Novel Derivatives of 4-Methyl-1,2,3-Thiadiazole-5-Carboxylic Acid Hydrazide: Synthesis, Lipophilicity, and In Vitro Antimicrobial Activity Screening
by
, , , and
Kinga Paruch
1,*
,
Łukasz Popiołek
1,
Anna Biernasiuk
2,
Anna Berecka-Rycerz
3,
Anna Malm
2,
Anna Gumieniczek
3 and
Monika Wujec
1 1
Chair and Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki Street, 20-093 Lublin, Poland
2
Chair and Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland
3
Chair and Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4 Jaczewskiego Street, 20-093 Lublin, Poland
*
Author to whom correspondence should be addressed.
Appl. Sci. 2021, 11(3), 1180; https://0-doi-org.brum.beds.ac.uk/10.3390/app11031180
Submission received: 10 January 2021
/
Revised: 23 January 2021
/
Accepted: 25 January 2021
/
Published: 27 January 2021
(This article belongs to the Special Issue Synthesis of Novel Heterocyclic Compounds and Evaluation of Their Antimicrobial Activity)
Abstract
:Bacterial infections, especially those caused by strains resistant to commonly used antibiotics and chemotherapeutics, are still a current threat to public health. Therefore, the search for new molecules with potential antimicrobial activity is an important research goal. In this article, we present the synthesis and evaluation of the in vitro antimicrobial activity of a series of 15 new derivatives of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid. The potential antimicrobial effect of the new compounds was observed mainly against Gram-positive bacteria. Compound 15, with the 5-nitro-2-furoyl moiety, showed the highest bioactivity: minimum inhibitory concentration (MIC) = 1.95–15.62 µg/mL and minimum bactericidal concentration (MBC)/MIC = 1–4 µg/mL.
1. Introduction
Antibiotics have been one of the most dynamically developing groups of medicines of the last decade [1]. The first use of an antibiotic (penicillin) in the early 20th century became a landmark in treating infections. Thanks to this, it was possible to reduce the mortality and the risk of postinfectious complications [2]. Unfortunately, as a result of the common use of penicillin, a strain of Staphylococcus aureus bacterium appeared, which produced the penicillinase enzyme, giving it resistance to penicillin [3]. In response to this fact, newer antibiotics were introduced as treatments. Additionally, strains of bacteria resistant to these new antibacterial agents were also isolated [4]. This was an important signal that the golden age of antibiotics would not last forever. This century has seen that the problem of antibiotic resistance poses a real threat to patients and global public health [5]. Alarm pathogens are particularly dangerous due to therapeutic limitations. These include multidrug-resistant pathogens (MDR), extended resistance pathogens (XDR), as well as pathogens resistant to all available antibacterial drugs (PDR) [6,7]. This group includes extremely virulent strains of methicillin-resistant S. aureus (MRSA) [3,8,9]. This etiological agent is thought to be one of the most common causes of life-threatening infections in palliative care facilities and during inpatient treatment [10]. This problem has been noticed by key institutions and global and European public health organizations [1]. The EAAD (European Antibiotic Awareness Day) and the WAAW (World Antibiotic Awareness Week) information campaigns, organized by the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO), aim to raise awareness of global antimicrobial resistance and encourage general public healthcare professionals to follow best practices to avoid the further emergence and spread of drug-resistant infections [11].
Among chemotherapeutics, we can find compounds which contain the hydrazide–hydrazone moiety in their chemical structure (i.e., nitrofurazone, furazolidone, and nitrofurantoin) [12] (Figure 1). As can be seen from the literature review, the compounds with an azomethine group (–NH–N=CH–) show a significant and broad spectrum of bioactivity, mainly antibacterial [13,14,15,16,17,18,19,20], antifungal [21], antitubercular [22], antimycobacterial [23], anticancer [24,25,26,27], anti-inflammatory [28], anticonvulsant [29], and antiviral activity [30]. Several previously published articles by our research team proved that hydrazide–hydrazones can exhibit significant antimicrobial and anticancer activity [12,31,32,33,34,35]. The method of synthesis that allowed us to obtain hydrazide–hydrazones with good yields was described in our previous articles: the condensation of hydrazide with an appropriate aldehyde in an ethyl alcohol environment [32,34,35].
The 1,2,3-thiadiazole moiety also has great potential for designing new molecules with potential antimicrobial activity [36,37]. In the work of Shin et al., the biological activities of a series of new 1β-methylcarbapenems were compared. Among the tested compounds, the 1,2,3-thiadiazole derivative showed the strongest antibacterial activity and advanced pharmacokinetics in rats compared with other five-membered and six-membered derivatives [37].
We assumed that the combination of these two pharmacophores—the hydrazide–hydrazone and 1,2,3-thiadiazole moieties—could have a beneficial biological effect.
Based on the results obtained so far and on literature reports on the biological potential of hydrazide–hydrazones, in this study, we synthesized novel compounds in order to obtain substances with significant antimicrobial activity.
2. Materials and Methods
2.1. Chemistry
The Procedure of the Synthesis 4-Methyl-1,2,3-Thiadiazole-5-Carbohydrazide Derivatives (2–16).
New derivatives of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide (2–16) were synthesized according to literature findings [31,32,34]. Hydrazide (1) (0.01 mol) was placed in a round-bottomed flask and 15 mL of ethanol (96%) was added. After dissolving the hydrazide (1) in ethanol, appropriate substituted aldehyde (0.01 mol) was added. The solution was heated under reflux for 3 h. After that, it was allowed to cool and was placed in a refrigerator for 24 h. The formed precipitate was filtered off and recrystallized from ethanol.
