eds.), Melatonin: Therapeutic Value and Neuroprotection. Taylor & Francis, Boca Raton, Chapter 21, 259–269.
Suzen S., Buyukbingol E., . Evaluation of anti-HIV activity of 5-(2-phenyl-3′-indolal)-2-thiohydantoin. Il Farmaco.. 1998;53(7):525-527.
[CrossRef] [Google Scholar]
Suzen S., Buyukbingol E., . Anti-cancer activity studies of indolalthiohydantoin (PIT) on certain cancer cell lines. Il Farmaco.. 2000;55(4):246-248.
[CrossRef] [Google Scholar]
Tamaddon F., Amirpoor F., . Improved catalyst-free synthesis of pyrrole derivatives in aqueous media. Synlett. 2013;24(14):1791-1794.
[CrossRef] [Google Scholar]
Wan Y., Li Y., Yan C., Yan M., Tang Z., . Indole: A privileged scaffold for the design of anti-cancer agents. Eur. J. Med. Chem.. 2019;183:111691
[CrossRef] [Google Scholar]

Introduction

Results and discussion

Chemistry
Cytotoxic activities

Conclusion

Experimental

Materials and methods
Cytotoxicity screening

Fulltext Views
711

PDF downloads
480

View/Download PDF
Download Citations

BibTeX
RIS

Show Sections

[1] Bandini M., . Electrophilicity: the “dark-side” of indole chemistry. Org. Biomol. Chem.. 2013;11(32):5206-5212.
[CrossRef] [Google Scholar]

[2] Bhat S.I., Trivedi D.R., . A catalyst-and solvent-free three-component reaction for the regioselective one-pot access to polyfunctionalized pyrroles. Tet. Lett.. 2013;54(41):5577-5582.
[CrossRef] [Google Scholar]

[3] Biava M., Fioravanti R., Porretta G.C., Deidda D., Maullu C., Pompei R., . New pyrrole derivatives as antimycobacterial agents analogs of BM212. Bioorg. Med. Chem.. 1999;9(20):2983-2988.
[CrossRef] [Google Scholar]

[4] Bortolozzi R., Carta D., Prà M.D., Antoniazzi G., Mattiuzzo E., Sturlese M., Di Paolo V., Calderan L., Moro S., Hamel E., Quintieri L., Ronca R., Viola G., Ferlin M.G., . Evaluating the effects of fluorine on biological properties and metabolic stability of some antitubulin 3-substituted 7-phenyl-pyrroloquinolinones. Eur. J. Med. Chem.. 2019;178:297-314.
[CrossRef] [Google Scholar]

[5] Büyükbingöl, E., Süzen, S., Klopman, G., 1994. Studies on the synthesis and structure-activity relationships of 5-(3'-indolal)-2-thiohydantoin derivatives as aldose reductase enzyme inhibitors. Farmaco (Societa chimica italiana: 1989, 49(6), 443-447. PMID: 8074787.

[6] Cantrell C.L., Groweiss A., Gustafson K.R., Boyd M.R., . A new staurosporine analog from the prosobranch mollusk Coriocella nigra. Nat. Prod. Lett.. 1999;14(1):39-46.
[CrossRef] [Google Scholar]

[7] Carbone A., Parrino B., Cusimano M.G., Spanò V., Montalbano A., Barraja P., Cascioferro S., . New thiazole nortopsentin analogues inhibit bacterial biofilm formation. Marine drugs. 2018;16(8):274.
[CrossRef] [Google Scholar]

[8] Carbone D., Parrino B., Cascioferro S., Pecoraro C., Giovannetti E., Di Sarno V., Diana P., . 1, 2, 4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells, Targeting GSK3β Kinase. ChemMedChem. 2021;16(3):537-554.
[CrossRef] [Google Scholar]

[9] Cascioferro S., Attanzio A., Di Sarno V., Musella S., Tesoriere L., Cirrincione G., Parrino B., . New 1, 2, 4-oxadiazole nortopsentin derivatives with cytotoxic activity. Marine drugs. 2019;17(1):35.
[CrossRef] [Google Scholar]

