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. 2023 Jun 27;14(9):1817–1826. doi: 10.1039/d3md00051f

Synthesis and antibacterial activity of 2-benzylidene-3-oxobutanamide derivatives against resistant pathogens†

Ankur Sood a, Venkitasamy Kesavan a,✉
PMCID: PMC10507797  PMID: 37731706

Abstract

Antibiotic resistance evolves naturally through random mutation. Resistance to antimicrobials is an urgent public health crisis that requires coordinated global action. The ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are primarily responsible for the rise in resistant pathogens. There is an immediate requirement to identify a novel molecular scaffold with potent anti-microbial properties. We developed an efficient one-step synthesis of 2-benzylidene-3-oxobutanamide and its derivatives, which allowed the introduction of an α,β-unsaturated ketone moiety in the quest to identify a new molecular scaffold. Seven compounds exhibited very good antibacterial activity in vitro against WHO priority drug-resistant bacteria such as methicillin resistant Staphyloccus aureus (MRSA) and Acinetobacter baumannii-Multi drug resistant (MDR-AB). In cultured human embryonic kidney cells and hemolysis assays, the potent compounds displayed minimal toxicity. These findings suggest that these small molecules with excellent diversity have the potential to combat antibacterial resistance.

Reaction scheme of (Z)-2-benzylidene-3-oxobutanamide derivatives against resistant pathogens.graphic file with name d3md00051f-ga.jpg

Introduction

In the twenty-first century, antimicrobial resistance (AMR) has been identified as one of the most serious public health issues.1,2 This phenomenon results from when microorganisms develop the ability to continue to grow, even when treated with antibiotics which are meant to either kill or inhibit the microorganism. As a result, antibiotics become less effective or resistant.3 The Review on Antimicrobial Resistance predicts that by 2050, AMR could lead to 10 million people dying per year and cost the world up to 100 trillion USD.4,5 While some have questioned these forecasts, the WHO and several other organizations and academics think that AMR is a serious problem that demands a worldwide, coordinated response.6–8 It is crucial to understand the current state of antimicrobial resistance, trends in different countries, as well as the most prevalent drugs and pathogen combinations that contribute to AMR. If AMR is not controlled, many bacterial infections might become even more deadly in the future.9,10

A critical barrier to combating AMR is the absence of new antibiotic discoveries.11 Antibiotics have transformed medical procedures and increased human life expectancy substantially, which is one of the most prominent accomplishments in healthcare of the previous century.12 On the other hand, antibiotics have finite therapeutic usefulness before being rendered obsolete by the inevitable increase in resistance.13 It only took a few years for resistance to develop towards antibiotics such as amoxicillin, vancomycin, carbapenem, etc.14,15

Due to their use as a last resort, carbapenem and vancomycin lasted longer before resistance developed.16 Nevertheless, intermediate and resistant pathogens towards vancomycin and carbapenem have become common.17 Identification or development of small molecules with potent activity against resistant pathogens is the need of the decade.

Contrary to expectations, large pharmaceutical companies have drastically reduced or eliminated their plans to develop new antibiotics.18,19 There are several explanations for this situation. The goldmine of antibiotics, the secondary metabolites of soil actinomycetes, dried up after decades of excavation. Researchers have yet to identify a chemical space with potency against drug resistant pathogens. Third, the financial return from antibiotic development is low.20–22 In light of this, antibiotic development has been fairly slow in recent years. Specifically, many new antibiotics are chemically modified compounds of existing pharmaceutical classes, which are mostly natural.23 Resistance mechanisms may adapt to resist these molecules if they do not already show partial cross-resistance.24 Therefore, it is necessary to explore alternative chemical spaces to identify novel antibiotics that can combat drug-resistant pathogens to avoid a post antibiotic era.25

Results and discussion

The role of α, β-unsaturated carbonyl compounds as antibacterial agents

α,β-Unsaturated carbonyl compounds play an important role in biological activity due to their ability to act as a Michael acceptor following the addition of nucleophiles to the electrophilic β-position of the unsaturated system.26

