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Publicly Available Published by De Gruyter September 15, 2015

Antibacterial, antifungal and antimycobacterial activities of some pyrazoline, hydrazone and chalcone derivatives

Begüm Evranos-Aksöz EMAIL logo , Fatma Kaynak Onurdağ and Selda Özgen Özgacar

Abstract

Twenty-seven previously reported chalcones and their pyrazoline and hydrazone derivatives as well as two further chalcones have been screened for their antimicrobial, antifungal and antimycobacterial activities against standard microbial strains and drug resistant isolates. The minimum inhibitory concentration (MIC) value of each compound was determined by a two-fold serial microdilution technique. The compounds were found to possess a broad spectrum of antimicrobial activities with MIC values of 8–128 μg/mL. One compound [(E)-1-(4-hydroxyphenyl)-3-p-tolylprop-2-en-1-one] had equal activity with gentamycin (8 μg/mL) against Enterococcus faecalis. Chalcones were found to be more active than their hydrazone and 2-pyrazoline derivatives against Staphylococcus aureus ATCC 29213 and E. faecalis ATCC 29212.

1 Introduction

The need for new antimicrobial agents is ever-increasing because of antibiotic resistance. Infections caused by methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) can be life threatening especially for immunocompromised patients due to HIV, surgery or any other illness [1, 2]. The human immunodeficiency virus (HIV) pandemic has increased the incidence of tuberculosis (TB) too [3]. Tuberculosis is a serious health problem and it has been estimated that approximately one-third of the world’s population is infected with Mycobacterium tuberculosis [4].

Although current first-line anti-TB drugs treat the illness, drug resistance often causes problems [5]. TB treatment requires at least 6 months to decrease the risk of reactivation of TB bacilli. Long-term tuberculosis treatment causes patient non-adherence, and thereby the number of multidrug resistant M. tuberculosis (MDR-MTB) strains increases rapidly [6]. Invasive fungal infections cause morbidity and mortality [7]. Antifungal therapies can be limited because of toxicity, drug resistance and low efficacy rates [8]. New antifungal drugs are necessary to improve the efficacy of therapy. Therefore, new antitubercular, antimicrobial and antifungal agents are needed.

Chalcones have different pharmacological activities such as antibacterial [9–13], antifungal [14, 15], antimycobacterial [3, 16], antiinflammatory [17, 18] and antiviral [19, 20]. Pyrazoline and hydrazone derivatives are of interest because of their similarity to isoniazid (isonicotinic acid hydrazide). It is also known that pyrazoline and hydrazone derivatives have antibacterial [21–24], antifungal [25, 26] and antimycobacterial [27, 28] activities.

In this study, twenty-nine compounds having a chalcone, 2-pyrazoline or hydrazone structure were screened for their antibacterial, antifungal and anti-mycobacterial activity.

2 Results and discussion

Chemical formulas of the synthesized compounds are shown in Scheme 1. The synthetic route used for the preparation of the target compounds (3a-3h, 5a-5j, 6a-6i) and data on the compounds (3a-3h, 5a-5j, 6a-6i) have been published earlier [29].

Scheme 1: Structures of compounds 3a-3j, 5a-5j and 6a-6i.
Scheme 1:

Structures of compounds 3a-3j, 5a-5j and 6a-6i.

Iproniazid, a non-selective, irreversible monoamine oxidase inhibitor (MAOI), was originally developed for the treatment of tuberculosis [30]. Linezolid, which is a synthetic antibacterial agent, is a reversible and weak MAOI at the same time [31]. Isoniazid and tedizolid are also monoamine oxidase inhibitors and are used for antimicrobial treatment [32]. According to this data, we investigated the antimicrobial effects of our compounds which we originally synthesized as inhibitors of monoamine oxidase.