Detailed physicochemical properties of new derivatives of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide are presented in the Supplementary Materials (2–16).
2.2. Microbiology
The in vitro bioactivity screening of compounds 2–16 (Table 1) was performed according to the procedure described earlier by our group [31,32,34], as well as by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute guidelines [38,39]. In microbiology assays, we used a panel of reference and clinical or saprophytic strains of microorganisms from the American Type Culture Collection (ATCC). All the experiments were repeated three times and representative data are presented. All the stock solutions of the tested compounds were dissolved in DMSO.
2.3. Lipophilicity
The experimental lipophilicity of new derivatives of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide (2–6, 8–16) (Table 2 and Table 3) was determined with the use of reversed-phase thin-layer chromatography. The detailed procedure is presented in the Supplementary Materials.
3. Results
3.1. Chemistry
For the purpose of this research, we synthesized 15 new hydrazide–hydrazones of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (2–16) (Scheme 1). Novel compounds (2–16) were obtained in good yields (57–98%). Synthesized substances are stable solids and can be dissolved in DMSO at room temperature. The successful synthesis of novel hydrazide–hydrazones was confirmed by elemental analysis and the FT-IR, 1H NMR, and 13C NMR spectra.
Novel derivatives of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (2–16) on the 1H NMR spectra possessed the following characteristic signals: The singlet signal for the NH group was in the range of 12.10–12.87 ppm and the singlet signal for the =CH group was at δ 8.06–8.63 ppm, which confirmed the successful conduction of condensation reactions. Signals for other fragments of synthesized molecules (2–16) were observed at expected values of chemical shift.
On the 13C NMR spectra for compounds (2–16), signals for =CH and C=O groups were observed in the range of δ 135.59–146.67 ppm and 163.31–164.61 ppm, respectively. Additionally, on the FT-IR spectra, we observed characteristic signals for =CH and C=O groups at expected regions.
Synthesized substances (2–16) were subjected to in vitro antimicrobial bioassays and to lipophilicity analysis (2–6, 8–16).
3.2. Microbiology
The results of the performed tests, as indicated in Table 1, show the potential antimicrobial activity of some of the obtained compounds, namely, 2, 3, 5, 6, 8, 9, and 14–16, against tested microorganisms. In contrast, for compounds 4, 7, 10, 11, 12, and 13, no antimicrobial activity was found.
Among the microorganisms that were taken into account in the evaluation of the activity of these substances, Gram-positive bacteria turned out to be the most sensitive. The tested compounds showed a similar effect to them, with the exception of hydrazide–hydrazone 15. This compound had particular effectiveness. The minimum inhibitory concentration (MIC) of substance 15 which inhibited bacterial growth ranged from 1.95 µg/mL (for some Staphylococcus spp.) to 15.62 µg/mL (for Enterococcus faecalis ATCC 29212). This proves the strong or very strong activity of this substance against these microorganisms. The minimum bactericidal concentration (MBC) values of hydrazide–hydrazone 15, which showed a lethal effect against Gram-positive bacteria, were in the range of 3.91–62.5 µg/mL. The MBC/MIC values for this hydrazide–hydrazone were within the range of 1–4, which indicates the lethal effect of this compound. The activity of compound 15 against the Staphylococcus aureus strains ATCC 25923 and ATCC 43300 was twofold greater than the reference compound—nitrofurantoin. On the other hand, against the S. aureus ATCC 6538 strain, the activity of this substance was seven times higher than for nitrofurantoin. Compound 15 also showed good activity in comparison to nitrofurantoin against strains of S. epidermidis ATCC 12228 and Micrococcus luteus ATCC 10240—two and eight times greater, respectively.
The remaining substances (2, 3, 5, 8, and 16) inhibited the growth of the bacterial strains at the concentrations of 250–1000 µg/mL. The minimum bactericidal concentrations that killed tested microbes were >1000 µg/mL. Compounds 6, 9, and 14 displayed similar ranges of activity against some Gram-positive bacteria (Staphylococcus spp., Bacillus subtilis ATCC 6633, and M. luteus ATCC 10240), or not at all.
Among Gram-negative bacteria, the antimicrobial effect was only demonstrated by compound 15 (MIC = 125–1000 µg/mL, MBC > 1000 µg/mL). Escherichia coli ATCC 25922 was the most sensitive strain against this substance (MIC = 125 µg/mL). In contrast, Pseudomonas aeruginosa ATCC 9027 did not have any sensitivity. Compound 2 was also found to have a weak effect against Bordetella bronchiseptica ATCC 4617. No antibacterial effect was observed for the remaining Gram-negative rods. In relation to yeast-like fungi of the genus Candida, a slight antifungal effect of compounds 2, 3, 5, 8, 15, and 16 was demonstrated (weak or moderate antimycotic effect). The minimum fungicidal concentration (MFC) values of the tested substances exceeded 1000 µg/mL. The Candida parapsilosis ATCC 22019 strain was the most sensitive to the tested substances (2, 3, 5, 8, 15, and 16). The remaining compounds (4, 6, 7, and 9–14) did not show an inhibitory effect on the growth of the fungi in the tested concentration ranges.