Several reports have shown that natural products containing α,β-unsaturated carbonyl units, especially polyphenolic compounds such as chalcones, caffeic acid, e.g., Butein (2) (Fig. 1), and chlorogenic acid, which are abundant in food plants such as dill, pepper, tea leaves, cocoa and cranberries, act as anticancer and antiaging phytochemicals (Fig. 1).27 The most prominent example of α,β-unsaturated carbonyl compounds is chalcone. In the past decade, it has been found that chalcones, also known as α,β-unsaturated ketones, represent a valuable class of natural drug scaffolds.28 In recent years, the chalcone family has drawn a lot of attention due to its broad range of biological activity, including antitumor, anti-inflammatory, and antimicrobial activity. However, the use of chalcone-based compounds as drugs has been limited to metochalcone (13a) and sofalcone (13b) (Fig. 2).29–31

Fig. 1. Structures of α,β-unsaturated carbonyl compounds that show biological activity adapted from S Amslinger, ChemMedChem, 2010.27.

Fig. 1

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Fig. 2. Examples of α,β-unsaturated carbonyl commercialized drugs.

Fig. 2

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In 2009, Batovska et al. examined the antibacterial activity of 62 chalcones against S. aureus and E. coli. The study determined that these compounds had no effect on E. coli but were active against S. aureus and a variety of substitutions on either the A or B rings produced varying levels of antibacterial activity32 (Fig. 3). Furthermore, compounds containing α,β-unsaturated carbonyl groups were reported to possess antibacterial properties.28 Despite these advances, many of the reported molecules have activity mainly against susceptible bacteria and not against resistant bacteria species. Also, many α,β-unsaturated carbonyl molecules have poor ADMET as well as exhibiting toxicity against normal human cell lines.27–33

Fig. 3. Antibacterial activity of simple chalcones against S. aureus and E. coli.

Fig. 3

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Hence, it is necessary to design and synthesize α,β-unsaturated carbonyl compounds which act against resistant bacterial species with good ADMET properties and minimal or no toxicity against normal human cell lines.

In order to find an alternative chemical space against resistant pathogens with drug-like ADMET properties, the synthesis of 2-benzylidene-3-oxo butanamides and their evaluation against drug-resistant pathogens are proposed herewith.

Synthesis of 2-benzylidene-3- oxobutanamide derivatives

An efficient one-step synthesis of 2-benzylidene-3-oxobutanamide 15 (Scheme 1) was achieved by treating benzaldehyde (A) with acetoacetamide (B) in the presence of l-proline (C) in ethanol at room temperature. More than two dozen compounds were synthesized to achieve our goal of identifying small molecules with potent antibacterial activity against resistant pathogens (Fig. 4).

Scheme 1. Synthesis of 2-benzylidene-3-oxo butanamide.

Scheme 1

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Fig. 4. Derivatives of 2-benzylidene-3-oxobutanamide.

Fig. 4

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All the compounds were synthesized in a single-step synthesis with an easy workup method in good to excellent yields. It was observed that aldehydes such as 4-fluorobenzaldehyde, 3-chlorobenzaldehyde and 2-hydroxybenzaldehyde did not yield the expected products. Similar results were obtained with heterocyclic aldehydes (Fig. 4, products: 24, 26, 31, and 41–44).

The stereochemistry of the obtained compounds was found to be the Z-isomer by NOESY experiment. A cross peak is observed in the NOESY spectrum between the methyl proton and the olefinic C Created by potrace 1.16, written by Peter Selinger 2001-2019 CH proton. This indicates they are spatially closer and the resulting compound is a Z-isomer. This inference was also confirmed by the XRD of compound 15 (CCDC – 2238743). The NOESY, COSY, crystal structure and XRD report are provided in ESI.†

Furthermore, with the help of the Swiss ADME program, the drug-likeness properties of these molecules were analysed. A simple chalcone and curcumin were also included in the analysis (Table 1). The analysis indicated that all the reported compounds possess drug-likeness properties (Lipinski's rule) superior to chalcone and curcumin (Table 1).

