Synthesis, biological evaluation and in silico study of bis-thiourea derivatives as anticancer, antimalarial and antimicrobial agents
Two sets of bis-thioureas including a para series (8–14) and a meta series (4, 5, 15–19), were synthesized and evaluated for their anticancer, antimalarial and antimicrobial activities. Most of the synthesized bis-thioureas, except for analogs 8–11, displayed cytotoxicity against MOLT-3 cell line (IC50 = 1.55–32.32 µM). Derivatives 5, 14, 18 and 19 showed a broad spectrum of anticancer activity. Analogs (4, 5, 8, 13, 14, 18 and 19) exhibited higher inhibitory efficacy in HepG2 cells than the control drug, etoposide. Significantly, bis-trifluoromethyl analog 19 was the promising potent cytotoxic agent (IC50 = 1.50–18.82 µM) with the best safety index (1.64–20.60). Antimalarial activity results showed that trifluoromethyl derivative 18 was the most potent compound (IC50 = 1.92 µM, selective index = 6.86). Antimicrobial activity revealed that bis-thioureas 12, 18 and 19 exhibited selective activity against Gram-positive bacteria and fungi. Promisingly, the bis-trifluoromethyl derivative 19 was the most potent compound in the series and displayed higher potency, against most of the Gram-positive bacteria and fungi, than that of ampicillin, the reference drug. Among the tested strains of microorganisms, compound 19 inhibited the growth of Staphylococcus epidermidis ATCC 12228 and Micrococcus luteus ATCC 10240 with the lowest MIC of 1.47 µM. The findings demonstrated that trifluoromethyl group plays a crucial role in their biological activities. Furthermore, the molecular docking was performed to reveal possible binding modes of the compounds against target proteins.
KeywordsThiourea Trifluoromethyl group Anticancer activity Antimalarial activity Antimicrobial activity Molecular docking
This project is financially supported by Srinakharinwirot University (grant no. 497/2559). Great supports from the office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative are appreciated. We are also indebted to Chulabhorn Research Institute for recording mass spectra and bioactivity testing.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Basarab GS, Manchester JI, Bist S, Boriack-Sjodin PA, Dangel B, Illingworth R, Sherer BA, Sriram S, Uria-Nickelsen M, Eakin AE (2013) Fragment-to-hit-to-lead discovery of a novel pyridylurea scaffold of ATP competitive dual targeting type II topoisomerase inhibiting antibacterial agents. J Med Chem 56:8712–8735CrossRefPubMedGoogle Scholar
- Bielenica A, Stefańska J, Stępień K, Napiórkowska A, Augustynowicz-Kopeć E, Sanna G, Madeddu S, Boi S, Giliberti G, Wrzosek M, Struga M (2015) Synthesis, cytotoxicity and antimicrobial activity of thiourea derivatives incorporating 3-(trifluoromethyl)phenyl moiety. Eur J Med Chem 101:111–125CrossRefPubMedGoogle Scholar
- BioVia (2017) Discovery Studio Visualizer version 220.127.116.1150, San Diego, CAGoogle Scholar
- Charifson PS, Grillot A-L, Grossman TH, Parsons JD, Badia M, Bellon S, Deininger DD, Drumm JE, Gross CH, Le Tiran A, Liao Y, Mani N, Nicolau DP, Perola E, Ronkin S, Shannon D, Swenson LL, Tang Q, Tessier PR, Tian S-K, Trudeau M, Wang T, Wei Y, Zhang H, Stamos D (2008) Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships. J Med Chem 51:5243–5263CrossRefPubMedGoogle Scholar
- ChemAxon (2013) MarvinSketch Version 6.0, Budapest, Hungary. https://www.chemaxon.com/
- Dallakyan S (2013) PyRx Version 0.8. http://pyrx.scripps.eduGoogle Scholar
- Delano W (2002) PyMOL Release 0.99. DeLano Scientific LLC, Pala Alto, CAGoogle Scholar
- Doyle A, Griffiths JB (1997) Mammalian cell culture: essential techniques. Wiley, Chichester, UKGoogle Scholar
- Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T. Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross, J.B., Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski V.G, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Gaussian Inc., Wallingford, CTGoogle Scholar
- Grillot A-L, Le Tiran A, Shannon D, Krueger E, Liao Y, O’Dowd H, Tang Q, Ronkin S, Wang T, Waal N, Li P, Lauffer D, Sizensky E, Tanoury J, Perola E, Grossman TH, Doyle T, Hanzelka B, Jones S, Dixit V, Ewing N, Liao S, Boucher B, Jacobs M, Bennani Y, Charifson PS (2014) Second-generation antibacterial benzimidazole ureas: discovery of a preclinical candidate with reduced metabolic liability. J Med Chem 57:8792–8816CrossRefPubMedGoogle Scholar
- Nowotarski SL, Pachaiyappan B, Holshouser SL, Kutz CJ, Li Y, Huang Y, Sharma SK, Casero Jr RA, Woster PM (2015) Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures. Bioorg Med Chem 23:1601–1612CrossRefPubMedPubMedCentralGoogle Scholar
- Prachayasittikul S, Worachartcheewan A, Nantasenamat C, Chinworrungsee M, Sornsongkhram N, Ruchirawat S, Prachayasittikul V (2011) Synthesis and structure-activity relationship of 2-thiopyrimidine-4-one analogs as antimicrobial and anticancer agents. Eur J Med Chem 46:738–742CrossRefPubMedGoogle Scholar
- Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Mod 17:57–61Google Scholar
- Stefanska J, Nowicka G, Struga M, Szulczyk D, Koziol AE, Augustynowicz-Kopec E, Napiorkowska A, Bielenica A, Filipowski W, Filipowska A, Drzewiecka A, Giliberti G, Madeddu S, Boi S, Colla PL, Sanna G (2015) Antimicrobial and anti-biofilm activity of thiourea derivatives incorporating a 2-aminothiazole scaffold. Chem Pharm Bull 63:225–236CrossRefPubMedGoogle Scholar
- Vega-Pérez JM, Periñán I, Argandoña M, Vega-Holm M, Palo-Nieto C, Burgos-Morón E, López-Lázaro M, Vargas C, Nieto JJ, Iglesias-Guerra F (2012) Isoprenyl-thiourea and urea derivatives as new farnesyldiphosphate analogues: Synthesis and in vitro antimicrobial and cytotoxic activities. Eur J Med Chem 58:591–612CrossRefPubMedGoogle Scholar
- Verlinden BK, de Beer M, Pachaiyappan B, Besaans E, Andayi WA, Reader J, Niemand J, van Biljon R, Guy K, Egan T, Woster PM, Birkholtz L (2015) Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thioureaisosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites. Bioorg Med Chem 23:5131–5143CrossRefPubMedPubMedCentralGoogle Scholar