3.3. Lipophilicity
It is well known that chromatographic methods allow for establishing the experimental lipophilicity. In this research, the standardization procedure with six reference substances covering the range of lipophilicity of 0.46–3.80 was used. As a result, their log P values were highly correlated with their RM0 values in four organic modifiers, namely, acetone, acetonitrile, 1,4-dioxane, and methanol solvent systems, and appropriate calibration curves for further lipophilicity study were obtained:
- (1)
- acetone: log PEXP = 1.250RM0 − 0.256; r2 = 0.7265
- (2)
- acetonitrile: log PEXP = 2.563RM0 − 2.402; r2 = 0.8984
- (3)
- 1,4-dioxane: log PEXP = 0.902RM0 + 0.662; r2 = 0.9457
- (4)
- methanol: log PEXP = 1.101RM0 − 0.242; r2 = 0.9821
The obtained coefficients of determination (r2) for the mentioned equations were above 0.89 for three organic modifiers (i.e., acetonitrile, 1,4-dioxane, and methanol). Moreover, the r2 values were rather high (>0.72) for all organic modifiers used, including acetone. Similarly, for six reference compounds, the correlations between the RF and RM0 values for 2–6 and 8–16 were sufficiently high (r2 ≥ 0.91) for all solvents used. In addition, even better correlations (i.e., r2 ≥ 0.98 for 12 or 11 compounds) were obtained for acetonitrile, acetone, and 1,4-dioxane solvent systems, providing accuracy for further lipophilicity determination (Table 2). Experimental lipophilicity (log PEXP) of the synthesized 14 hydrazide–hydrazones (2–6 and 8–16) was calculated on the basis of the above calibration equations and respective RM0 values (Table 3). Generally, the highest log PEXP values were calculated for the methanol–water solvent systems, except for compounds 4 and 13, while the lowest values were obtained for acetonitrile, except for compound 14. As far as more detailed differences were concerned, the highest log PEXP values were calculated for compounds 2–4 containing monochloro(phenyl) substituents in ortho-, meta-, or para-positions. This was observed for all solvent systems used in our experiments. Thus, it can be stated that the position of the chloride atom in a phenyl ring did not affect the lipophilicity of these three derivatives (2–4). On the contrary, clearly seen differences were observed for dimethoxyphenyl-substituted hydrazide–hydrazones (compounds 12–14). Between them, compound 13, with a 2,4-dimethoxyphenyl substituent, showed the highest log P values for all solvent systems used in our experiments, illustrating the importance of positional isomerism in the lipophilicity of these compounds. At the same time, two chlorophenyl substituted derivatives (i.e., 2 and 3) showed higher log P values than similar fluorophenyl-substituted compounds (5 and 6). When compounds 8 and 10 were compared, the 4-hydroxy-3-iodo-5-methoxyphenyl-substituted hydrazide–hydrazone (10) was found to be more lipophilic than compound 8 with a 4-hydroxy-5-ethoxyphenyl substituent. This was observed for almost all solvent systems used in the present study (i.e., for the mixtures with acetonitrile, 1,4-dioxane, and methanol). Bearing in mind all the tested hydrazide–hydrazones (2–6 and 8–16), the lowest lipophilicity was shown for compound 15 substituted with the 5-nitro-2-furyl moiety.
4. Discussion
Condensation reaction of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide (1) with appropriate aldehydes allowed us to obtain a series of new hydrazide–hydrazone derivatives (2–16). The reaction efficiency was in the range of 57–98%, what can be considered as satisfactory. The most active compound was the hydrazide–hydrazone numbered 15, which had a 5-nitro-2-furyl moiety in its structure (i.e., a moiety analogous to a group of medicines, such as nitrofurazone, furazolidone, and nitrofurantoin). Due to this, it can be concluded that this fragment of compound 15 is essential for its bioactivity. It can also be seen that compounds 2, 3, 5, and 6, with the halogen atom in the ortho- and meta-position of the phenyl ring, had greater antimicrobial activity in comparison to compounds 4 and 7 with the halogen atom in the para-position, which did not show any activity.
5. Conclusions
In this research, we designed, synthesized, and analyzed 15 novel hydrazide–hydrazones (2–16) and evaluated them for their in vitro antimicrobial potential and lipophilicity.
The performed activity assays of the hydrazide–hydrazones showed that the best activity was attributed to substance 15 with the 5-nitro-2-furyl moiety, which showed activity especially against all tested Gram-positive bacterial strains. Based on the lipophilicity measured in methanol, because in this case the correlation coefficient is the highest, it can be concluded that despite the differences in the structure of Gram-negative bacteria and Gram-positive bacteria, the most desirable lipophilicity is within the limits of 2.25 (compound 15). Above this value, activity decreases. On the other hand, lipophilicity in the range of 3.63–4.09 causes activity against Gram-positive bacteria (compounds 2, 3, 5, and 16).
Supplementary Materials
The following are available online at https://0-www-mdpi-com.brum.beds.ac.uk/2076-3417/11/3/1180/s1.