Drug likeness properties of 2-benzylidene-3-oxobutanamide derivatives.

Compounds No. of H donors No. of H acceptors Log PO/W Mol. Wt. g mol−1 Rotatable bond Water solubility
15 1 2 1.60 189.31 3 Soluble
16 1 4 1.09 234.21 4 Soluble
17 1 4 1.15 234.21 4 Soluble
18 1 4 1.13 234.21 4 Soluble
19 1 2 1.62 268.11 3 Soluble
20 1 2 1.73 268.11 3 Soluble
21 1 2 1.62 268.11 3 Soluble
22 1 3 1.66 207.20 3 Soluble
23 1 3 1.49 207.66 3 Soluble
25 1 2 1.38 223.66 3 Soluble
27 1 2 1.88 223.66 3 Soluble
28 1 3 1.09 214.22 3 Soluble
29 1 3 1.15 214.22 3 Soluble
30 1 3 1.13 214.22 3 Soluble
32 2 3 0.94 205.21 3 Soluble
33 1 4 1.30 249.26 5 Soluble
34 1 5 1.41 279.29 6 Soluble
35 1 2 1.68 203.24 3 Soluble
36 1 2 1.99 217.26 4 Soluble
37 1 4 1.31 262.26 5 Soluble
38 1 5 2.43 257.21 4 Soluble
39 1 3 2.72 295.33 6 Moderate soluble
40 1 4 1.23 233.22 3 High
Curcumin 2 6 3.03 368.38 8 Moderate soluble
Chalcone 0 1 3.29 208.26 3 Moderate soluble
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The log Po/w of the derivatives was found to be between 1.01 to 2.31, which is an indication of better bioavailability when compared to chalcone and curcumin. Compounds (15–40) have good water solubility and a good partition coefficient and are expected to display better ADMET properties than chalcone and curcumin.

Antimicrobial studies of the novel compounds

The in vitro activity against ESKAPE resistant bacterial strains was undertaken in the primary antimicrobial screening. Only the active compounds were taken into the HIT assay for MIC.

Primary antimicrobial screening of the synthesized compounds

A primary antimicrobial screening study was carried out with all molecules in duplicate at a single concentration of 32 μg mL−1, using whole cell growth inhibition assays (n = 2). The percentage inhibition of growth was measured against five bacterial resistant strains: Klebsiella pneumoniae (Kp), Escherichia coli (E. coli), Acinetobacter baumannii (Ab), Pseudomonas aeruginosa (Pa), and Staphylococcus aureus (Sa), as well as two fungi: Candida albicans (Ca) and Cryptococcus neoformans (Cn).

Out of the twenty-three molecules, nine molecules were found to possess promising activity against the Staphylococcus aureus-MRSA (Sa-MRSA), E. coli (E. coli), and Acinetobacter baumannii-Multi Drug Resistant (Ab-MDR) bacteria.

None of these molecules displayed significant activity against fungal strains such as Cryptococcus neoformans (Cn) and Candida albicans (Ca). This result indicates that these molecules have the potential to act as anti-bacterial agents.

In the primary antimicrobial screening, all the nine molecules showed mild activity against E. coli but (Z)-2-benzylidene-3-oxobutanamide derivatives such as 17, 18, 19, 21, 25, 27 and 37 possess moderate to very good growth inhibition against Staphylococcus aureus-MRSA (Sa-MRSA), whereas 17 and 28 displayed good growth inhibition against Acinetobacter baumannii-Multidrug Resistant (Ab-MDR).

Growth of Gram-negative and Gram-positive bacteria strain such as Acinetobacter baumannii-Multidrug resistant (Ab-MDR) and Staphylococcus aureus-MRSA (Sa-MRSA) respectively was inhibited by (Z)-2-(3-nitrobenzylidene)-3-oxobutanamide 17 (Fig. 5).

