Antimicrobial and antiprotozoal activity of 3-acetyl-2,5-disubstituted-1,3,4-oxadiazolines: a review

MEDICINAL CHEMISTRY RESEARCH Medicinal Chemistry Research https://doi.org/10.1007/s00044-019-02463-w REVIEW ARTICLE Antimicrobial and antiprotozoal activity of 3-acetyl-2,5disubstituted-1,3,4-oxadiazolines: a review Kinga Paruch 1 ● Łukasz Popiołek1 Monika Wujec1 ● 1234567890();,: 1234567890();,: Received: 12 July 2019 / Accepted: 21 October 2019 © The Author(s) 2019 Abstract In the last 20 years there has been a significant increase in interest in the structure of oxadiazole derivatives, especially 3-acetyl-1,3,4-oxadiazolines. It is known that these derivatives possess: antibacterial, antifungal, antitubercular, antiprotozoal, anticancer and anti-inflammatory activity. Therefore, many medicinal chemists choose 3-acetyl-1,3,4oxadiazoline scaffold for the synthesis of new potentially active substances with a better effectiveness and less toxicity. This article is a literature review since 2000 presenting new derivatives with proven antimicrobial and antiprotozoal activity, containing in its structure a 3-acetyl-1,3,4-oxadiazoline system. Keywords 3-acetyl-1,3,4-oxadiazolines Antimicrobial activity Antiprotozoal activity ● Introduction The 1,3,4-oxadiazoles constitute an important class of chemical compounds, which possess significant biological activity. The 1,3,4-oxadiazole system is also present in several currently used medicines, e.g. furamizole (Bala et al. 2010), nesapidil (Schlecker and Thieme 1988), raltegravir (Cocohoba and Dong 2008), tiodazosin (Vardan et al. 1983) and zibotentan (James and Growcott 2009) (Fig. 1). Among 1,3,4-oxadiazoles, the 3-acetyl-1,3,4-oxadiazoline derivatives are currently being synthesized by many medicinal chemists due to the fact that these derivatives exhibit wide spectrum of activities, mainly antibacterial, antifungal, antitubercular, antiprotozoal, anticancer and anti-inflammatory activity (Habibullah et al. 2016). Their mechanism of synthesis is usually based on two step reactions. Firstly, the condensation reaction between appropriate carboxylic acid hydrazide and aldehydes is performed and subsequently obtained hydrazones are subjected to cyclization reaction with acetic anhydride (Desai and Dodiya 2016). The identification and confirmation of the chemical * Kinga Paruch 1 Department of Organic Chemistry, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin, 4A Chodźki Street, Lublin, Poland ● structure of 3-acetyl-1,3,4-oxadiazolines is possible, e.g. by commonly used 1H NMR and 13C NMR spectra analysis. In the 1H NMR spectra we can find characteristic signals for this group of compounds like, singlet signal for CH group, which is present in the 1,3,4-oxadiazoline ring and singlet signal for methyl group present in acetyl substituent. Similarly, in 13C NMR spectra we should seek for carbon signal of CH group and carbon atom of 1,3,4-oxadiazole ring and carbonyl group in acetyl substituent (Popiołek et al. 2019). This review article gather literature findings since 2000 and is focused on the antimicrobial and antiprotozoal activity of compounds containing 3-acetyl-1,3,4-oxadiazoline scaffold. Antibacterial activity Due to the still current problem of bacterial and fungal infections caused by the increasing resistance of microorganisms to commonly used antibiotics and a limited number of drugs effective in combating with them, it is necessary to constantly search for new chemotherapeutic agents that will be more effective in the fight with microorganisms, less toxic and better tolerated by the patients. Many of the currently tested molecules have in their structure a 3-acetyl-1,3,4-oxadiazoline system and microbiological tests confirm great potential of this class of compounds as antimicrobial agents against Gram-positive and Gram-negative bacterial strains. Medicinal Chemistry Research Fig. 1 Chemical structures of furamizole a, nesapidil b, raltegravir c, tiodazosin d and zibotentan e Fig. 2 3-acetyl-2,5-disubstituted-1,3,4-oxadiazoline (1) with significant activity against S. aureus According to Zheng et al. (2018) the 1,3,4-oxadiazole derivatives displayed activity against S. aureus, which is attributed in part to the presence of a toxophoric –N = C–O– linkage group, which may react with the nucleophilic centers of the microbial cells. The same research group also suggested that 1,3,4-oxadiazole derivatives, which they have synthesized may affect the transcription of biofilmrelated genes, such as sarA, icaA, spa, fnbA and fnbB, which are essential for biofilm formation (Zheng et al. 2018). Rollas et al. (2002) synthesized a series 4-fluorobenzoic acid derivatives, which were tested against three bacterial strains: S. aureus, E. coli and P. aeruginosa. Ceftriaxone was used as positive control. Tested compounds displayed high activity against S. aureus and the most active was 1 with MIC = 8 µg/ml (Fig. 2). Other derivatives showed Fig. 3 Novel 3-acetyl-1,3,4-oxadiazoline of 4-(pyrrol-1-yl)benzoic acid hydrazide (2) with significant antibacterial activity lower activity but may serve as the basis for future modification in searching for more active substances (Rollas et al. 2002). Joshi et al. (2008) synthesized new derivatives of 4-(pyrrol-1-yl)benzoic acid hydrazide. Among synthesized 3-acetyl-1,3,4-oxadiazolines compound 2 displayed significant antibacterial activity. Antimicrobial activity assays were performed against three Gram-positive and three Gram-negative bacterial strains. The MIC values of synthesized compound 2 were within the range of 31.25–62.5 µg/ml (Fig. 3). Reference substances: ciprofloxacin and norfloxacin showed MIC values below 5 µg/ml (Joshi et al. 2008). The series of 1-(2-aryl-5-phenethyl-1,3,4-oxadiazol-3 (2H)-yl)ethanones were synthesized by cyclization of imines with acetic anhydride (Fuloria et al. 2009). Obtained Medicinal Chemistry Research derivatives were tested for antibacterial activity against S. aureus and P. aeruginosa. On the basis of conducted assays it was revealed that obtained derivatives showed similar or better activity than ampicillin, which was used as reference substance. In addition, it was proved that introduction of substituent in para position of phenyl ring of 1,3,4-oxadiazole moiety strengthen antimicrobial activity, what was Fig. 4 New 1-(2-aryl-5-phenethyl-1,3,4-oxadiazol-3(2H)-yl)ethanones (3–7) with antibacterial activity Fig. 5 The influence of substituents of 1,3,4-oxadiazoline derivatives (3–7) on antibacterial activity Table 1 Antimicrobial activity-sensitivity testing results of 1-(2-aryl5-phenethyl-1,3,4-oxadiazol-3(2H)-yl)ethanones (3–7) Compound number R1 R2 Zone of inhibition in mm S. aureus P. aeruginosa 3 H N(CH3)2 24 24 4 H Cl 25 24 5 OH OH 23 20 6 H H 22 23 7 H OH 19 20 25 24 Ampicillin Fig. 6 New oxadiazoles obtained from 3-chloro-1-benzo [b]thiophene-2-carbohydrazine (8–23) with antibacterial properties especially seen in compounds 3: ZOI = 24 mm (S. aureus) and 24 mm (P. aerugin (...truncated)