Amine oxidases (AOs), a widespread class of enzymes, are present in all living systems, where they control the level of physiologically very active compounds, i.e. mono-, di-, and polyamines. Amine oxidases have been divided into two main categories, depending on the nature of the cofactor involved. One class is characterized by the presence of flavin adenine dinucleotide (FAD) as the redox cofactor. The enzymes belonging to this class are further subdivided into monoamine oxidases (MAOA and MAOB) and polyamine oxidases (PAOs). The second class is represented by enzymes having a tightly bound CuII ion and 2,4,5-trihydroxyphenethylamine quinone (TPQ) at the active site [33]. Monoamine oxidase catalyses the oxidation of tyramine, tryptamine, norepinephrine and some other monoamines of natural origin [34]. This enzyme is also present in bacteria and fungi. This enzyme is defined for Escherichia coli as a copper containing amine oxidase enzyme (CuAOs) [35, 36]. No membrane-bound monoamine oxidase activity was detected in Pseudomonas aeruginosa IFO 3456 [37] P. aeruginosa converts substrates with a membrane bound, uncharacterized amine dehydrogenase (quite different types of oxidoreductases) instead of monoamine oxidase [38]. Human monoamine oxidases contain FAD (flavin adenine dinucleotide) but usually bacterial amine oxidases contain copper and 2,4,5-trihydroxyphenethylamine quinone (TPQ) at their active site [39, 40].

In bacteria, the CuAOs have a well-defined role in the metabolism of primary amines as alternative sources of carbon and nitrogen to support growth [41]. Murooka et al., declared that monoamine oxidases were not essential for growth of bacterial cells [40]. The antimicrobial activity of the compounds can be related to the inhibition of mono amine oxidase enzyme. Similarities of microbial MAOs and hMAO are important for inhibition of the bacterial enzymes. Sheepard et al., tested some amine derivatives as monoamine oxidase inhibitors against mammalian, plant, bacterial, and fungal copper-containing amine oxidases. Distinctions among the active sites were found to be responsible for differentiating the chemical interactions between the inhibitors and enzymes selected [36]. According to these data, more investigations are necessary for understanding the properties of amine oxidase enzymes of bacteria and fungi.

As seen in Table 1, 2-pyrazolines (5a-5j) and hydrazones (6a-6i) had similar but low antibacterial activity against S. aureus with a minimum inhibitory concentration (MIC) value of 128 μg/mL. Chalcones (3a-3j) had variable MIC values of 16–256 μg/mL against S. aureus. Compound 3g is the most active one against the resistant S. aureus isolate (MRSA), having a MIC value of 32 μg/mL. All derivatives had low activity against standard strains of E. coli in comparison with the standard drugs. All compounds showed low activity against M. tuberculosis. Compounds 5b-5g had moderate activity against Enterococcus faecalis with MIC values of 32 μg/mL. Compound 3g has equal activity with gentamicin (8 μg/mL) against E. faecalis. Compound 6e is the most active one against a resistant E. faecalis isolate (VRE), with a MIC value of 32 μg/mL. Compounds 5d-5g had moderate activity against Candida albicans with a MIC value of 32 μg/mL MIC. Compound 3g is the most active one against C. albicans (MIC 16 μg/mL). Compound 3g (4′-hydroxy-4-methyl chalcone) had the lowest MIC values against S. aureus, E. faecalis and C. albicans (16, 8 and 16 μg/mL, respectively). All compounds had MIC values of 32–128 μg/mL against Candida krusei. Compounds 5g, 5h, 6f and 3j had equal activity with fluconazole against C. krusei with a MIC value of 32 μg/mL.

Table 1

In vitro antimicrobial activities of 2-pyrazoline (5a-5i), hydrazone (6a-6i) and chalcone (3a-3j) derivatives in comparison with reference drugs.

MIC (μg/mL)
CompoundGram-negative bacteriaGram-positive bacteriaFungi
E.c.E.c.*E.c.**P.a.P.a *S.a.S.a.*E.f.E.f.*C.a.C.k.M.t.
5a12812812864641286464646464128
5b64128128641281286432646464128
5c128128128641281286432646412864
5d641286412864128643264326464
5e6412812864128128643264326464
5f64641286464128643264326464
5g6412812864641286432128323264
5h641281281281281286464128643264
5i6412812864641286464128646464
5j64128128128641286464128646464
6a6412812812864128641281281286464
6b12812812812812812864128641286464
6c6412812812812812864641281286464
6d128128128128128128641281281286464
6e1281281281281281286412832646464
6f64128128128641283264128643264
6g6412812864641286464128646464
6h12812812864128128641281281286464
6i1281281286464128641281281286464
3a12812812864646464128128646464
3b12812812812812864641281281286464
3c12812812864128256641281281286464
3d1281281286464256641281281286464
3e12812812864128128641281281286464
3f128128128128128128641281281286464
3g12812812812812816648128166464
3h6412812812812864641281281286464
3i64128128128646464128128646464
3j64128128646412832128128643264
Ampicillin2n.d.>1024n.d.n.d.0.5n.d.0.50.5n.d.n.d.n.d.
Gentamicin0.25n.d.2561640.512888n.d.n.d.n.d.
Ofloxacin0.015n.d.16110.1250.514n.d.n.d.n.d.
Meropenem0.008n.d.0.0150.250.0150.03n.d.48n.d.n.d.n.d.
Vancomycinn.d.n.d.n.d.n.d.n.d.0.5118n.d.n.d.n.d.
Ampicillin/sulbactam (1/1)n.d.16n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.
Amoxicillin/clavulanic acid (2/1)n.d.16n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d
Fluconazoln.dn.dn.d.n.dn.dn.d.n.d.n.d.n.d.0.062532n.d.
Amphothericin Bn.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.n.d.<0.030.5n.d.
Ethambuthol4
Isoniazid0.125