[10] Chen I., Safe S., Bjeldanes L., . Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells. Biochem. Pharm.. 1996;51(8):1069-1076.
[CrossRef] [Google Scholar]

[11] Ciulla M.G., Zimmermann S., Kumar K., . Cascade reaction based synthetic strategies targeting biologically intriguing indole polycycles. Org. Biomol. Chem.. 2019;17(3):413-431.
[CrossRef] [Google Scholar]

[12] El-Nezhawy A.O., Eweas A.F., Radwan M.A., El-Naggar T.B., . Synthesis and Molecular Docking Studies of Novel 2-Phenyl-4-Substituted Oxazole Derivatives as Potential Anti-cancer Agents. J. Het. Chem.. 2016;53(1):271-279.
[CrossRef] [Google Scholar]

[13] Estevão M.S., Carvalho L.C., Ribeiro D., Couto D., Freitas M., Gomes A., Ferreira L.M., Fernandes E., Marques M.M.B., . Antioxidant activity of unexplored indole derivatives: synthesis and screening. Europ. J. Med. Chem.. 2010;45:4869-4878.
[Google Scholar]

[14] Ferguson P.J., Phillips J.R., Selner M., Cass C.E., . Differential activity of vincristine and vinblastine against cultured cells. Cancer research.. 1984;44(8):3307-3312. PMID: 6744266
[Google Scholar]

[15] Galano A., . Computational-aided design of melatonin analogues with outstanding multifunctional antioxidant capacity. RSC Adv.. 2016;6:22951-22963.
[CrossRef] [Google Scholar]

[16] Giagoudakis G., Markantonis S.L., . Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen. Pharmacotherapy: The Journal of Human Pharmacology and Drug. Therapy.. 2005;25(1):18-25.
[CrossRef] [Google Scholar]

[17] Ghorab M., Taha N.M., Radwan M.A.A., Amin N.E., Shehab M.A., Faker I.M., . Dapson in Heterocyclic Chemistry, Part I: Novel Synthesis of Sulfone Biscompounds for Antimicrobial and Antitumor Activities. Phosphorus, Sulfur, and Silicon.. 2008;183(12):2891-2905.
[CrossRef] [Google Scholar]

[18] Gul W., Hamann M.T., . Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases. Life sciences.. 2005;78(5):442-453.
[CrossRef] [Google Scholar]

[19] Hamid H.A., Ramli A.N., Yusoff M.M., . Indole alkaloids from plants as potential leads for antidepressant drugs: A mini review. Front. Pharmacol.. 2017;8:96.
[CrossRef] [Google Scholar]

[20] Hidalgo F.J., Nogales F., Zamora R., . Effect of the pyrrole polymerization mechanism on the antioxidative activity of nonenzymatic browning reactions. J. Agric. Food Chem.. 2003;51(19):5703-5708.
[CrossRef] [Google Scholar]

[21] Homer J.A., Sperry J., . Mushroom-derived indole alkaloids. J. Nat. Prod.. 2017;80(7):2178-2187.
[CrossRef] [Google Scholar]

[22] Jeong-Chae L., Hak-Ryul K., Ju K., Yong-Suk J., . Antioxidant property of an ethanol extract of the stem of Opuntia ficusindica var. saboten. J. Agr. Food Chem.. 2002;50:6490-6496.
[CrossRef] [Google Scholar]

[23] Kaushik N.K., Kaushik N., Attri P., Kumar N., Kim C.H., Verma A.K., Choi E.H., . Biomedical importance of indoles. Molecules.. 2013;18(6):6620-6662.
[CrossRef] [Google Scholar]

[24] Ke S., Yang Z., Zhang Z., Liang Y., Wang K., Liu M., Shi L., . Multisubstituted indole–acrylonitrile hybrids as potential cytotoxic agents. Bioorg. Med. Chem. Lett.. 2014;24(8):1907-1911.
[CrossRef] [Google Scholar]

