Elsevier

Bioorganic Chemistry

Volume 116, November 2021, 105381
Bioorganic Chemistry

Design, synthesis, and molecular docking study of some 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff bases as potential Eg5 inhibitory agents

https://doi.org/10.1016/j.bioorg.2021.105381Get rights and content

Highlights

  • Synthesis of some 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff base heterocyclic compounds.

  • Out of eighteen compounds, seven compounds exhibited promising Eg5 inhibitory activity.

  • In vitro evaluation of the antioxidant (DPPH) assay and cytotoxicity (MTT) activities.

  • Molecular docking studies were carried out using Glide software.

  • ADME and Drug-likeness parameters are predicted using Qikprop software.

Abstract

In Search of new microtubule-targeting compounds and to identify a promising Eg5 inhibitory agents, a series of 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff bases molecules (6 a-r) were synthesized using appropriate synthetic method. The synthesized compounds were characterized by using FTIR, Proton NMR, Carbon NMR and mass spectral analysis. All eighteen compounds were evaluated for their Eg5 inhibitory activity. Among the evaluated compounds, only seven compounds are shown inhibitory activity. The results of Steady state ATPase reveled that compounds 6b, 6l and 6p exhibited promising inhibitory activity with IC50 Values of 2.720 ± 0.69, 2.676 ± 0.53 and 2.408 ± 0.46 respectively. Malachite Green Assay results reveled that 6q compound showed better inhibitory activity with IC50 Value of 0.095 ± 0.27. In vitro antioxidant capacity of the synthesized compounds was investigated. A molecular docking studies were performed to evaluate interaction in to binding site of kinesin spindle protein, these interaction influencing may support Eg5 inhibitory activity. The drug like parameters of the eighteen synthesized compounds were also computed using Qikprop software. In conclusion, some of 2-((7-chloroquinolin-4-yl) amino) benzohydrazide Schiff base compounds represent promising drug like agents for discovery of effective anticancer molecules.

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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