engleski

Green Synthesis of Novel Benzoxazole Derivatives with Antitumoral Potential

The low survivability associated with lung cancer is a clear indication of the need for more effective drugs, particularly those that act on targets or pathways of greater relevance to the disease [1]. Benzoxazole is a privileged scaffold that represents a promising class of heterocycles and the backbone of many bioactive compounds and possess antitumor activity. In recent times, much progress has been made to develop benzoxazole derivatives into clinical candidates. The growing importance of benzoxazole derivatives as therapetuic anticancer agents has fuelled the development of benzoxazole based drugs. Trends in environmentally friendly and sustainable process development during past years are abridged involving the use of alternative organic synthesis including mechanochemistry, ultrasound or microwave irradiation and greener organic solvents. Conventional organic solvents are not only hazardous to the environment but also show acute and chronic toxicity, carcinogenicity, ecological toxicity and nonbiodegradability. Deep eutectic solvents (DES) have emerged as an interesting type of ionic liquid and have proven useful as an environmentally benign sustainable alternative to the conventional organic solvents in synthetic chemistry to increase the efficiency of organic transformations. Herein we present the synthesis of novel benzoxazole derivatives substituted at position 2 with disubstituted phenyl moiety by using mechanochemical and microwave reactions as well as application of different DES, and their cytostatic and antibacterial evaluations. 4-O-alkylated benzaldehydes, as key precursors for the synthesis of target benzoxazole derivatives, were prepared in DES (ChCl/glycerol) with K2CO3 as a base and subsequent mechanochemical reactions with 2-aminophenole were afforded corresponding Schiff bases. Microwave assisted cyclization reaction of Schiff bases with NaCN in ethanol gave target 2-(3, 4-disubstitutedphenyl)benzoxazole derivatives. The novel benzoxazole derivatives were evaluated against tumor cell lines (Capan-1, NCI- H460, DND-41, K- 562, Z-138) and on the growth of grampositive and gram-negative bacterial strains. Of all tested compounds benzoxazole derivatives with 4- (N, N-diethylethoxy)phenyl substituent showed the most pronounced activity against lung carcinoma cell lines (NCI-H460, IC50=0.4-1.4 μM), while 2-(4-(2- morpholinoethoxy)phenyl)benzoxazole showed considerable activities against pancreatic adenocarcinoma (Capan-1, IC50=2 μM), colorectal carcinoma (HCT-116, IC50=5.7 μM), glioblastoma (Ln229, IC50=2.2 μM) and lung carcionoma (NCI-H460, IC50=1.3 μM) cell lines.

green synthesis, antitumor activity, benzoxazoles, antimicrobial activity

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