Design, synthesis and anticancer activity of Novel benzimidazole containing quinoline hybrids
Shashidhar Bharadwaj Srinivasa, Boja Poojary, Bhuvanesh Sukhlal Kalal, Usha Brahmavara, Dhanashri Vaishali, Anupam J. Das, Thobias Mwalingo Kalenga, Maruthibabu Paidikondala, S. Madan Kumar
Abstract
In this work we present the synthesis of benzimidazole-quinoline hybrids series (9a-c and 10a-f), characterized using spectroscopy studies (FT-IR, 1H NMR, and mass spectroscopy). The precursor for the hybrid compounds consists of two schemes: i. synthesis of substituted quinoline-4-carboxylic acids (3a-b) with various acetophenones. ii. The key intermediates (8a-c) were obtained initially from the benzimidazole-5-carboxylates (7a-c), were efficiently synthesized by ‘one pot’ nitro reductive cyclization reaction between ethyl 3-nitro-4-(substituted amino) benzoates 6a-c and 5-bromothiophene-2-carbaldehyde. iii. Further, the benzimidazole esters (7a-c) were converted into the corresponding hydrazides (8a-c) and then finally obtained the benzimidazole-quinoline hybrids series (9a-c and 10a-f). Compounds 7a and 7b were crystallized and their molecular structures were determined using a single crystal X-ray diffraction method. The resultant compounds from the synthesis were screened (in-silico and in-vitro) for their anti-cancer activities (human melanoma cell line (A375) and human breast cancer cell line (MDA-MB-231)). The p53 receptor protein was used for the molecular docking analysis and compound (name) 10b binds the target site with four hydrogen bonds (−6.25 Kcal/mol). The antioxidant activity revealed compounds 9a (IC50 = 604.8 μg/mL) and 9b (IC50 = 604.8 μg/mL 683.7 μg/mL) to exhibit the highest percentage of inhibition and lowest IC50 value. In addition, compounds 10a and 10b showed high scavenging activity. The compounds 9a (A375: IC50 = 34.7 ± 0.9 µg/mL and MDA-MB-231: IC50 = 20.4 ± 1.1 µg/mL), 10a (A375: IC50 = 19.6 ± 1.3 µg/mL and MDA-MB-231: IC50 = 37.0 ± 1.3 µg/mL) and 10b (A375: IC50 = 16.5 ± 1.5 µg/mL and MDA-MB-231: IC50 = 13.4 ± 1.5 µg/mL) showed the significant cytotoxicity against these human cancer cell lines (melanoma and breast cancer) and can be potential anti-cancer molecules.