[25] Kilic-Kurt Z., Bakar-Ates F., Aka Y., Kutuk O., . Design, synthesis and in vitro apoptotic mechanism of novel pyrrolopyrimidine derivatives. Bioorg. Chem.. 2019;83:511-519.
[CrossRef] [Google Scholar]

[26] Lehuédé J., Fauconneau B., Barrier L., Ourakow M., Piriou A., Vierfond J.M., . Synthesis and antioxidant activity of new tetraarylpyrroles. Eur. J. Medicinal Chem.. 1999;34(11):991-996.
[CrossRef] [Google Scholar]

[27] Li L., Xu H., Dai L., Xi J., Gao L., Rong L., . An efficient metal-free cascade process for the synthesis of 4-arylpyrimido [1, 2-b] indazole-3-carbonitrile derivatives. Tetrahedron. 2017;73(36):5358-5365.
[CrossRef] [Google Scholar]

[28] Lipinski C., Hopkins A., . Navigating chemical space for biology and medicine. Nature.. 2004;432:855-861.
[CrossRef] [Google Scholar]

[29] MacLean P.D., Chapman E.E., Dobrowolski S.L., Thompson A., Barclay L.R.C., . Pyrroles as antioxidants: solvent effects and the nature of the attacking radical on antioxidant activities and mechanisms of pyrroles, dipyrrinones, and bile pigments. J. Organic Chem.. 2008;73(17):6623-6635.
[CrossRef] [Google Scholar]

[30] Muhammad Z.A., Radwan M.A., Farghaly T.A., Gaber H.M., Elaasser M.M., . Synthesis and antitumor activity of novel [1, 2, 4, 5]-tetrazepino [6, 7-b] indole derivatives: marine natural product Hyrtioreticuline C and D analogues. Mini Rev. Medicinal Chem.. 2019;19(1):79-86.
[CrossRef] [Google Scholar]

[31] Mukhopadhyay D., Dasgupta P., Roy D.S., Palchoudhuri S., Chatterjee I., Ali S., Dastidar S.G., . A Sensitive In vitro Spectrophotometric Hydrogen Peroxide Scavenging Assay using 1,10-Phenanthroline. Free Rad Antiox. 2016;6:124-132.
[Google Scholar]

[32] Netz N., Opatz T., . Marine indole alkaloids. Marine drugs.. 2015;13(8):4814-4914.
[CrossRef] [Google Scholar]

[33] Parrino B., Carbone D., Cascioferro S., Pecoraro C., Giovannetti E., Deng D., Diana P., . 1, 2, 4-Oxadiazole topsentin analogs as staphylococcal biofilm inhibitors targeting the bacterial transpeptidase sortase A. Eur. J. Med. Chem.. 2021;209:112892
[CrossRef] [Google Scholar]

[34] Petri G.L., Spanò V., Spatola R., Holl R., Raimondi M.V., Barraja P., Montalbano A., . Bioactive pyrrole-based compounds with target selectivity. Eur. Med. Chem.. 2020;112783
[CrossRef] [Google Scholar]

[35] Quiroga J., Trilleras J., Sanchez A.I., Insuasty B., Abonia R., Nogueras M., Cobo J., . Regioselective three-component synthesis of indolylpyrazolo [3, 4-b] pyridines induced by microwave and under solvent-free conditions. Lett. Org. Chem.. 2009;6(5):381-383.
[CrossRef] [Google Scholar]

[36] Radwan M.A., Abbas E.M., . Synthesis of some pyridine, thiopyrimidine, and isoxazoline derivatives based on the pyrrole moiety. Monatshefte für Chemie-Chemical Monthly.. 2009;140(2):229-233.
[CrossRef] [Google Scholar]