Author Contributions
K.P. participated in the design of the study, performed the synthesis of new hydrazide-hydrazones, participated in the analysis of the spectral data of obtained compounds, and wrote the first draft of the manuscript, with the exception of antimicrobial activity and lipophilicity sections. K.P. also revised critically the final version of manuscript. Ł.P. participated in the design of the study and in the analysis of the spectral data of obtained compounds and wrote the associated section of the manuscript. A.B. performed the antimicrobial activity analysis of the obtained compounds and wrote the associated section of the manuscript. A.B.-R. performed the lipophilicity analysis of the obtained compounds and wrote the associated section of the manuscript. A.M. supervised and was involved in the conception of the antimicrobial activity analysis, helped with interpretation of antimicrobial activity data of synthesized compounds. A.G. supervised and was involved in the conception of the lipophilicity analysis, helped with interpretation of lipophilicity data of synthesized compounds. M.W. participated in the discussion section of the manuscript and revised critically the final version of manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article or supplementary material.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Beyer, P.; Moorthy, V.; Paulin, S.; Hill, S.R.; Sprenger, M.; Garner, S.; Simão, M.; Guerra, R.; Magrini, N.; Swaminathan, S. The drugs don’t work: WHO’s role in advancing new antibiotics. Lancet 2018, 392, 264–266. [Google Scholar] [CrossRef]
- Bellini, D.; Koekemoer, L.; Newman, H.; Dowson, C.G. Novel and Improved Crystal Structures of H. influenzae, E. coli and P. aeruginosa gonorrhoeae PBP2: Toward a Better Understanding of β-Lactam Target-Mediated Resistance. J. Mol. Biol. 2019, 3, 3501–3519. [Google Scholar] [CrossRef] [PubMed]
- Son, N.T.; Huong, V.T.T.; Lien, V.T.K.; Nga, D.T.Q.; Hai Au, T.T.; Nga, T.T.; Minh Hoa, L.N.; Binh, T.Q. First Report on Multidrug-Resistant Methicillin-Resistant Staphylococcus aureus Isolates in Children Admitted to Tertiary Hospitals in Vietnam S. J. Microbiol. Biotechnol. 2019, 29, 1460–1469. [Google Scholar] [CrossRef]
- Morehead, M.S.; Scarbrough, C. Emergence of Global Antibiotic Resistance. Prim. Care Clin. Off. Pract. 2018, 45, 467–484. [Google Scholar] [CrossRef]
- Zheng, Z.; Liu, Q.; Kim, W.; Tharmalingam, N.; Fuchs, B.B.; Mylonakis, E. Antimicrobial activity of 1,3,4-oxadiazole derivatives against planktonic cells and biofilm of Staphylococcus aureus. Future Med. Chem. 2018, 10, 283–296. [Google Scholar] [CrossRef]
- Alabresm, A.; Chen, Y.P.; Wichter-Chandler, S.; Lead, J.; Benicewicz, B.C.; Decho, A.W. Nanoparticles as antibiotic-delivery vehicles (ADVs) overcome resistance by MRSA and other MDR bacterial pathogens: The grenade hypothesis. J. Glob. Antimicrob. Resist. 2020, 22, 811–817. [Google Scholar] [CrossRef]
- Wang, Y.; Liao, J.; Mehmood, K.; Chang, Y.F.; Tang, Z.; Zhang, H. Escherichia coli isolated in pigs, Guangdong, China: Emergence of extreme drug resistance (XDR) bacteria. J. Infect. 2020, 81, 318–356. [Google Scholar] [CrossRef]
- Ishii, M.; Jorge, S.D.; De Oliveira, A.A.; Palace-Berl, F.; Sonehara, I.Y.; Pasqualoto, K.F.M.; Tavares, L.C. Synthesis, molecular modeling and preliminary biological evaluation of a set of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole as potential antibacterial, anti-Trypanosoma cruzi and antifungal agents. Bioorg. Med. Chem. 2011, 19, 6292–6301. [Google Scholar] [CrossRef] [Green Version]
- Chen, Z.; Han, C.; Huang, X.; Liu, Y.; Guo, D.; Ye, X. A molecular epidemiological study of methicillin-resistant and methicillin-susceptible staphylococcus aureus contamination in the airport environment. Infect. Drug Resist. 2018, 11, 2363–2375. [Google Scholar] [CrossRef] [Green Version]
- Welte, T.; Pletz, M.W. Antimicrobial treatment of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) pneumonia: Current and future options. Int. J. Antimicrob. Agents 2010, 36, 391–400. [Google Scholar] [CrossRef]
- European Centre for Disease Prevention and Contro Antimicrobial resistance in the EU/EEA (EARS-Net). Annu. Epidemiol. Rep. 2019 2020. [CrossRef]
- Popiołek, Ł. Hydrazide–hydrazones as potential antimicrobial agents: Overview of the literature since 2010. Med. Chem. Res. 2017, 26, 287–301. [Google Scholar] [CrossRef] [Green Version]
- Küçükgüzel, S.G.; Mazi, A.; Sahin, F.; Öztürk, S.; Stables, J. Synthesis and biological activities of diflunisal hydrazide-hydrazones. Eur. J. Med. Chem. 2003, 38, 1005–1013. [Google Scholar] [CrossRef] [PubMed]
- Metwally, K.A.; Abdel-Aziz, L.M.; Lashine, E.S.M.; Husseiny, M.I.; Badawy, R.H. Hydrazones of 2-aryl-quinoline-4-carboxylic acid hydrazides: Synthesis and preliminary evaluation as antimicrobial agents. Bioorg. Med. Chem. 2006, 14, 8675–8682. [Google Scholar] [CrossRef]
- Abdelrahman, M.A.; Salama, I.; Gomaa, M.S.; Elaasser, M.M.; Abdel-Aziz, M.M.; Soliman, D.H. Design, synthesis and 2D QSAR study of novel pyridine and quinolone hydrazone derivatives as potential antimicrobial and antitubercular agents. Eur. J. Med. Chem. 2017, 138, 698–714. [Google Scholar] [CrossRef] [PubMed]
- Özkay, Y.; Tunali, Y.; Karaca, H.; Işikdaǧ, I. Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazone moiety. Eur. J. Med. Chem. 2010, 45, 3293–3298. [Google Scholar] [CrossRef]
- Krátký, M.; Bősze, S.; Baranyai, Z.; Stolaříková, J.; Vinšová, J. Synthesis and biological evolution of hydrazones derived from 4-(trifluoromethyl)benzohydrazide. Bioorg. Med. Chem. Lett. 2017, 27, 5185–5189. [Google Scholar] [CrossRef]