n.d., not determined (microbiological assays were not performed due to following reasons: P. aeruginosa is naturally resistant to ampicillin; E. coli ATCC 35218 has ESBL; Gram-negative bacteria employed in the study are naturally resistant to vancomycin; antibacterial drugs were not assayed against fungi; antifungal drugs were not assayed against bacteria). E.c., E. coli ATCC 25922; E.c.*, E. coli ATCC 35218; E.c.**, E. coli isolate (ESBL); P.a., P. aeruginosa ATCC 25853; P.a.*, P. aeruginosa isolate (resistant to gentamicin); S.a., S. aureus ATCC 29213; S.a.*, S. aureus isolate (MRSA); E.f., E. faecalis ATCC 29212; E.f.*, E. faecalis isolate (VRE); C.a., C. albicans ATCC 10231; C.k., C. krusei ATCC 6258; M.t. M. tuberculosis H37RV ATCC 27294.

Enterococcus faecalis is an opportunistic pathogen and a major cause of both community-acquired and nosocomial infections, including pelvic infections, endocarditis, neonatal infections, respiratory infections and urinary tract infections. The rise in prevalence of antibiotic-resistant enterococci, including vancomycin-resistant enterococci (VRE), linezolid (LZD)-resistant enterococci has gained much attention in the clinical setting [42].

Increasing resistance against E. faecalis calls for the development of new drugs. Compound 3g, having an activity against E. faecalis equal to that of gentamycin, is promising, but as it is not equally active against resistant E. faecalis, its applicability in clinical practice is restricted. Obviously, the comparative evaluation of active compounds requires further studies; the data reported in this article may be a helpful guide for medicinal chemists working in this area.

3 Experimental

3.1 Antibacterial and antifungal activity

Standard strains of E. coli (ATCC 25922 and ATCC 35218), P. aeruginosa (ATCC 27853), S. aureus (ATCC 29213), E. faecalis (ATCC 29212), C. albicans (ATCC 10231) and C. krusei (ATCC 6258) were included in the study. Candida krusei was used because of the natural resistance of the strain to fluconazole. An E. coli isolate (extended spectrum β-lactamases [ESBL), a S. aureus isolate (methicilline resistant S. aureus[MRSA]), resistant to all β-lactam antibiotics, a P. aeruginosa isolate (resistant to gentamicin), β-lactam antibiotics, and an E. faecalis isolate (resistant to vancomycin) were also used. Bacterial and fungal susceptibility tests were performed according to Clinical Laboratory Standards Institute (CLSI) guidelines M100-S16 [43] and M27-A3 [44], respectively.

Mueller Hinton Agar (MHA) (Merck, Darmstadt, Germany), Mueller Hinton Broth (MHB) (Merck), Sabouraud Dextrose Agar (SDA) (Merck), Sabouraud Liquid Medium (SLM) (Merck) and RPMI-1640 medium with L-glutamine (Sigma-Aldrich, St. Louis, MO, USA) buffered to pH 7 with MOPS (Sigma-Aldrich) were used in the study for subcultures and microdilution tests.

Standard preparations of ampicillin (Mustafa Nevzat Pharmaceuticals, Istanbul, Turkey), gentamicin (Paninkret Chem.-Pharm., Westerhorn, Germany), ofloxacin (Zhejiang Huangyan East Asia Chemical Co. Ltd., Huangyan, Zhejiang, China), meropenem (Astra Zeneca, Istanbul, Turkey), vancomycin (Mayne Pharma, Melbourne, Australia), ampicillin/sulbactam (1:1) (Mustafa Nevzat Pharmaceuticals), amoxicillin/clavulanic acid (2:1) (Deva, Istanbul, Turkey), fluconazole (Pfizer, Istanbul, Turkey), and amphotericin B (Bristol Myers Squibb, Istanbul, Turkey) were obtained from the manufacturers. Stock solutions of the tested compounds were made in dimethyl sulfoxide (DMSO) (Sigma-Aldrich). Standard antibiotic solutions were made in appropriate solvents recommended by CLSI guidelines [43, 44].