Fig. 5. Percentage growth inhibition against different bacterial species at 32 μg mL−1.

Fig. 5

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Based on this result, we can surmise a good structure activity relationship (SAR) for the molecules in Fig. 4. Compounds with nitro substitution at the −3 and −4 positions in the aryl ring (Compound 17 and 18) exhibited significant antimicrobial activity. Halogen substitutions are beneficial at the −2 and −4 positions of the aryl ring (Compounds 19, 21, 22, 25, and 27). Hydrophilic substitutions (Compounds 31, 32, 33 and 34) diminished the antibacterial activity. The electronegative group substitution (–CN) at the ortho position (Compound 28) exhibited activity specifically against Gram-negative bacteria.

For further studies, these molecules were re-tested against the strains in a dose–response assay to determine their minimum inhibitory concentration (MIC).

Hit confirmation

MIC was calculated in duplicate (n = 2) by performing 8-point dose responses on the active compounds to confirm their activity against whole cell growth inhibition assays in HIT confirmation. Growth inhibition is measured against microorganisms susceptible to the compounds tested in the primary screening.

In the HIT assay, out of nine molecules, seven molecules exhibited an excellent MIC. Out of those seven compounds, (Z)-2-(3-nitrobenzylidene)-3-oxobutanamide 17 (Column II and III, Fig. 6) inhibited bacterial growth against Staphylococcus aureus-MRSA (Sa-MRSA) (99.4%) and against Acinetobacter baumannii-Multi Drug Resistant (Ab-MDR) (98.2%) at 2 μg mL−1 and 16 μg mL−1, respectively.

Fig. 6. MIC of HIT compounds against Staphylococcus aureus-MRSA (Sa-MRSA) and Acinetobacter baumannii-multi drug resistant (Ab-MDR).

Fig. 6

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The MIC of (Z)-2-(4-nitrobenzylidene)-3-oxobutanamide 18 (Column IV, Fig. 6) was determined as 2 μg mL−1 with an impressive growth inhibition of 98.7% against Staphylococcus aureus-MRSA (Sa-MRSA).

In the primary antimicrobial screening, all the compounds were tested at 32 μg mL−1. The compounds which exhibited more than 70% percentage growth inhibition were selected for the HIT assay. The HIT assay 8-dose point assay was conducted for the active compounds only against those bacterial strains which showed good percentage growth inhibition in the primary antimicrobial screening.

Now compound 17 in the primary antimicrobial screening at 32 μg mL−1 showed 84% growth inhibition, whereas the HIT assay showed 94% growth inhibition at 2 μg mL−1 against S. aureus (Sa-MRSA). This could possibly be due to the solubility of the compound.

There may be solubility/saturation issues at higher concentrations and therefore as the compound is diluted through the serial dilution process in the HIT assay, it become more available and therefore more active or vice versa in the case of compound 28.

The National Healthcare Safety Network (NHSN) has reported high levels of antibiotic resistance among Gram-positive and Gram-negative bacteria that cause healthcare infections.34,35 Methicillin resistance was reported in more than 50% of staphylococcal isolates. Hospital-acquired MRSA infections cause significant morbidity, mortality, length of stay, and cost burdens.36Acinetobacter baumannii, a Gram-negative bacterium, has become a global health challenge in recent decades.37Acinetobacter baumannii was reportedly resistant to carbapenem in 45–75% of Acinetobacter baumannii isolates.38 Pneumonia, wounds, soft tissue, and bloodstream infections are caused by this pathogen and are common in intensive care units (ICUs).39

