Design, Synthesis and Biological Evaluation of 1,3-Diphenyl-3- (phenylthio)propan-1-ones as New Cytotoxic Agents

Document Type : Research article


1 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Protein Technology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Department of Toxicology and Pharmacology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.



Cancers in terms of morbidity and mortality are one of the major universal issues. New compounds of anticancer agents based on β-aryl-β-mercapto ketones scaffold possessing piperidinyl­ethoxy or morpholinyl­ethoxy groups were synthesized and evaluated as cytotoxic agents. Cytotoxic effects of synthesized compounds were measured against MCF-7, human ER-positive breast cancer cell lines, using MTT assay. The results indicated that all compounds had high cytotoxic activity on MCF-7 cancerous cells, even more than the reference drug Tamoxifen. Among them, compounds 3-(4-(2-morpholinoethoxy)phenyl)-1-phenyl-3-(phenylthio)propan-1-one (4a) and 1-(4-methoxyphenyl)-3-(3-(2-morpholinoethoxy)phenyl)-3-(phenylthio)propan-1-one (4h) had no significant cytotoxic effects on normal cells compared to Tamoxifen. Our results also indicated that adding tertiary amine basic side chain, found in Tamoxifen drug, to 1,3-diphenyl-3-(phenylthio)propan-1-ones improves the cytotoxic effects of these compounds on breast cancer cells.

Graphical Abstract

Design, Synthesis and Biological Evaluation of 1,3-Diphenyl-3- (phenylthio)propan-1-ones as New Cytotoxic Agents


