Elsevier

Bioorganic Chemistry

Volume 101, August 2020, 104014
Bioorganic Chemistry

Antimicrobial and antiproliferative activity studies of some new quinoline-3-carbaldehyde hydrazone derivatives

https://doi.org/10.1016/j.bioorg.2020.104014Get rights and content

Highlights

  • 22 piece quinoline-3-carbaldehyde hydrazone derivatives were synthesized.

  • Antimicrobial effects were evaluated against some bacteria and fungus.

  • Antiproliferatif activity studies performed on A549 and MCF- cell line.

  • Molecular docking studies of all compounds were performed.

  • DFT/B3LYP theory study of compounds were carried out with 6-311G (d,p) base set.

Abstract

In this study, a total of 22 piece quinoline-3-carbaldehyde hydrazone derivative compounds were designed and synthesized, 2 of which were not original, their antimicrobial activities were determined with microdilution method and their in vitro cytotoxic effect was investigated in MCF-7 and A549 cells by MTT assay. When the activity results are examined, although the antimicrobial effects of quinoline derivatives, in general, are weaker than standard drugs; 3q5 and 3q6 against MRSA showed promising activity with MIC:16 µg/ml compared to reference drugs. Compounds generally showed weaker cytotoxic activity on the A549 and MCF-7 cell line. 3q12, 3q17 and 3q22 at 100 µM reduced cell viability to 59.28%, 76.24% and 72.92% on A549 cells, respectively. Compound 3q6, one of the most effective compounds against MRSA, formed a 2.10 Å long hydrogen bond between the quinoline nitrogen and ARG132 in the DNA topoisomerase IV active site (PDB: 3FV5). Theoretical ADME profiles of all compounds comply with Lipinski and other limiting rules. In addition, MEP analysis of 3q6, geometric optimization and molecular reactivity analysis were calculated with the 6-311G (d,p) base set DFT/B3LYP theory, and ΔE = ELUMO-EHOMO, which is a measure of the stable structure of the molecule, was calculated as 0.13377 for 3q6 and had the most stable electronic structure among all compounds.

Introduction

Infectious diseases caused by bacteria and fungi are still one of the most important threats to public health, despite huge advances in pharmaceutical and medicinal chemistry. Although there are many antimicrobial drugs used and effective in the clinic, it becomes less effective in a short time because microorganisms rapidly develop resistance to these drugs [1]. In particular, widespread drug resistance such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF) are among the most important problems of our age [2], [3]. In S. aureus, methicillin resistance is realized by “Penicillin Binding Protein” (PBP), which is a different mechanism than penicillinase (beta-lactamase) production. PBPs are responsible for carrying and attaching their peptidoglycan precursors to the cell wall being constructed, and a different PBP called PBP2 or PBP2a is synthesized in MRSAs. Unlike other PBPs, PBP2/2a shows a low affinity for antibiotics in beta-lactam structure [4]. Today, 700.000 people die every year all over the world only due to antibiotic-resistant bacterial infectious diseases. If new remedies cannot be developed in the prevention or treatment of this type of infectious disease, the number of people who die each year due to the infectious diseases in question is estimated to reach 10 million people worldwide by 2050 [5]. Therefore, the discovery of new and more effective antimicrobial drugs is very important, and many studies have made efforts to design new agents.

Cancer, another important disease, is a complex disease that manifests itself as a result of uncontrolled proliferation of cells as a result of environmental and genetic factors, showing spread to surrounding organs and tissues and thus causing secondary tumors by metastasis [6]. It is predicted that by 2030, 21.7 million new cases will occur and 13 million people will die from cancer due to the increase in the world population and average life expectancy [7]. Cytotoxic drugs slow down cell division by slowing down the synthesis of DNA, thus causing the growth rate of cancer cells to be lower than the death rate. As cancerous cells multiply much faster than healthy cells, any effect that will slow this proliferation is of great importance [8], [9], [10]. For this reason, a lot of research is being done to discover and develop cytotoxic drugs.

Many natural and synthetic compound have quinoline rings that exhibit a wide range of pharmacological properties [11], [12]; such as antimalarial [13], anti-rheumatoid arthritis [14], anti SARS-Cov-2 [15], antimicrobial [16], antiparasitic [17], antituberculosis [18], antidiabetic [19], anti-inflammatory [20], antioxidant [21], anticancer [22], antiarthritic [23] and analgesic [24] (Some drug molecules are shown in Fig. 1). Quinolines are antibacterial agents that act by inhibiting enzymes called topoisomerase II (DNA gyrase) and topoisomerase IV, which are involved in DNA replication, transcription and recombination in bacterial cells [25], [26], [27]. The inhibition of this enzyme is an important target for the discovery and development of new antibacterial drugs, as it prevents them from multiplying by dividing bacteria. In recent studies, antimicrobial and anticancer activity of quinoline ring-bearing compounds against existing bacteria has been investigated and some derivatives have been reported to be more effective than standard drugs.

Based on these data, in this study, some new compounds whose general structure was quinoline-3-carbaldehyde hydrazone were designed (Fig. 2), synthesized and their structures were illuminated by 1H NMR and 13C NMR spectroscopy and HRMS. In addition, antimicrobial effects of all compounds against various Gram (+), Gram (−) bacteria and fungi and in vitro cytotoxic effects on MCF-7 and A549 cell lines were determined. Estimation of ADME profiles of all compounds was calculated and molecular docking studies were performed. Also, molecular electrostatic potential (MEP) analysis, geometric optimization and molecular reactivity analysis (HOMO-LUMO) of 3q6 was calculated 6-311G (d, p) base set and the DFT/B3LYP theory, and the results were displayed.

Section snippets

Chemistry

Chemicals and solvents were purchased from Sigma-Aldrich, Merck, Riedel de Haen and Fluka and used without further purification. For the TLC, 60 F254 coated aluminum plates (Merck) were used and the UV light at 254 and 366 nm wavelength was used for the detection of stains. The TLC mobile phase composition used in each step was demonstrated in the respective method. Melting points were determined by Electrothermal 9100 (Varian, Palo Alto, CA) instrument and the results were given without

Chemistry

In this study, a new series of quinoline-3-carbaldehyde hydrazone derivative (3q1-3q22) was synthesized using the procedure given in the literature as shown in Scheme 1 [49]. All compounds are original except for 3q1 and 3q15. Their structures were confirmed by HRMS and 1H NMR and 13C NMR spectroscopy. Melting points of the synthesized structures were determined and uncorrected. Physical and spectral data of the synthesized compounds were reported in Chapter 2 (see also Supplementary

Conclusion

In this study, a series of quinolone-3-carbaldehyde hydrazone derivatives that we hope may be a new antimicrobial and cytotoxic agents were synthesized and their antimicrobial and cytotoxic activities were determined. While the compounds show a moderate activity against the structures and isolates examined; In particular, 3q5 and 3q6 against MRSA showed activity comparable to reference drugs. Compounds has no significant cytotoxic activity on MCF-7 and A549 cell line. Molecular docking studies

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

This work has been supported by Erciyes University Scientific Research Projects Coordination Unit with research projects TSA-2019-9442 and THD-2019-8849. NMR analysis of the compounds was performed by Erciyes University Technology and Research Center (TAUM) and HRMS analysis was performed by Bilkent University National Nanotechnology Research Center (UNAM).

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