A MIC of 1 μg mL−1 is needed for Vancomycin to be active against the susceptible bacterial strain Staphylococcus aureus and it does not inhibit the growth of Staphylococcus aureus-MRSA (Sa-MRSA). On the other hand, growth of the Gram-negative susceptible bacterial strain Acinetobacter baumannii would require Colistin Sulphate with an MIC of 0.25 μg mL−1 and again Colistin sulphate does not work against Acinetobacter baumannii-Multi Drug Resistant (Ab-MDR). In this study, we identified a novel, (Z)-2-(3-nitrobenzylidene)-3-oxobutanamide 17 which mitigated the above serious concerns posed by Sa-MRSA and Ab-MDR. (Z)-2-(3-Nitrobenzylidene)-3-oxobutanamide 17 (Column II and III, Fig. 6) inhibited bacterial growth against Staphylococcus aureus-MRSA (Sa-MRSA) (99.4%) and against Acinetobacter baumannii-Multi Drug Resistant (Ab-MDR) (98.2%) at 2 μg mL−1 and 16 μg mL−1 respectively. Thus (Z)-2-(3-nitrobenzylidene)-3-oxobutanamide 17 has the potential to become a drug molecule which can be used for the treatment of diseases caused by Acinetobacter baumannii-Multidrug resistant strain (Ab-MDR) as well as by Staphylococcus aureus-MRSA (Sa-MRSA).

Human cells are highly tolerant towards active compounds

Any potential antibiotic candidate must be able to inhibit prokaryotic cell growth selectively.40 For this purpose, an embryonic kidney cell line, HEK293, was used to screen compounds for cytotoxicity.

The cell viability of compound 17 (Column I, Fig. 7) was found to be 93.81% at the concentration of 64 μg mL−1 against human cells which is a 32 times higher concentration compared to the MIC against Gram-positive resistant bacteria (Sa-MRSA) and a 4 times higher concentration compared to the MIC against Gram-negative resistant bacteria (Ab-MDR).

Fig. 7. Toxicity analysis of the active compound against HEK-293 cell lines.

Fig. 7

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In the assay, all active compounds were highly tolerable to the HEK cell line at a concentration of 64 μg mL−1 (Fig. 7). Tamoxifen was used as a positive cytotoxicity standard.

Active compounds are hemocompatible

Hemolysis can significantly impair the function of organs. For example, hemolysis is associated with decreased nitrous oxide signaling, leading to systolic, diastolic, and elevated mean arterial blood pressure, as well as other cardiovascular and renal dysfunction, inflammation, thrombosis, and infections.41 In addition, the active molecules were tested to see if they would rupture red blood cells or not.

In the hemolysis assay, all compounds were hemocompatible at concentrations of 64 μg mL−1 (Fig. 8). Melittin was used as a positive haemolytic standard.

Fig. 8. Haemolysis assay of active compounds.

Fig. 8

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Compound 17 only lysed 5% RBC cells, whereas compound 19 only lysed 2% RBC cells at 64 μg mL−1 (Column I and column III, Fig. 8), which is 32 times higher than the MIC of the compound. Other compounds also have minor lysis.

Time-kill assay of the active compounds

The time-kill kinetics assay is employed to investigate if an antimicrobial agent can kill or inhibit a bacterial strain over time and is used to assess an agent's bactericidal or bacteriostatic potential.42

The term “bactericidal activity” refers to a reduction in colonies (surviving bacteria) less than 3 log 10-fold, which equals 99.9% death of the inoculum.43

Time-kill assay of active compounds against S. aureus-MRSA

Time-kill studies showed that our potent compounds (17, 18, 19 and 21) are bacteriostatic against Staphylococcus aureus-MRSA (Sa-MRSA). The positive control Vancomycin hydrochloride showed minimal activity as the log CFU mL−1 remains constant from 4 h to 24 h compared to the control media which was not treated with any antibiotics and for which log CFU mL−1 increases within the time period (Fig. 9–12).

Fig. 9. Time-kill assay of compound 17 against S. aureus.

Fig. 9

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Fig. 10. Time-kill assay of compound 18 against S. aureus.

Fig. 10

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Fig. 11. Time-kill assay of compound 19 against S. aureus.

