Synthesis, characterization, and antimicrobial evaluation of novel spiropiperidones

Introduction

Many heterocyclic compounds bearing a piperidine skeleton show pharmacological activity and are widely distributed in nature [1–3]. Among these heterocycles, spiropiperidines have been identified as privileged structures in medicinal chemistry and have attracted increasing interest in the past few years. The most recent reports are representative of their wide range of biological activities as components of new stearoyl CoA desaturase 1(SCD-1) inhibitors, nociceptin receptor ligands, chemokine receptor type 5 (CCR5) antagonists, neuropeptide Y (NPYY) receptor antagonists, calcitonin gene-related peptide (CGRP), receptor antagonists, tryptase inhibitors, prostaglandin d2 (PGD2) receptor antagonists, and checkpoint (ChK1) kinase inhibitors. Piperidones were reported to possess analgesic, anti-inflammatory, central nervous system, local anesthetic, anticancer, and antimicrobial activity [4, 5].

The objective of the present study is to develop a novel cluster of spiro derivatives of N-methyl-4-piperidones with better pharmacological properties than the reference drugs gentamicin and fluconazole. Literature survey revealed chloro, methoxy, and nitro functional groups are important functionalities in medicinal chemistry [6]. In particular, the chloro substitution of piperidone derivatives increases the antibacterial potency, and the compounds substituted with a methoxy group show better antifungal activity [7]. Several studies have pointed out the major role of lipophilicity in antimicrobial activity [8, 9], and in particular, it has been suggested that the mode of action of piperidone derivatives with antibacterial activity involves an unspecific interaction, which is related to the hydrophobic character of the molecules on protein thiol groups [10–13]. In particular, the increased activity of spiro piperidone derivatives can be explained on the basis of that compounds have better fit at the receptor site and can be transformed into more effective compounds with antimicrobial activity point of view. It was therefore thought to synthesize some novel spiro derivatives of piperidone bearing methoxy and chloro and nitro groups to produce compounds with the expected enhanced activity.

Results and discussion

The synthetic route to the proposed compounds is shown in Scheme 1. The synthesis of 3,5-bis(4-substituted benzylidene)-1-methyl-2,6-diphenylpiperidin-4-ones 1a–c and the subsequent formation of Schiff bases 2a–c were achieved by using the known literature procedures [14]. The formation of thiazolidinone ring in 3a–c was achieved by intermolecular cyclization of 2a–c with mercaptoacetic acid. The Claisen condensation of 3a–c with substituted benzaldehydes furnished the final products 4a–f. The structural assignments of the compounds 4a–f were based on the analysis of their ¹H NMR, ¹³C NMR, and mass spectra. Satisfactory elemental analyses were obtained.

Scheme 1

The synthesized compounds 4a–f were screened for their antimicrobial activity against a panel of several bacterial strains [Staphylococcus aureus (Sa), Bacillus subtilis (Bs), Pseudomonas aeruginosa (Pa), Escherichia coli (Ec), and Klebsiella pneumoniae (Kp)] and fungal strains [Candida albicans (Ca), Aspergillus niger (An), Aspergillus fumigatus (Af), Penicillium chrysogenum (Pc), and Trichophyton rubrum (Tr)]. The antimicrobial activities were evaluated by measuring the diameter of zone of inhibition and minimal inhibitory concentrations (MIC) values against the test organisms. Ampicillin, chloramphenicol, ciprofloxacin, fluconazole, and gentamicin [15, 16] were used reference antibiotics (see Supplementary Information). Although all spiro derivatives of piperidone were found to show antimicrobial activity against different strains in these two assays, compounds 4d and 4f are clearly outstanding in their antimicrobial properties. For several pathogens, these compounds were more active than the reference drugs. Compound 4d selectively inhibits the growth of C. albicans, and compound 4fis highly active against S. aureus and P. aeruginosa with MIC values of 3.12 μg/mL. Detailed activity results are summarized in Table 1.

Conclusion

New piperidone derivatives were synthesized and screened for their antimicrobial activity. Compounds 4d and 4f exhibit outstanding antifungal and antibacterial properties.

Experimental

Melting points were determined in an open capillary tube and are uncorrected. IR spectra (KBr pellets) were recorded on a Perkin-Elmer FTIR spectrophotometer; ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded in CDCl₃ on a Bruker 400 MHz instrument. EI mass spectra were recorded on a Va 70–70H mass spectrometer at 70 eV. Elemental analysis was performed on a Perkin-Elmer 2400 series II elemental CHNS analyzer.

In vitro antibacterial and antifungal activities were conducted using a disc-diffusion method [17, 18] by standard microbroth dilution as per NCCLS protocol. 3,5-Bis(4-substituted benzylidene)-1- methyl-2,6-diphenylpiperidin-4-ones 1a–c [19] and N-(3,5-bis(4-substituted benzylidene)-1-methyl-2,6-diphenyl piperidin-4-ylidene)pyridin-2-amines 2a–c [20] were prepared by known literature procedures.