(1) Ferlay J, Colombet M, Soerjomataram I, Mathers
C, Parkin D, Piñeros M, Znaor A and Bray F.
Estimating the global cancer incidence and
mortality in 2018: GLOBOCAN sources and
methods. Int. J. Cancer. (2019) 144: 1941-53.
(2) Awan Z, Kutbi HI, Ahmad A, Syed R, Alsulaimany
F and Shaik NA. Molecular design, synthesis and
biological characterization of novel Resveratrol
derivative as potential anticancer agent targeting
NF-κB. J. Appl. Biomed. (2020) 18/1: 8-17.
(3) Vaidyanathan S, Pehlivan I, Dolvis LG, Jacques K,
Alcin M, Tuna M and Koyuncu I. A novel ANNbased four-dimensional two-disk hyperchaotic
dynamical system, bifurcation analysis,
circuit realisation and FPGA-based TRNG
implementation. Int. J. Comput. Appl. Technol.
(2020) 62: 20-35.
(4) Hu L, Cai X, Dong S, Zhen Y, Hu J, Wang S, Jiang
J, Huang J, Han Y and Qian Y. Synthesis and
anticancer activity of novel actinonin derivatives
as HsPDF inhibitors. J. Med. Chem. (2020) 63:
(5) Salimi A, Aghvami M, Azami Movahed M, Zarei MH,
Eshghi P, Zarghi A and Pourahmad J. Evaluation
of cytotoxic potentials of novel cyclooxygenase-2
inhibitor against ALL lymphocytes and normal
lymphocytes and its anticancer effect through
mitochondrial pathway. Cancer Invest. (2020) 38:
(6) Nourbakhsh M, Farzaneh S, Taghikhani A, Zarghi
A and Noori S. The effect of a newly synthesized
ferrocene derivative against MCF-7 breast
cancer cells and spheroid stem cells through
ROS production and inhibition of JAK2/STAT3
signaling pathway. Curr. Med. Chem.: Anti-Cancer
Agents (2020) 20: 875-86.
(7) Pinheiro S, Pessôa JC, Pinheiro EM, Muri EM,
Figure 2. Important interactions measure of 4h docked in the active site of ERα Figure 2. Important interactions measure of 4h docked in the active site of ERα 
Bayanati M et al. / IJPR (2021), 20 (4): 229-237
Venturini Filho E, Loureiro LB, Freitas MCR,
Junior CMS, Fiorot RG and Carneiro JWM. 2H-1,
2, 3-Triazole-chalcones as novel cytotoxic agents
against prostate cancer. Bioorg. Med. Chem. Lett.
(2020) 30: 127454.
(8) Mahapatra DK, Bharti SK and Asati V. Anticancer
chalcones: Structural and molecular target
perspectives. Eur. J. Med. Chem. (2015) 98: 69-
(9) Won S-J, Liu C-T, Tsao L-T, Weng J-R, Ko H-H, Wang
J-P and Lin C-N. Synthetic chalcones as potential
anti-inflammatory and cancer chemopreventive
agents. Eur. J. Med. Chem. (2005) 40: 103-12.
(10) Boumendjel A, Ronot X and Boutonnat J. Chalcones
derivatives acting as cell cycle blockers: potential
anti cancer drugs? Curr. Drug Targets. (2009) 10:
(11) Yuan C and Smith WL. A cyclooxygenase-2-
dependent prostaglandin E2 biosynthetic system
in the Golgi apparatus. J. Biol. Chem. (2015) 290:
(12) Allameh A, Vansoun EY and Zarghi A. Role
of glutathione conjugation in protection of
weanling rat liver against acetaminophen-induced
hepatotoxicity. Mech. Ageing Dev. (1997) 95: 71-9.
(13) Mirian M, Zarghi A, Sadeghi S, Tabaraki P,
Tavallaee M, Dadrass O and Sadeghi-aliabadi H.
Synthesis and cytotoxic evaluation of some novel
sulfonamidederivativesagainst a few human cancer
cells. Iran. J. Pharm. Res. (2011) 10: 741-8.
(14) Mahboubi Rabbani SMI and Zarghi A. Selective
COX-2 inhibitors as anticancer agents: a patent
review (2014-2018). Expert Opin. Ther. Pat.
(2019) 29: 407-27.
(15) Borer JS and Simon LS. Cardiovascular and
gastrointestinal effects of COX-2 inhibitors and
NSAIDs: achieving a balance. Arthritis Res. Ther.
(2005) 7: S14.
(16) Sivakumar P, Prabhakar P and Doble M. Synthesis,
antioxidant evaluation, and quantitative structure–
activity relationship studies of chalcones. Med.
Chem. Res. (2011) 20: 482-92.
(17) Doan TN and Tran DT. Synthesis, antioxidant
and antimicrobial activities of a novel series
of chalcones, pyrazolic chalcones, and allylic
chalcones. J. Pharm. Pharmacol. (2011) 2: 282.
(18) Loa J, Chow P and Zhang K. Studies of structure–
activity relationship on plant polyphenol-induced
suppression of human liver cancer cells. Cancer
Chemother. Pharmacol. (2009) 63: 1007-16.
(19) Liu Z, Tang L, Zou P, Zhang Y, Wang Z, Fang Q,
Jiang L, Chen G, Xu Z and Zhang H. Synthesis and
biological evaluation of allylated and prenylated
mono-carbonyl analogs of curcumin as antiinflammatory agents. Eur. J. Med. Chem. (2014)
74: 671-82.
(20) Bano S, Javed K, Ahmad S, Rathish I, Singh S,
Chaitanya M, Arunasree K and Alam M. Synthesis
of some novel chalcones, flavanones and flavones
and evaluation of their anti-inflammatory activity.
Eur. J. Med. Chem. (2013) 65: 51-9.
(21) Mirzaei S, Hadizadeh F, Eisvand F, Mosaffa F and
Ghodsi R. Synthesis, structure-activity relationship
and molecular docking studies of novel quinolinechalcone hybrids as potential anticancer agents
and tubulin inhibitors. J. Mol. Struct. (2020) 1202:
(22) Severi F, Benvenuti S, Costantino L, Vampa G,
Melegari M and Antolini L. Synthesis and activity
of a new series of chalcones as aldose reductase
inhibitors. Eur. J. Med. Chem. (1998) 33: 859-66.
(23) Zarghi A, Zebardast T, Hakimion F, Shirazi FH,
Rao PP and Knaus EE. Synthesis and biological
evaluation of 1, 3-diphenylprop-2-en-1-ones
possessing a methanesulfonamido or an azido
pharmacophore as cyclooxygenase-1/-2 inhibitors.
Bioorg. Med. Chem. (2006) 14: 7044-50.
(24) Zarghi A, Arfaee S, Rao PP and Knaus EE.
Design, synthesis, and biological evaluation of
1, 3-diarylprop-2-en-1-ones: A novel class of
cyclooxygenase-2 inhibitors. Bioorg. Med. Chem.
(2006) 14: 2600-5.
(25) Zarghi A and Arfaei S. Selective COX-2 inhibitors:
a review of their structure-activity relationships.
Iran. J. Pharm. Res. (2011) 10: 655-83.
(26) Edwards DN, Ngwa VM, Raybuck AL, Wang
S, Hwang Y, Kim LC, Cho SH, Paik Y, Wang Q
and Zhang S. Selective glutamine metabolism
inhibition in tumor cells improves anti-tumor
T lymphocyte activity in triple-negative breast
cancer. J. Clin. Investig. (2020) 15: 140100.
(27) Rossouw JE, Anderson GL, Prentice RL, LaCroix
AZ, Kooperberg C, Stefanick ML, Jackson RD,
Beresford SA, Howard BV and Johnson KC. Risks
and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results from the
Women’s Health Initiative randomized controlled
trial. J. Am. Med. Assoc. (2002) 288: 321-33.
(28) Farzaneh S and Zarghi A. Estrogen receptor ligands:
a review (2013–2015). Scientia pharmaceutica.
(2016) 84: 409-27.
(29) Kakhki S, Shahosseini S and Zarghi A. Design
and synthesis of pyrrolo [2, 1-a] isoquinolinebased derivatives as new cytotoxic agents. Iran. J.
Pharm. Res. (2016) 15: 743-51.
(30) Kakhki S, Shahosseini S and Zarghi A. Design,
synthesis and cytotoxicity evaluation of new
2-aryl-5, 6-dihydropyrrolo [2, 1-a] isoquinoline 
1,3-Diphenyl-3-(phenylthio)propan-1-ones as Cytotoxic Agents
derivatives as topoisomerase inhibitors. Iran. J.
Pharm. Res. (2014) 13: 71-7.
(31) Ghodsi R, Azizi E, Grazia Ferlin M, Pezzi V
and Zarghi A. Design, synthesis and biological
evaluation of 4-(imidazolylmethyl)-2-arylquinoline derivatives as aromatase inhibitors and
anti-breast cancer agents. Lett. Drug. Des. Discov.
(2016) 13: 89-97.
(32) Aghvami M, Pourahmad J, Zarghi A, Eshghi P, Zarei
MH, Farzaneh S and Sattari F. A newly synthetized
ferrocenyl derivative selectively induces apoptosis
in all lymphocytes through mitochondrial estrogen
receptors. Curr. Med. Chem.: Anti-Cancer Agents.
(2018) 18: 1032-43.
(33) Zarghi A, Hajimahdi Z, Mohebbi S, Rashidi H,
Mozaffari S, Sarraf S, Faizi M, Tabatabaee SA
and Shafiee A. Design and synthesis of new
2-substituted-5-[2-(2-halobenzyloxy) phenyl]-1,
3, 4-oxadiazoles as anticonvulsant agents. Chem.
Pharm. Bull. (Tokyo) (2008) 56: 509-12