Fig. 11

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Fig. 12. Time-kill assay of compound 21 against S. aureus.

Fig. 12

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The strain used for the time kill assay is ATCC 700698. The ATCC 700698 Staphylococcus aureus strain as it is methicillin resistant as well showed reduced vancomycin susceptibility.44 This might be the reason that even vancomycin hydrochloride is bactericidal against susceptible bacteria but against the resistant strain it showed reduced susceptibility and acted as a bacteriostatic compared to control media.

Based on the bacteria strains and the media, log CFU mL−1 is determined at time 0 and subsequent time intervals up to 24 h.

Compound 17, 18, 19 and 21 showed the bacteriostatic effect as the log CFU mL−1 decreased 2 logs or remained same as the starting log CFU mL−1 concentration (Fig. 9–12).

Time-kill assay of the active compound against Acinetobacter baumannii

Compound (Z)-2-(3-nitrobenzylidene)-3-oxobutanamide 17 showed bacteriostatic activity against Staphylococcus aureus-MRSA (Sa-MRSA) but it displayed bactericidal activity against Acinetobacter baumannii-Multidrug resistant (Ab-MDR) where it reduces the starting log CFU mL−1 in the time-kill assay by greater than 3 logs (Fig. 13).

Fig. 13. Time-kill assay of compound 17 against A. baumannii.

Fig. 13

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Compound 28 also showed bactericidal activity against Acinetobacter baumannii. As it also reduces the starting log CFU mL−1 in the time-kill assay by greater than 3 logs (Fig. 14).

Fig. 14. Time-kill assay of compound 28 against A. baumannii.

Fig. 14

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In this study, we found a small molecule that is active against WHO priority drug resistant pathogens. Aside from the topic of this publication, future research will focus on the specific mechanism of action behind this antibacterial activity as well as pharmacokinetic and pharmacodynamic studies of the active molecules.

Conclusions

We have identified that promising compounds of 2-benzylidine-3-oxobutanamide exhibited very good antibacterial activity against Staphylococcus aureus-MRSA (Sa-MRSA) and Acinetobacter baumannii-MDR (Ab-MDR). Additionally, the compounds possess hemocompatibility and tolerability to human cell lines.

Furthermore, compound 17 is active against both Gram-positive and Gram-negative resistant species, i.e., Staphylococcus aureus-MRSA (Sa-MRSA) and Acinetobacter baumannii-MDR (Ab-MDR) bacteria, which makes compound 17 a promising antibacterial compound. These compounds could be used alone against multidrug-resistant Staphylococcus-MRSA (Sa-MRSA) and Acinetobacter baumannii-Multidrug Resistant (Ab-MDR).

Overall, this study contributes to the growing list of studies that have sought to combat antimicrobial resistance with new small compounds.45–53

Conflicts of interest

There is no conflict to declare.

Supplementary Material

MD-014-D3MD00051F-s001
MD-014-D3MD00051F-s002

Acknowledgments

We thank CO-ADD for the antimicrobial screening performed by CO-ADD (The Community for Antimicrobial Drug Discovery) was funded from the Welcome Trust (UK) and The University of Queensland (Australia) for primary screening and HIT assays. We thank Dr C Baby and Stella Mary SAIF-IIT Madras for the NMR data. We thank Dr Shobhana Krishnaswamy SAIF-IIT Madras for XRD and CIF data. We thank the Department of Biotechnology IIT Madras for LCMS. Ankur thanks the Half Time Research Assistantship (HTRA) for the fellowship. Ankur thanks IC&SR, IIT Madras for the innovative research scholarship for this work.

†

Electronic supplementary information (ESI) available. CCDC 2238743. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3md00051f

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MD-014-D3MD00051F-s001
MD-014-D3MD00051F-s001.pdf (2.1MB, pdf)
MD-014-D3MD00051F-s002
MD-014-D3MD00051F-s002.cif (19KB, cif)

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