Synthesis and Cytotoxicity of New Mannich Bases of 6-[3-(3,4,5-Trimetoxyphenyl)-2- propenoyl]-2(3H)-Benzoxazolone

Abstract

Background: Chemotherapy is one of the mainstays of cancer treatment, despite the serious side effects of the clinically available anticancer drugs. In recent years increasing attention has been directed towards novel agents with improved efficacy and selectivity. Compounds with chalcone backbone have been reported to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic, antioxidant, etc. It was reported that aminomethylation of hydroxy chalcones to the corresponding Mannich bases increased their cytotoxicity. In this context, our interest has been focused on the design and synthesis of the so-called multi-target molecules, containing two or more pharmacophore fragments. Methods: A series of Mannich bases were synthesized by the reaction between 6-[3-(3,4,5- trimethoxyphenyl)-2-propenoyl]-2(3Н)-benzoxazolone, formaldehyde, and a secondary amine. The structures of the compounds were confirmed by elemental analysis, IR and NMR spectra. The new Mannich bases were evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines, including BV-173, SKW-3, K-562, HL-60, HD-MY-Z and MDA-MB-231. The effects of selected compounds on the cellular levels of glutathione (GSH) were determined. Results: The new compounds 4a-e exhibited concentration-dependent cytotoxic effects at micromolar concentrations in MTT-dye reduction assay against a panel of human tumor cell lines, similar to those of starting chalcone 3. The tested agents led to concentration - dependent depletion of cellular GSH levels, whereby the effects of the chalcone prototype 3 and its Mannich base-derivatives were comparable. Conclusion: The highest chemosensitivity to the tested compounds was observed in BV- 173followed by SKW-3 and HL-60 cell lines.

Anticancer Activity of Mannich Bases: A Review of Recent Literature

“…Piperidine Mannich bases 175 (Figure 21) of phthalimide was found to have IC 50 =110.113 μg/mL (approximately 0.45 mM) against HeLa cells [170] . Cytotoxicity of new Mannich bases 176 (Figure 21) of 6‐[3‐(3,4,5‐trimetoxyphenyl)‐2‐propenoyl]‐2( 3H )‐benzoxazolone towards a panel of cancer cell lines (BV‐173, SKW‐3, K‐562, HL‐60, HD‐MY−Z and MDA−B‐231) was generally below 10 μM and comparable to the activity of the initial substrate [171] . Also, from an evaluation of a library of Mannich bases of 3,4‐dihydro‐3‐methyl‐2( 1H )‐quinazolinone against Hep‐G2 liver cancer cells, compound 177 (NR 2 =N(C 2 H 5 ) 2 ) (Figure 21) emerged as the most potent compound with IC 50 of 6.48 μM after 72 h [172] .…”

“…[170] Cytotoxicity of new Mannich bases 176 (Figure 21) of 6-[3-(3,4,5-trimetoxyphenyl)-2propenoyl]-2(3H)-benzoxazolone towards a panel of cancer cell lines (BV-173, SKW-3, K-562, HL-60, HD-MYÀ Z and MDAÀ B-231) was generally below 10 μM and comparable to the activity of the initial substrate. [171] Also, from an evaluation of a library of Mannich bases of 3,4-dihydro-3-methyl-2(1H)-quinazolinone against Hep-G2 liver cancer cells, compound 177 (NR 2 = N(C 2 H 5 ) 2 ) (Figure 21) emerged as the most potent compound with IC 50 of 6.48 μM after 72 h. [172] In a series of indole N-Mannich bases 178 (Figure 21), only one compound (R = 4-HOC 6 H 4 ) showed potent action against HepG2, MCF-7 and HeLa cell lines (IC 50 values below 1 μM). [173] A single example in recent literature deals with aminomethylation of an oxadiazolone with a view to prepare potential anticancer agents.…”

Anticancer Activity of Chalcones and Its Derivatives: Review and In Silico Studies

“…Petrov and collaborators (2020) [ 62 ], carried out the synthesis of benzoxazolone derivatives to evaluate the inhibition of human leukemia strains. Compound ( 52 ) ( Figure 9 ) demonstrated dose-dependent effect of cytotoxicity, being more sensitive for BV-173, SKW-3 and HL-60 strains (IC50 = 3.6–10.7 μM).…”

“…The results showed that 2-((E)-4-((E)-3-oxo-3-(p-tolyl)prop-1-en-1yl)benzylidene)hydrazine-1-carboximidamide (58) (Figure 10) was the most potent compound, with IC50 values of 7.17 µM and 3.05 µM of in vitro anti-proliferative activity against HepG2 human hepatocarcinoma cells and SMMC-7721 cells, respectively. This re- Petrov and collaborators (2020) [62], carried out the synthesis of benzoxazolone derivatives to evaluate the inhibition of human leukemia strains. Compound (52) (Figure 9) demonstrated dose-dependent effect of cytotoxicity, being more sensitive for BV-173, SKW-3 and HL-60 strains (IC50 = 3.6-10.7 µM).…”