Stock solutions of the test compounds and standard drugs were diluted two-fold in the wells of microplates. Solutions of the synthesized compounds were prepared at 1024–0.5 μg/mL concentrations and standard drugs were prepared at 512–0.001 μg/mL concentrations.

For antibacterial susceptibility testing, 100 μL of Mueller Hinton Broth (MHB) was added to each well of the microplates. The bacterial suspensions used for inoculation were prepared at 105 CFU/mL by diluting fresh cultures at McFarland 0.5 density (107 CFU/mL). Suspensions of the bacteria at 105 CFU/mL concentration were inoculated into the solutions of the compounds. A 10 μL bacterial inoculum was added to each well of the microplates. Microplates were incubated at 37°C overnight. After incubation, the lowest concentrations of the compounds that completely inhibited macroscopic growth were determined and reported as minimum inhibitory concentrations (MICs).

For fungal susceptibility testing, RPMI-1640 medium with L-glutamine buffered to pH 7 with MOPS was added to each well of the microplates. The yeast suspensions used for inoculation were prepared at 104 CFU/mL by diluting fresh cultures at McFarland 0.5 density (106 CFU/mL). Suspensions of the yeast at 104 CFU/mL concentrations were inoculated into the solutions of the compounds. A 10 μL yeast inoculum was added to each well of the microplates. Microplates were incubated at 37°C for 24–48 h. After incubation, the lowest concentrations of the compounds that completely inhibited macroscopic growth were determined and reported as minimum inhibitory concentrations (MICs).

3.2 Antitubercular activity

Mycobacterium tuberculosis H37RV (ATCC 27294) was grown on Middlebrook 7H11 agar (BD, Becton Dickinson, NJ, USA). Culture suspensions were prepared in 0.04% (v/v) Tween 80–0.2% bovine serum albumin (Sigma-Aldrich) at MacFarland 1 density. Suspensions were then diluted 1:25 in 7H9GC broth containing 4.7 g of Middlebrook 7H9 broth base (Difco, Detroit, MI, USA), 20 mL of 10% (v/v) glycerol (Sigma-Aldrich), 1 g of Bacto Casitone (Difco), 880 mL of distilled water, 100 mL of OADC (oleic acid, albumin, dextrose, catalase) supplement (Sigma-Aldrich) that includes 5 g bovine albumin fraction, 2 g dextrose, 0.004 g catalase, 0.05 g oleic acid and 0.85 g sodium chloride.

Compounds were dissolved in dimethyl sulfoxide (DMSO) (Merck) at a final concentration of 4096 μg/mL and sterilized by filtration using 0.22 μm syringe filters (Merck-Millipore, Darmstadt, Germany) and used as the stock solutions. The stock solutions of the agents were diluted within liquid media. Isoniazid (INH) and ethambutol (EMB) were obtained from Sigma-Aldrich. Stock solutions of INH and EMB were prepared in deionized water. The solutions of the compounds and drugs were prepared and diluted at 4096-0.0625 μg/mL concentrations in the wells of microplates in the liquid media.

Two hundred microliters of sterile deionized water were added to the outer-perimeter wells to minimize evaporation of the medium in the test wells during incubation. One hundred microliters of 7H9GC broth was added to the wells in rows B to G in columns 3 to 11. One hundred microliters of stock solutions were added to the wells in rows B to G in columns 2 and 3 by using a multichannel pipette. One hundred microliters was transferred from column 3 to column 4, and the contents of the wells were mixed. Serial two-fold dilutions were made through column 10.

One hundred microliters of M. tuberculosis inoculum was added to the wells in rows B to G in columns 2 to 11 by using a multichannel pipette. The wells in column 11 were used for growth controls. The plates were sealed with parafilm and were incubated at 37°C for 5 days. Fifty microliters of a freshly prepared 1:1 mixture of 10X Alamar Blue (AbD Serotec) reagent and 10% Tween 80 were added to well B11. The plates were incubated at 37°C for 24 h. B11 turned pink and 50 μL of the reagent mixture were added to all wells in the microplate. The microplates were resealed with parafilm and were incubated for 24 h at 37°C, and the colors of all wells were recorded. A blue color in the well was recorded as no growth, and a pink color was scored as growth. The MIC was defined as the lowest drug concentration which prevented a color change from blue to pink [45].