[37] Radwan M.A., Alminderej F.M., Awad H.M., . One-pot multicomponent synthesis and cytotoxic evaluation of novel 7-substituted-5-(1H-indol-3-yl) tetrazolo [1, 5-a] pyrimidine-6-carbonitrile. Molecules.. 2020;25(2):255.
[CrossRef] [Google Scholar]

[38] Schreiber S.L., . Target-oriented and diversity-oriented organic synthesis in drug discovery. Science.. 2000;287:1964-1969.
[CrossRef] [Google Scholar]

[39] Shirinzadeh H., Ghalia M., Tascioglu A., Adjali F.I., Gunesacar G., Gurer-Orhan H., Suzen S., . Bioisosteric modification on melatonin: synthesis of new naphthalene derivatives, in vitro antioxidant activity and cytotoxicity studies. Brazilian J. Pharmaceut. Sci.. 2020;56
[CrossRef] [Google Scholar]

[40] Shirinzadeh H., Ince E., Westwell A.D., Gurer-Orhan H., Suzen S., . Novel indole-based melatonin analogues substituted with triazole, thiadiazole and carbothioamides: studies on their antioxidant, chemopreventive and cytotoxic activities. J. Enzyme Inhibition Medicinal Chem.. 2016;31(6):1312-1321.
[CrossRef] [Google Scholar]

[41] Shirinzadeh H., Neuhaus E., Erguc E.I., Aliyev A.T., Gurer-Orhan H., Suzen S., . New indole-7-aldehyde derivatives as melatonin analogues; synthesis and screening their antioxidant and anticancer potential. Bioorg. Chem.. 2020;104:104219
[CrossRef] [Google Scholar]

[42] Sundberg R.J., . Indoles Academic Press. San Diego. 1996;113
[Google Scholar]

[43] Suzen, S., 2007. Antioxidant Activities of Synthetic Indole Derivatives and Possible Activity Mechanisms. In: V. Khan, M.T.H. (Ed.) Topics in Heterocyclic Chemistry, Bioactive Heterocycles. Spinger-Verlag Berlin Heidelberg, 11, 145-178. doi.org/10.1007/7081_2007_074.

[44] Suzen, S., 2015. Evaluation of synthetic melatonin analog antioxidant compounds. Srinivasan, V., Gobbi, G., Shillcutt, S.D., Suzen, S. (Eds.), Melatonin: Therapeutic Value and Neuroprotection. Taylor & Francis, Boca Raton, Chapter 21, 259–269.

[45] Suzen S., Buyukbingol E., . Evaluation of anti-HIV activity of 5-(2-phenyl-3′-indolal)-2-thiohydantoin. Il Farmaco.. 1998;53(7):525-527.
[CrossRef] [Google Scholar]

[46] Suzen S., Buyukbingol E., . Anti-cancer activity studies of indolalthiohydantoin (PIT) on certain cancer cell lines. Il Farmaco.. 2000;55(4):246-248.
[CrossRef] [Google Scholar]

[47] Tamaddon F., Amirpoor F., . Improved catalyst-free synthesis of pyrrole derivatives in aqueous media. Synlett. 2013;24(14):1791-1794.
[CrossRef] [Google Scholar]

[48] Wan Y., Li Y., Yan C., Yan M., Tang Z., . Indole: A privileged scaffold for the design of anti-cancer agents. Eur. J. Med. Chem.. 2019;183:111691
[CrossRef] [Google Scholar]

Synthesis and cytotoxic activity of new indolylpyrrole derivatives

Abstract

Abstract

Keywords

Indole

Pyrrole

Cytotoxicity

SRB assay

PC-3

SKOV3

LS174T

1 Introduction

2 Results and discussion

2.1 Chemistry

2.2 Cytotoxic activities

3 Conclusion

4 Experimental

4.1 Materials and methods

4.1.1 General procedure for the synthesis of indolylpyrrole derivatives (5a-l)

4.2 Cytotoxicity screening

4.2.1 Cell culture

4.2.2 Cytotoxicity assay

Acknowledgment

Declaration of Competing Interest

References

Suggested read for related articles: