A new class of nifuroxazide analogues: Synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus

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Abstract

Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been an increasing problem worldwide since the initial reports over 40 years ago. To examine new drug leads with potential antibacterial activities, 14 p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides were designed, synthesized, and tested against standard and multidrug-resistant S. aureus strains by serial dilution tests. All compounds exhibited significant bacteriostatic activity and some of them also showed bactericidal activity. The results confirmed the potential of this class of compounds as an alternative for the development of selective antimicrobial agents.

Graphical abstract

In this study it was evaluated the antibacterial activity of 14 acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides (Fig. 1) against multidrug-resistant (3SP/R33) Staphylococcus aureus strain. Compounds were designed according to physicochemical properties and all of them exhibited significant bacteriostatic activity. It was observed bactericidal activity for some compounds tested. These new compounds confirming the potential of nifuroxazide analogs as antimicrobial agents and represent an alternative for the development of promising antibacterial drugs.

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Introduction

The resistance of bacteria against antimicrobial agents has become a widespread medical problem especially as nosocomial pathogens. Treatment options for these infections are often limited, especially in debilitated and immunocompromised patients.1, 2

In the last decade, there has been a reemergence of Gram-positive bacteria, in particular Staphylococcus aureus, which is considered one of the main causes of nosocomial infections.3, 4, 5 The infectious disease caused by MRSA (methicillin-resistant Staphylococcus aureus) is currently a serious problem because these bacteria show a multidrug-resistant phenotype, that is, resistance not only to methicillin but also to several other drugs except vancomycin and teicoplanin. Although potent antistaphylococcal drugs are available, this infection continues to present significant morbidity and mortality rates, justifying the need for the development of more effective compounds for its treatment.6, 7, 8, 9

Nifuroxazide, Figure 1, a synthetic antimicrobial agent used as second or third choice in enteric infection treatments, presents excellent characteristics such as wide spectrum of activity, inability to promote significant bacterial resistance, and chemical structure favorable to synthetic modifications.10, 11, 12

In previous studies of nifuroxazide analogues accomplished by Tavares and co-workers,13, 14 the furanic ring was substituted by the thiophenic one and several p-aromatic substitutions were made, with a significant improvement of antibacterial activity being observed in the case of p-acetyl derivatives. The thiophenic analogues have the potential to be an ideal therapy for immunocompromised and hospitalized patients suffering from opportunistic infection and/or superinfection due to microbial substitution.

The physicochemical properties of a drug refer to any structural, physical or chemical properties that have an effect on its biological activity. The knowledge of these properties allows the medicinal chemist to identify which features are important or not for biological activity resulting, in a way, in a successful lead development process. With the constant advancement of QSAR (quantitative structure–activity relationships) studies as a molecular modification approach, this procedure has been applied in several scientific areas.10, 15

In order to use these medicinal chemistry advances to counter the high incidence of antibiotic-resistant microorganisms, this study is aimed at the design, synthesis, and determination of antimicrobial activity of p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides against S. aureus strains. The nifuroxazide phenolic hydroxyl was substituted by 14 groups conveniently selected according to physicochemical properties such as hydrophobicity and electronic distribution.15, 16 The choice of substituent groups was made in two steps. The first one involved the application of the Topliss’17 operational scheme for aromatic substitution. In a second step, more derivatives were selected according to a previously determined hydrophobicity range. In addition to the substituent selection, the furanic ring was substituted by a thiophenic one resulting in increased hydrophobicity of the compounds.

The potency of compounds obtained was determined using serial dilution tests18 against standard (ATCC 25923) and multidrug-resistant (3SP/R33)19 S. aureus strains. Good antimicrobial activity values were observed for most of the compounds tested.

Section snippets

Synthesis of p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides

Fourteen p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides were synthesized with good yields (90%) according to three standard methods: esterification reaction, ammonolysis reaction, and Schiff’s base preparation.13, 14 The synthesis of target compounds is outlined in Fig. 2. The Schiff bases (D) were prepared by reacting the substituted benzhydrazides (B) and 5-nitro-2-thiophene carboxaldehyde in a solution with strongly acidic pH. This reaction condition is essential

Conclusions

Fourteen 5-nitro-2-thiophenylidene derivatives were synthesized, structurally identified, and tested against standard (ATCC 25923) and multidrug-resistant (3SP/R33) S. aureus strains. The most active compound was 4-acetylbenzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazide and the least one was 4-butylbenzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazide. The results obtained for the multidrug-resistant S. aureus strain were consistent with those determined for the ATCC 25923 strain,

Synthesis and structural identification of p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazide derivatives

Target compounds were synthesized by reacting p-substituted benzoic acids with hydrazine and 5-nitro-2-thiophene carboxaldehyde (Fig. 2). Synthetic starting material, reagents, and solvents were purchased from Aldrich, Fluka or Labsynth. All solvents were of reagent grade and dried prior to use. Methods already described in the literature were used for the preparation of the compounds.13, 14, 20 Initially, the methyl esters (B) were synthesized from their respective substituted benzoic acids (1 

Acknowledgments

CAPES and FAPESP supported this research. The authors wish to thank Dra.Elsa Masae Mamizuka, coordinator of LRNFSA—FBC/FCF/USP, for providing the 3SP/R33 S. aureus strain and the necessary infrastructure to perform the microbiological assays.

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