All organisms were tested in triplicate in each run of the experiments. Before the inoculum preparation, the microorganisms passaged at least twice to ensure purity and viability. The quality control strains (ATCC strains) demonstrated the accuracy of the experiment because all the results were within the MIC values mentioned in CLSI standards. Non-inoculated and antimicrobial free medium was used as the sterility control. Inoculated and sterile medium was used as microbial growth control.

3.3 Chemistry

Chalcone derivatives were prepared by the reaction of acetophenone and benzaldehyde derivatives, 1 and 2, in KOH/MeOH. The ensuing chalcone derivatives 3a-3j were then reacted with hydrazide compounds to furnish hydrazone and 2-pyrazoline derivatives, 5a-5j and 6a-6i (Scheme 1). Synthesis details, physicochemical and spectral characterization of the synthesized compounds have been reported earlier for all compounds except 3i, 3j [29]. The last-mentioned compounds were prepared analogously from acetophenone derivatives and 3-thiophenecarboxaldehyde.

3.3.1 General procedure for the preparation of chalcone derivatives (3i, 3j):

To a stirred solution of KOH (50% w/v) in water (5 mL) cooled in an ice bath, a solution of the acetophenone 1 (4.99 mmol) and the 3-thiophenecarboxaldehyde 2 (6.018 mmol) in ethanol (20 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. Then the mixture was poured into ice, adjusted to a pH of 3–4 with 1 M HCl, and then filtered. The precipitate was crystallized from ethanol [46].

3.3.2 (E)-1-(2-hydroxy-4-methoxyphenyl)-3-(thiophen-3-yl)prop-2-en-1-one (3i):

Brown colored solid (ethanol).-Yield:72.7%. M.p. 103.4°C. – IR (KBr): ν = 3429 (OH), 1680 (C=O). 1H NMR (DMSO-d6, 400 MHz): δ = 3.82 (s, 3H, -OCH3), 6.49–6.56 (2H, aromatic-H), 7.64-8.23 (6H, aromatic-H, α-ethylenic-H, β-ethylenic-H), 13.52 (s, 1H, -OH). – MS (ESI): m/z = 261 [M + H]+ (99%), 262 [M + H + 1]+ (33%). C14H12O3S: C 64.27, H 4.76, S 12.25; calcd. C 64.60, H 4.65, S 12.32.

3.3.3 (E)-1-(2,4-dimethoxyphenyl)-3-(thiophen-3-yl)prop-2-en-1-one (3j):

Black colored solid (ethanol).-Yield:79.6%. M.p. 81°C. – IR (KBr): ν = 1692 (C=O). – 1H NMR (DMSO-d6, 400 MHz): δ = 3.82 (s, 3H, -OCH3), 3.85 (s, 3H, -OCH3), 6.59–6.65 (2H, aromatic-H), 7.32 (d, 1H, J = 16 Hz, α-ethylenic-H), 7.49-7.96 (5H, aromatic-H, β-ethylenic-H). – MS (ESI): m/z = 275 [M + H]+ (100%), 297 [M + Na]+ (97%). C15H14O3S: C 65.58, H 5.33, S 11.74; calcd. C 65.67, H 5.14, S 11.69 [21–24].

4 Conclusion

In conclusion, we have designed and synthesized several chalcone, hydrazone and 2-pyrazoline compounds and evaluated their antibacterial, antimycobacterial and antifungal activities. The 2-pyrazoline and hydrazone functions did not increase the antimicrobial activity. Chalcones had better activity against S. aureus and E. faecalis, as compared to hydrazone and 2-pyrazoline derivatives. A hydroxy group at the fourth position of the A ring increased the activity against S. aureus,E. faecalis and C. albicans for chalcones. If the same scaffold on A ring was on a hydrazone structure, the activity was decreased.


Corresponding author: Begüm Evranos-Aksöz, Analysis and Control Laboratories of General Directorate of Pharmaceuticals and Pharmacy, Ministry of Health of Turkey, 06100 Sıhhiye, Ankara, Turkey, Fax: +90 312 565 52 57, E-mail:

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Received: 2014-11-17
Revised: 2015-7-29
Accepted: 2015-7-30
Published Online: 2015-9-15
Published in Print: 2015-7-1

©2015 by De Gruyter

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