- Pham, V.H.; Phuong, T.; Phan, D.; Phan, D.C.; Vu, B.D. Synthesis and Bioactivity of Hydrazide-Hydrazones with the 1-Adamantyl-Carbonyl Moiety. Molecules 2019, 24, 4000. [Google Scholar] [CrossRef] [Green Version]
- Haiba, N.S.; Khalil, H.H.; Moniem, M.A.; El-Wakil, M.H.; Bekhit, A.A.; Khattab, S.N. Design, synthesis and molecular modeling studies of new series of s-triazine derivatives as antimicrobial agents against multi-drug resistant clinical isolates. Bioorg. Chem. 2019, 89, 103013. [Google Scholar] [CrossRef]
- Ajani, O.O.; Iyaye, K.T.; Aderohunmu, D.V.; Olanrewaju, I.O.; Germann, M.W.; Olorunshola, S.J.; Bello, B.L. Microwave-assisted synthesis and antibacterial propensity of N’-s-benzylidene-2-propylquinoline-4-carbohydrazide and N’-((s-1H-pyrrol-2-yl)methylene)-2-propylquinoline-4-carbohydrazide motifs. Arab. J. Chem. 2020, 13, 1809–1820. [Google Scholar] [CrossRef]
- Backes, G.L.; Neumann, D.M.; Jursic, B.S. Synthesis and antifungal activity of substituted salicylaldehyde hydrazones, hydrazides and sulfohydrazides. Bioorg. Med. Chem. 2014, 22, 4629–4636. [Google Scholar] [CrossRef] [PubMed]
- Savini, L.; Chiasserini, L.; Gaeta, A.; Pellerano, C.; Moro, V.A. Synthesis and Anti-tubercular Evaluation of 4-Quinolylhydrazones. Bioorg. Med. Chem. 2002, 10, 2193–2198. [Google Scholar] [CrossRef]
- Angelova, V.T.; Valcheva, V.; Vassilev, N.G.; Buyukliev, R.; Momekov, G.; Dimitrov, I.; Saso, L.; Djukic, M.; Shivachev, B. Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-chromene and coumarin scaffold. Bioorg. Med. Chem. Lett. 2017, 27, 223–227. [Google Scholar] [CrossRef] [PubMed]
- Sreenivasulu, R.; Reddy, K.T.; Sujitha, P.; Kumar, C.G.; Raju, R.R. Synthesis, antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives. Bioorg. Med. Chem. 2019, 27, 1043–1055. [Google Scholar] [CrossRef] [PubMed]
- Vicini, P.; Incerti, M.; Doytchinova, I.A.; La Colla, P.; Busonera, B.; Loddo, R. Synthesis and antiproliferative activity of benzo[d]isothiazole hydrazones. Eur. J. Med. Chem. 2006, 41, 624–632. [Google Scholar] [CrossRef]
- Terzioglu, N.; Gürsoy, A. Synthesis and anticancer evaluation of some new hydrazone derivatives of 2,6-dimethylimidazo[2,1-b][1,3,4]thiadiazole-5-carbohydrazide. Eur. J. Med. Chem. 2003, 38, 781–786. [Google Scholar] [CrossRef]
- Mohareb, R.M.; Fleita, D.H.; Sakka, O.K. Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumor activity. Molecules 2011, 16, 16–27. [Google Scholar] [CrossRef] [Green Version]
- Sondhi, S.M.; Dinodia, M.; Kumar, A. Synthesis, anti-inflammatory and analgesic activity evaluation of some amidine and hydrazone derivatives. Bioorg. Med. Chem. 2006, 14, 4657–4663. [Google Scholar] [CrossRef]
- Dimmock, J.R.; Vashishtha, S.C.; Stables, J.P. Anticonvulsant properties of various acetylhydrazones, oxamoylhydrazones and semicarbazones derived from aromatic and unsaturated carbonyl compounds. Eur. J. Med. Chem. 2000, 35, 241–248. [Google Scholar] [CrossRef]
- Gürsoy, E.; Dincel, E.D.; Naesens, L.; Ulusoy Güzeldemirci, N. Design and synthesis of novel Imidazo[2,1-b]thiazole derivatives as potent antiviral and antimycobacterial agents. Bioorg. Chem. 2020, 95, 103496. [Google Scholar] [CrossRef]
- Popiołek, Ł.; Biernasiuk, A. Design, synthesis, and in vitro antimicrobial activity of hydrazide–hydrazones of 2-substituted acetic acid. Chem. Biol. Drug Des. 2016, 88, 873–883. [Google Scholar] [CrossRef] [PubMed]
- Popiołek, Ł.; Biernasiuk, A.; Berecka, A.; Gumieniczek, A.; Malm, A.; Wujec, M. New hydrazide–hydrazones of isonicotinic acid: Synthesis, lipophilicity and in vitro antimicrobial screening. Chem. Biol. Drug Des. 2018, 91, 915–923. [Google Scholar] [CrossRef] [PubMed]
- Popiołek, Ł.; Biernasiuk, A. Synthesis and investigation of antimicrobial activities of nitrofurazone analogues containing hydrazide-hydrazone moiety. Saudi Pharm. J. 2017, 25, 1097–1102. [Google Scholar] [CrossRef] [PubMed]
- Popiołek, Ł.; Biernasiuk, A.; Paruch, K.; Malm, A.; Wujec, M. Synthesis and in Vitro Antimicrobial Activity Screening of New 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazoline Derivatives. Chem. Biodivers. 2019, 16, e1900082. [Google Scholar] [CrossRef] [PubMed]
- Popiołek, Ł.; Patrejko, P.; Gawrońska-Grzywacz, M.; Biernasiuk, A.; Berecka-Rycerz, A.; Natorska-Chomicka, D.; Piątkowska-Chmiel, I.; Gumieniczek, A.; Dudka, J.; Wujec, M. Synthesis and in vitro bioactivity study of new hydrazide-hydrazones of 5-bromo-2-iodobenzoic acid. Biomed. Pharmacother. 2020, 130, 110526. [Google Scholar] [CrossRef]
- Popiołek, Ł.; Patrejko, P.; Gawrońska-Grzywacz, M.; Biernasiuk, A.; Berecka-Rycerz, A.; Natorska-Chomicka, D.; Piątkowska-Chmiel, I.; Gumieniczek, A.; Dudka, J.; Wujec, M. Synthesis, Characterization, Antimicrobial Activity, and Genotoxicity Assessment of Two Heterocyclic Compounds Containing 1,2,3-Selena- or 1,2,3-Thiadiazole Rings. Molecules 2019, 24, 4082. [Google Scholar]
- Shin, K.J.; Koo, K.D.; Yoo, K.H.; Kang, Y.K.; Park, S.W.; Kim, D.J. Synthesis and biological properties of new 1β-methylcarbapenems containing heteroaromatic thioether moiety. Bioorg. Med. Chem. Lett. 2001, 11, 2397–2399. [Google Scholar] [CrossRef]
- Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, M27-S4; Clinical and Laboratory Standards Institute (CLSI): Wayne, PA, USA, 2012. [Google Scholar]
- Committee, E.; Testing, S.; Microbiology, C.; Escmid, I.D. EUCAST DISCUSSION DOCUMENT E. Dis 5. 1 MARCH 2003 Determination of minimum inhibitory concentrations (MICs) of antibacterial agents by broth dilution. Clin. Microbiol. Infect. 2003, 9, ix–xv. [Google Scholar]
Figure 1.
