Synthesis of novel Schiff bases and azol-β-lactam derivatives starting from morpholine and thiomorpholine and investigation of their antitubercular, antiurease activity, acethylcolinesterase inhibition effect and antioxidant capacity

https://doi.org/10.1016/j.bioorg.2019.102928Get rights and content

Abstract

In this study, new Schiff bases and β-lactam derivatives containing morpholine and thio morpholine nuclei were synthesized. Antimicrobial, antioxidant, antimicrobial and antioxidant properties of all synthesized compounds were investigated and highly effective products were obtained. In this context, new effective structures were introduced to the literature.

Introduction

The azetidine-2-one ring also known as β-lactam is a four-membered ring that is a class of important bioactive compound. Penicillin, Klavam, Penem, Carbapenem, Cephalosporin, Oxasefem, Izosefem and Izooxasefem are known drugs and contain a β-lactam ring in their molecular structure and are also known β-lactam antibiotics [1]. Recent clinical studies on bacterial infections and the discovery of β-lactam chemistry and biology have led to important advances [2], [3], [4], [5], [6], [7].

Tuberculosis (TB) is a devastating disease caused by poverty, and according to World Health Organization (WHO) 2016 data, 95% of 1.4 million people infected with TB in developing countries are killed and 10 million children are orphaned as a result [8]. Moreover, the emergence of a drug-resistant microorganism with the lethal combination of TB, particularly multidrug-resistant TB and HIV-1 infection, makes this disease one of the greatest global health problems of our time [9]. Therefore, new antitubercular drugs and drug targets are urgently needed. The need to identify, detect and synthesize agents that will be effective against rapid action and intracellular Mycobacterium tuberculosis by reducing treatment time is of great importance nowadays.

Azole rings are heterocyclic compounds containing nitrogen atoms and constitute a class of compounds with a broad biological effect. Some of these effects are anti-bacterial, anti-malarial, anti-fungal, anti-HIV, anti-inflammatory and anti-TB [8], [10]. The antibacterial resistance of pathogenic microorganisms against the drugs used clinically is developing very rapidly all over the world and this threatens public health. As a result of the low number of antimicrobial compounds used and the rapid development of bacterial resistance, the synthesis of new antimicrobial compounds has become an attractive subject for organic medicinal chemists. In last decades in order to obtain antitumor drugs, many compounds with different structure have been synthesized. These include complex molecules containing an azole ring as well as structurally simple azole derivatives [8], [11], [12], [13], [14]. Some examples of azole drugs are Trazodone, Ribavirin, Rizatriptan, Vorazol, Alprazolam and Nefazonon that contain a 1,2,4-triazole ring in their molecular structure [15], [16], [17], [18], [19]. Cefazedone and Sevazolin, which are cephalosporin-derived antibiotics, are important drugs containing 1,3,4-thiadiazole ring [20]. Acetozolamide and methazolamide, which are used in the treatment of glaucoma and epilepsy diseases, are another important molecule in the structure of thiadiazole ring [21], [22]. Also, Raltegravir (HIV-infections), Furamizol (antibacterial), Zibotentan (anticancer candidate drug) and Tiodazosin (antihypertensive agent) are an important drug or drug candidate containing oxadiazole nucleus [23], [24].

In the point of this information, in this study, the effects of antimicrobial, antioxidant properties, antiureas and acetylcholinesterase effects were investigated by the synthesis of new hybrid compounds by combining different active groups in a single molecule.

Section snippets

Chemistry

In this study there are two starting material thiomorpholine and morpholine. Separately thio/morpholine was reacted with ethyl bromoacetate and hydrazinhydrate to afford the corresponding asetohydrazide compounds 2a and 2b and then they were converted to 1,3,4-oxadiazole ring (3a/3b) separately with carbondisulfide in basic media. The carbonyl group of compounds 2a/2b disappeared and the Cdouble bondS bond was occurred at 1295 cm−1 in IR spectrum. And in 1H NMR spectrum the 1,3,4-oxadiazole single bondNH was

Conclusion

In summary we report here the synthesis of some new kind of Schiff base and of β-lactam derivatives starting from morpholine and thiomorpholine. And all the newly synthesized compounds were screened for their antituberculosis and anti-Urease activity, acetylcholinesterase inhibition effects and antioxidant capacity. Among them compounds 3b, 7d and 7e showed very good antituberculosis activity, compounds 6a, 7b, 7e, 9b, 9c, 10e and 10f showed Acetylcholinesterase Inhibition effect, compounds 3b,

Chemistry

All the chemicals were purchased from FlukaChemie AG Buchs (Switzerland) and used without further purification. Melting points of the synthesized compounds were determined in open capillaries on a Büchi B-540 melting point apparatus and are uncorrected. Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F254 aluminium sheets. The mobile phase was ethyl acetate:diethyl ether (1:2), and detection was made using UV light. FT-IR spectra were recorded using a Perkin Elmer

Conflict of interests

The authors declare that there is no conflict of interests regarding the publication of the paper.

Acknowledgments

This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) [grant numbers 115Z770].

References (30)

  • I.F.F. Benzie et al.

    Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration

    Methods Enzymol.

    (1999)
  • J.A. Rad et al.

    Synthesis of some novel indeno[1,2-b]quinoxalinspiro-β-lactam conjugates

    Tetrahedron

    (2017)
  • F. Von Nussbaum et al.

    Antibacterial natural products in medicinal chemistry-exodus or revival

    Angew. Chem Int. Ed.

    (2006)
  • F. Broccolo et al.

    Design, synthesis, and biological evaluation of 4-Alkyliden-beta Lactams: new products with promising antibiotic activity against resistant bacteria

    J. Med. Chem.

    (2006)
  • A.K. Havle et al.

    Bioorg. Med. Chem. Lett.

    (2007)
  • Cited by (36)

    • Synthesis of hydrazides of heterocyclic amines and their antimicrobial and spasmolytic activity: Synthesis of hydrazides of heterocyclic amines

      2022, Saudi Pharmaceutical Journal
      Citation Excerpt :

      The reports describe antimicrobial, antioxidant, antimicrobial and antioxidant activity of various morpholine derivatives being attributed to Schiff bases and β-lactam functionalities. ( Cebeci, Bayrak et al. 2019) It was reported that glycine hydrazides derivatives possess high spasmolytic activity, transient hypotension and might have effects on the central nervous system and revealed low toxicity with LD50 more than 1000 mg/kg (Rips, Derappe et al. 1965). A detailed methods of synthesis of thiosemicarbazides of N-piperidinylacetic acid was described previously as well as and strategies of its cyclisation to bisheterocyclic compounds (Misra, Dwivedi et al. 1978, Dyusebaeva and Kalugin 2015).

    View all citing articles on Scopus
    View full text