Design, synthesis, and molecular docking study of some 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff bases as potential Eg5 inhibitory agents
Graphical abstract
Introduction
Cancer is the second leading cause of death throughout the world and accounts for more than 18 million new cases and 9.6 million deaths in 2018. Among them lung, prostate, colorectal, stomach and liver cancer are the most common types of cancer in men. Whereas Brest, cervical and thyroid cancers are most common among women [1].
Among the current management approaches like immunotherapy, hormonal therapy, targeted therapy, radiotherapy and surgery for cancer prevention and treatment, chemotherapy stands as the most common therapeutic approach, which involves application of active pharmaceutical ingredients [2]. Toxicity to healthy cells, adverse effect and resistance are most common for existing therapeutic agents [3]. Thus, there is need for new therapeutic compounds for better management of cancer treatment.
Quinoline heterocyclic systems are recognized as a promising molecule under alkaloid class of natural products and exist in many pharmacological active plants, [4] the quinoline is a well-known moiety present in a various active pharmaceutical compounds with relevant broad spectrum of pharmacological properties. Presently, quinoline scaffolds are available as antitubercular and antibacterial (bedaquiline, ciprofloxacin, ofloxacin, gatifloxacin, sparfloxacin), antiplasmodial and antimalarial (chloroquine, piperaquin, amodiaquine, meflaquin), anticancer (pelitinib, dactolisib) in addition, recently approved cabozantinib (4,6,7-trisubstited quinoline analogue) for the management for advanced kidney, liver, and progressive metastatic medullary thyroid cancer, and RXDX-106, TAS-115, AMG-458, Feretinib and Ningetinib are in developing in various phases of clinical trials [5], [6], [7]. Hybridization of quinoline and hetero aromatic compounds shows excellent management therapy for the management of cancer biology. During the literature review we observed that7-chloro-4-aminoquinoline ring bearing compounds display broad range of pharmacological activity. Shobeiri et al. have reported that, 2-aryl-trimethoxyquinoline hybrids and tested for cytotoxic activity out of which (5,6,7-trimethoxy-2-(3,4,5-trimethoxyphenyl)quinolin-4-yl) methanol has demonstrated promising activity [8]. Lee et al have reported that 2-(Phenylsulfonyl)quinoline N-hydroxyacrylamides posess promising activity on A549 cell lines with IC-50 value of 0.27 mM [9]. Elbadawi et al, have synthesized 4-alkoxy-2-aryl-6,7-dimethoxyquinolines as a new class of topoisomerase I inhibitors and reported that the compound 6,7-Dimethoxy-4-(3-(pyrrolidin-1-yl)propoxy)-2-(4-(trifluoromethyl) phenyl)quinoline showed promising anticancer activity [10].
Apart from these, quinolines were promising Pim-1 kinase, potential epidermal growth factor receptor (EGFR), Vascular endothelial growth factor receptor (VEGFR), c-Mat kinase and c-Kit inhibitors [11] (Fig. 1).
Spindle-Targeting agents play important role in management of various types of cancer by affecting proteins such as Eg5 (Kinesin spindle protein). According literature [12] Kinesin spindle protein is a promising biological target for potential antitumor efficacy, when compared to other microtubule targets, furthermore, some of the Kinesin spindle protein inhibitors exhibited promising efficacy in tumor cell resistant to paclitaxel [13], [14]. On the other hand, quinoline-benzohydrazide schiff bases compounds showed potent anti-proliferative activity against hepatocellular carcinoma cell lines; In addition, benzohydrazide schiff bases showed significant biological activities like Enoyl ACP-reductase inhibitors, Anti-Tubercular, Anticancer, acetylcholinesterase and butyrylcholinesterase inhibitors, antimicrobial, anti-inflammatory and anticonvulsant activities [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25].
On the bases of above facts, Kinesin spindle protein is an significant target and previously published data on quinoline analogues like tetrahydroquinoline, 1,4-dihydroquinolin-4-ones showed promising inhibitors of Kinesin spindle protein [26], [27], [28] Herein we presented design and synthesis of 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff bases molecules as a potent Kinesin spindle protein inhibitors.
Section snippets
Chemistry
7-chloro-N-phenylquinolin-4-amine based Schiff bases (6a-r) were prepared according to the reaction order presented in Scheme 1. The 4,7-disubstituted intermediate quinolin (3) was synthesized by reaction between methyl anthranilate and 4, 7-dichloroquinoline in presence of Hydrochloric acid (HCl). Quinoline substituted benzo hydrazide compound (4) was obtained reaction between methyl ester compound (3) and hydrazine hydrate in presence of methanol. The target
Conclusions
In conclusions, a series of 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff bases molecules were designed, synthesized, characterized and evaluated as a mitotic kinesin spindle protein inhibitors. Compounds like 6b, 6h, 6j, 6l, 6p, 6q and 6r were exhibited comparable Eg5 inhibitory activity. Compound 6b was the most influenced ligand compared to standard radical scavenger ascorbic acid. Furthermore, selected scaffold caused low cytotoxicity in Normal Mouse Fibroblast-L929 cells. The
Synthesis of methyl 2-((7-chloroquinolin-4-yl) amino) benzoate (3)
Methyl 2-((7-chloroquinolin-4-yl) amino) benzoate was prepared by using modified procedure of previous literatures [40], [41], [42], [43], equimolar quantity of 4, 7 dichloro quinoline and methyl anthranilate (0.01 mol) in 2 N HCl solution. Reaction mixture is refluxed for 6–7 h. The reaction was monitored by thin-layer chromatography (TLC) for completion. Reaction mixture was cooled, neutralized with base to form crude product, followed by recrystallization using ethanol to get off-white
Funding
No funding was obtained for this study.
CRediT authorship contribution statement
Rohini S. Kavalapure: Synthesis, characterization, Analytical work. Shankar G. Alegaon: Designed and outlined the study. U. Venkatasubramanian: Biological activities. Soundarya Priya A: Biological activities. Shriram D. Ranade: Biological activities. Pukar Khanal: Biological activities. Sanjay Mishra: Biological activities. Dhanashree Patil: Biological activities. Preeti S. Salve: Biological activities. Sunil S. Jalalpure: Biological activities.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Authors are grateful to Principal, KLE College of Pharmacy, Belagavi, for providing necessary facilities for the research. Authors are also grateful to NMR Research center, IISC, Bangalore, India, for providing the spectral data.
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