Commonly used antimicrobial agents with hydrazide–hydrazone scaffold.
Scheme 1.
Synthesis scheme of novel derivatives of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide.
Scheme 1.
Synthesis scheme of novel derivatives of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide.
Table 1.
The antimicrobial activity assay results for compounds 2–16.
| Species/Compound No. | MIC (MBC or MFC) (µg/mL) and {MBC/MIC or MFC/MIC} Compounds and Reference Substances | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 3 | 5 | 6 | 8 | 9 | 14 | 15 | 16 | CIP/NY * | NIT | CFX | APC | ||
| Gram-positive bacteria | Staphylococcus aureus ATCC 25923 | 500 (>1000) {>2} | 500 (>1000) {>2} | 500 (>1000) {>1} | - | 500 (>1000) {>2} | - | 1000 (>1000) {>1} | 7.81 (7.81) {1} | 500 (>1000) {>2} | 0.48 (0.48) | 15.62 (15.62) | 0.49 | nd |
| Staphylococcus aureus ATCC 6538 | 1000 (>1000) {>1} | 1000 (>1000) {>1} | 1000 (>1000) {>1} | - | 1000 (>1000) {>1} | - | - | 1.95 (3.91) {2} | 250 (>1000) {>4} | 0.24 (0.24) | 15.62 (15.62) | 0.98 | nd | |
| Staphylococcus aureus ATCC 43300 | 500 (>1000) {>2} | 500 (>1000) {>2} | 500 (>1000) {>1} | - | 500 (>1000) {>2} | - | - | 3.91 (3.91) {1} | 250 (>1000) {>4} | 0.24 (0.24) | 7.81 (15.62) | nd | nd | |
| Staphylococcus aureus ATCC 29213 | 500 (>1000) {>2} | 500 (>1000) {>2} | 1000 (>1000) {>1} | - | 500 (>1000) {>2} | - | 1000 (>1000) {>1} | 3.91 (7.81) {2} | 1000 (>1000) {>1} | 0.48 (0.48) | nd | nd | nd | |
| Staphylococcus epidermidis ATCC 12228 | 500 (>1000) {>2} | 500 (>1000) {>2} | 1000 (>1000) {>1} | - | 500 (>1000) {>2} | 1000 (>1000) {>1} | 1000 (>1000) {>1} | 1.95 (3.91) {2} | 500 (>1000) {>2} | 0.12 (0.12) | 3.91 (7.81) | 0.24 | nd | |
| Enterococcus faecalis ATCC 29212 | 500 (>1000) {>2} | 1000 (>1000) {>1} | 1000 (>1000) {>1} | - | 500 (>1000) {>2} | - | - | 15.62 (62.5) {4} | 1000 (>1000) {>1} | 0.98 (1.95) | nd | nd | nd | |
| Micrococcus luteus ATCC 10240 | 500 (>1000) {>2} | 500 (>1000) {>2} | 500 (>1000) {>1} | 250 (>1000) {>4} | 250 (>1000) {>2} | 250 (>1000) {>2} | 1000 (>1000) {>1} | 7.81 (31.25) {4} | 250 (>1000) {>4} | 0.98 (1.95) | 62.5 (62.5) | 0.98 | nd | |
| Bacillus subtilis ATCC 6633 | 500 (>1000) {>2} | 500 (>1000) {>2} | 500 (>1000) {>1} | - | 500 (>1000) {>2} | - | 250 (>1000) {>4} | 3.91 (3.91) {1} | 1000 (>1000) {>1} | 0.03 (0.03) | 3.91 (3.91) | 15.62 | 62.5 | |
| Bacillus cereus ATCC 10876 | 1000 (>1000) {>1} | 500 (>1000) {>2} | 1000 (>1000) {>1} | 1000 (>1000) {>1} | 1000 (>1000) {>1} | - | 1000 (>1000) {>1} | 7.81 (31.25) {4} | 500 (>1000) {>2} | 0.06 (0.12) | 7.81 (15.62) | 31.25 | nd | |
| Gram-negative bacteria | Bordetella bronchiseptica ATCC 4617 | 1000 (>1000) {>1} | - | - | - | - | - | - | 1000 (>1000) {>1} | - | 0.98 (0.98) | 125 (>1000) | nd | nd |
| Klebsiella pneumoniae ATCC 13883 | - | - | - | - | - | - | - | 500 (>1000) {>2} | - | 0.12 (0.24) | 15.62 (31.25) | nd | nd | |
| Proteus mirabilis ATCC 12453 | - | - | - | - | - | - | - | 500 (>1000) {>2} | - | 0.03 (0.03) | 62.5 (125) | nd | nd | |
| Salmonella typhimurium ATCC 14028 | - | - | - | - | - | - | - | 500 (>1000) {>2} | - | 0.06 (0.06) | 31.25 (62.5) | nd | nd | |
| Escherichia coli ATCC 25922 | - | - | - | - | - | - | - | 125 (>1000) {>1} | - | 0.004 (0.008) | 7.81 (15.62) | nd | nd | |
| Pseudomonas aeruginosa ATCC 9027 | - | - | - | - | - | - | - | - | - | 0.48 (0.98) | - | nd | nd | |
| Fungi | Candida albicans ATCC 2091 | - | 1000 (>1000) {>1} | - | - | 1000 (>1000) {>1} | - | - | - | 1000 (>1000) {>1} | 0.24 * (0.24) | na | na | na |
| Candida albicans ATCC 10231 | 1000 (>1000) {>1} | 1000 (>1000) {>1} | 1000 (>1000) {>1} | - | 1000 (>1000) {>1} | - | - | 1000 (>1000) {>1} | 1000 (>1000) {>1} | 0.48 * (0.48) | na | na | na | |
| Candida parapsilosis ATCC 22019 | 1000 (>1000) {>1} | 500 (>1000) {>2} | 1000 (>1000) {>1} | - | 500 (>1000) {>2} | - | - | 1000 (>1000) {>1} | 500 (>1000) {>2} | 0.24 * (0.48) | na | na | na | |
| Candida glabrata ATCC 90030 | - | 1000 (>1000) {>1} | - | - | - | - | - | - | - | 0.24 * (0.48) | na | na | na | |
| Candida krusei ATCC 14243 | - | - | - | - | 1000 (>1000) {>1} | - | - | - | - | 0.24 * (0.24) | na | na | na | |
“–” no activity; nd, not determined; na, not applicable; MIC = minimum inhibitory concentration; MBC = minimum bactericidal concentration; MFC = minimum fungicidal concentration. The standard chemotherapeutics used as positive controls: ciprofloxacin (CIP), nitrofurantoin (NIT), cefuroxime (CFX), and ampicillin (APC) for bacteria and nystatin (NY *) for fungi. Compounds with bactericidal effect (MBC/MIC ≤ 4) or fungicidal effect (MFC/MIC ≤ 4) are bolded. No bioactivity—MIC > 1000 µg/mL; mild bioactivity—MIC = 501–1000 µg/mL; moderate bioactivity—MIC = 126–500 µg/mL; good bioactivity—MIC = 26–125 µg/mL; strong bioactivity—MIC = 10–25 µg/mL; very strong bioactivity—MIC < 10 µg/mL.
Table 2.
The RM0 values of the synthesized 4-methyl-1,2,3-thiadiazole-5-carbooxylic acid derivatives (2–6 and 8–16).
Table 2.
The RM0 values of the synthesized 4-methyl-1,2,3-thiadiazole-5-carbooxylic acid derivatives (2–6 and 8–16).
| Compound No. | RM0 | S | r2 | φ |
|---|---|---|---|---|
| Acetone–water | ||||
| 2 | 3.04 | −0.04 | 0.9969 | 71.65 |
| 3 | 3.31 | −0.05 | 0.9937 | 71.41 |
| 4 | 3.33 | −0.05 | 0.9908 | 71.81 |
| 5 | 3.12 | −0.05 | 0.9933 | 68.74 |
| 6 | 2.54 | −0.04 | 0.9974 | 65.19 |
| 8 | 2.98 | −0.04 | 0.9937 | 68.59 |
| 9 | 3.45 | −0.05 | 0.9932 | 70.94 |
| 10 | 2.87 | −0.04 | 0.9926 | 65.99 |
| 11 | 2.20 | −0.04 | 0.9909 | 62.60 |
| 12 | 2.48 | −0.04 | 0.9613 | 69.78 |
| 13 | 3.05 | −0.04 | 0.9891 | 69.24 |
| 14 | 1.77 | −0.03 | 0.9147 | 65.78 |
| 15 | 1.60 | −0.03 | 0.9765 | 59.34 |
| 16 | 3.03 | −0.04 | 0.9942 | 68.79 |
| Acetonitrile–water | ||||
| 2 | 2.15 | −0.03 | 0.9968 | 74.34 |
| 3 | 2.11 | −0.03 | 0.9939 | 74.16 |
| 4 | 2.07 | −0.03 | 0.9971 | 75.29 |
| 5 | 1.70 | −0.02 | 0.9888 | 69.37 |
| 6 | 1.81 | −0.03 | 0.9933 | 56.23 |
| 8 | 1.91 | −0.03 | 0.9892 | 68.36 |
| 9 | 2.14 | −0.03 | 0.9971 | 70.08 |
| 10 | 2.12 | −0.03 | 0.9862 | 64.32 |
| 11 | 1.70 | −0.03 | 0.9956 | 56.05 |
| 12 | 1.92 | −0.03 | 0.9955 | 69.76 |
| 13 | 1.96 | −0.03 | 0.9970 | 71.49 |
| 14 | 1.96 | −0.04 | 0.9447 | 66.23 |
| 15 | 0.89 | −0.02 | 0.9643 | 52.19 |
| 16 | 1.85 | −0.03 | 0.9862 | 68.01 |
| 1,4-Dioxane–water | ||||
| 2 | 3.08 | −0.05 | 0.9900 | 66.87 |
| 3 | 3.01 | −0.05 | 0.9831 | 64.51 |
| 4 | 3.09 | −0.05 | 0.9973 | 65.47 |
| 5 | 2.87 | −0.05 | 0.9785 | 62.08 |
| 6 | 1.97 | −0.04 | 0.9873 | 55.08 |
| 8 | 2.63 | −0.04 | 0.9858 | 64.05 |
| 9 | 3.00 | −0.05 | 0.9978 | 63.29 |
| 10 | 2.70 | −0.05 | 0.9824 | 59.91 |
| 11 | 2.02 | −0.04 | 0.9812 | 55.25 |
| 12 | 2.80 | −0.05 | 0.9830 | 62.22 |
| 13 | 3.01 | −0.05 | 0.9724 | 64.55 |
| 14 | 1.83 | −0.03 | 0.9433 | 55.45 |
| 15 | 1.30 | −0.03 | 0.9867 | 50.08 |
| 16 | 2.72 | −0.04 | 0.9806 | 62.01 |
| Methanol–water | ||||
| 2 | 3.94 | −0.05 | 0.9672 | 84.91 |
| 3 | 3.88 | −0.05 | 0.9778 | 86.13 |
| 4 | 3.54 | −0.04 | 0.9792 | 88.16 |
| 5 | 3.71 | −0.05 | 0.9849 | 82.17 |
| 6 | 2.88 | −0.04 | 0.9915 | 77.01 |
| 8 | 3.47 | −0.04 | 0.9796 | 82.13 |
| 9 | 3.87 | −0.04 | 0.9826 | 84.45 |
| 10 | 3.58 | −0.05 | 0.9834 | 81.74 |
| 11 | 3.20 | −0.04 | 0.9821 | 77.20 |
| 12 | 3.79 | −0.05 | 0.9878 | 83.11 |
| 13 | 3.85 | −0.04 | 0.9621 | 85.94 |
| 14 | 3.18 | −0.04 | 0.9717 | 81.44 |
| 15 | 2.26 | −0.03 | 0.9456 | 71.85 |
| 16 | 3.51 | −0.04 | 0.9729 | 81.72 |
φ is the amount of organic modifier in the mobile phase, RM0 and S are the intercept and slope of the linear calibration equation, and r is the correlation coefficient.
Table 3.
The log PEXP values of the synthesized 4-methyl-1,2,3-thiadiazole-5-carbooxylic acid derivatives (2–6 and 8–16).
Table 3.
The log PEXP values of the synthesized 4-methyl-1,2,3-thiadiazole-5-carbooxylic acid derivatives (2–6 and 8–16).
| Compound No. | Log Pacetone | Log Pacetonitrile | Log P1,4-dioxane | Log Pmethanol |
|---|---|---|---|---|
| 2 | 3.55 | 3.10 | 3.44 | 4.09 |
| 3 | 3.89 | 3.02 | 3.37 | 4.02 |
| 4 | 3.90 | 2.90 | 3.45 | 3.66 |
| 5 | 3.64 | 1.96 | 3.25 | 3.84 |
| 6 | 2.92 | 2.23 | 2.44 | 2.93 |
| 8 | 3.47 | 2.48 | 3.03 | 3.57 |
| 9 | 4.05 | 3.09 | 3.37 | 4.01 |
| 10 | 3.33 | 3.02 | 3.09 | 3.70 |
| 11 | 2.49 | 1.94 | 2.49 | 3.28 |
| 12 | 2.84 | 2.52 | 3.18 | 3.92 |
| 13 | 3.55 | 2.62 | 3.38 | 4.00 |
| 14 | 1.96 | 2.62 | 2.31 | 3.25 |
| 15 | 1.74 | −0.11 | 1.84 | 2.24 |
| 16 | 3.53 | 2.34 | 3.11 | 3.63 |
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Paruch, K.; Popiołek, Ł.; Biernasiuk, A.; Berecka-Rycerz, A.; Malm, A.; Gumieniczek, A.; Wujec, M. Novel Derivatives of 4-Methyl-1,2,3-Thiadiazole-5-Carboxylic Acid Hydrazide: Synthesis, Lipophilicity, and In Vitro Antimicrobial Activity Screening. Appl. Sci. 2021, 11, 1180. https://0-doi-org.brum.beds.ac.uk/10.3390/app11031180
AMA Style
Paruch K, Popiołek Ł, Biernasiuk A, Berecka-Rycerz A, Malm A, Gumieniczek A, Wujec M. Novel Derivatives of 4-Methyl-1,2,3-Thiadiazole-5-Carboxylic Acid Hydrazide: Synthesis, Lipophilicity, and In Vitro Antimicrobial Activity Screening. Applied Sciences. 2021; 11(3):1180. https://0-doi-org.brum.beds.ac.uk/10.3390/app11031180
Chicago/Turabian StyleParuch, Kinga, Łukasz Popiołek, Anna Biernasiuk, Anna Berecka-Rycerz, Anna Malm, Anna Gumieniczek, and Monika Wujec. 2021. "Novel Derivatives of 4-Methyl-1,2,3-Thiadiazole-5-Carboxylic Acid Hydrazide: Synthesis, Lipophilicity, and In Vitro Antimicrobial Activity Screening" Applied Sciences 11, no. 3: 1180. https://0-doi-org.brum.beds.ac.uk/10.3390/app11031180
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