1. Introduction

2. Structure-Activity Relationships in Antimicrobial Thiazole-based Hybrid Compounds

2.2. Thiazole Clubbed with Five-Membered Heterocycles

Five-membered heterocycles represent an extensive group of valuable structures for designing pharmacologically active compounds, including antimicrobials. Compared to four-membered heterocycles, they have a significantly greater chemical stability and versatility, which is transposed in their ubiquitarian usage in pharmaceutical research and development.

Based on the literature search of the last six years, we will discuss further the structure-activity relationships in antimicrobial hybrid compounds containing thiazole clubbed with the following five-membered heterocycles and their derivatives: pyrazoline, pyrazolinone, pyrazole, imidazole, thiazolidinone, thiazolidindione, 1,3,4-thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, and thioxo-1,3,4-oxadiazole.

2.2.1. Thiazolyl-2-Pyrazoline Hybrid Compounds

2-Pyrazoline is an important scaffold in anti-infective drugs, possessing antibacterial, antifungal, antiviral, antiparasitic, and antituberculosis potential [9]. Herein, we present the structure-activity relationship for some series of thiazole linked with 2-pyrazoline derivatives with promising antimicrobial potential, to establish how clubbing these two heterocycles influences the biological activity of the entire molecule.

Based on the found structures, it can be concluded that there is one general scaffold consisting of both heterocycles linked directly, but in different positions. Therefore, there have been identified three types of linking patterns: the fifth position of the thiazole ring to the fifth position of 2-pyrazoline ring [10], the second position of the thiazole ring to the first position of 2-pyrazoline ring [11,12,13,14,15,16], and the fifth position of the thiazole ring to the third position of 2-pyrazoline ring [17] (Figure 4).

Cuartas et al. designed four series (8a-14a, 8b-14b, 8c-14c, 8d-14d) of 2-(N-mustard)-5-(2-pyrazolin-5-yl)-thiazoles (Figure 5), with two points of variation: the substituted phenyl from the third position of the 2-pyrazoline (R) and the first position of the 2-pyrazoline ring (R₁) [10]. The compounds are bearing a nitrogen mustard moiety, known for its DNA alkylating properties. Depending on each case, R₁ can be a carbonylic group (a and b) or a phenyl ring (c and d), while R can be hydrogen (14), a halogen atom (8-10), or etheric groups (11-13).

The compounds were tested for their antifungal activity against Candida sp. and Cryptococcus sp. strains and for their antibacterial activity against Gram-positive and Gram-negative strains. The results were quantified as IC₅₀, representing the minimum concentration that inhibits 50% of growth, and MIC [10]. Compounds 8c-14c (R₁ = -C₆H₅) and 12d-14d (R₁ = -3,5-di-Cl-C₆H₃) showed inferior activity (IC₅₀ = 15.6-125 µg/mL) against Cryptococcus neoformans ATCC 32264 compared to amphotericin B (IC₅₀ = 0.50 µg/mL) [10].

In terms of antibacterial activity, the compounds showed significant effect against vancomycin-intermediate S. aureus (VISA) (MICs = 3.25-500 µg/mL), methicillin-susceptible S. aureus (MSSA ATCC 25923) (MICs = 62.5-500 µg/mL), methicillin-resistant S. aureus (MRSA ATCC 43300) (MICs = 125-500 µg/mL), and Neisseria gonorrhoeae ATCC 31426 (MICs = 125-500 µg/mL), compared to penicillin, ceftriaxone, and ciprofloxacin [10].

SAR studies revealed that the nature of the substituents on 2-pyrazoline (a-d) and phenyl (8-14) were the most important for the antibacterial and antifungal activities (Figure 5) [10]. The phenyl substituent from the first position of the 2-pyrazoline ring (c) conferred anticryptococcal activity regardless of the other substituents (8c-14c), while 3,5-dichlorophenyl substituent (d) was conditioned by electron-donating groups, particularly methoxy (12d) or trimethoxy (13d) or no substituent at all (14d) on the phenyl ring from the third position of the 2-pyrazoline ring. It is worth mentioning that 3,5-dichlorophenyl substituent is found in the structure of some important antifungal azoles like miconazole, ketoconazole, or itraconazole. However, the situation is opposite for the antibacterial activity. The 3,5-dichlorophenyl substituent abolished the antibacterial effect, while for phenyl-substituted derivatives it was very low. The best activity was observed when small substituents in R₁ were present, like acetyl (a) and formyl (b). Another important aspect is that the presence of chloro (8a and 8b), bromo (9a and 9b), and fluoro (9c) substituents or no substituents (14b) increased the activity against VISA (Figure 5) [10]. No potential target was reported by the authors.

Rashdan and Abdelmonsef designed 2-(4-(1-thiazol-2-yl)-2-pyrazolin-3-yl)-1,2,3-triazol-1-yl)-1,3,4-thiadiazole, with a single point of variation: fifth position of the 2-pyrazoline ring (R) (Figure 6) [11].

These compounds were assayed for their antibacterial activity against Gram-positive and Gram-negative bacteria and for their antifungal activity against C. albicans [11]. The thiophene substituted compound 15 showed promising results against E. coli, P. aeruginosa, and S. aureus (MICs = 5-10 µg/mL), compared to ciprofloxacin (MICs = 1.25-7 µg/mL) [11].

Concerning the antifungal activity, the same compound showed identic activity to nystatin against C. albicans (MIC = 5 µg/mL) [11].

Based on the minimal structural differences between the obtained derivatives, it seems that switching from a bulkier (3-metoxy-4-hydroxy-phenyl in 16) to a smaller substituent (2-thienyl in 15) enhanced the activity (Figure 6) [11].

Additionally, compound 15 was a potent inhibitor of SARS-CoV-2 transmembrane serine protease 2 (TMPRSS2), which plays an important role in the disease propagation, based on molecular docking studies [11].

Budak et al. reported the synthesis of a series of 2-(4-(1-(thiazol-2-yl)-2-pyrazolin-3-yl)-phenyl)-methanoisoindol-1,3-dione derivatives. The obtained compounds varied by the substituent in the fifth position of the 2-pyrazoline ring (R), which can be an aryl (17-23) or hetaryl ring (24-25) (Figure 7) [12].

The compounds were tested for the antimicrobial activity against Gram-positive and Gram-negative bacteria and C. albicans ATCC 1213 [12]. The results were quantified by inhibition zone (IZ), through disk diffusion method. All compounds (17-25) showed inferior activity against S. aureus ATCC 29213 (IZs = 10-19 mm), compared to cefoperazone-sulbactam (IZs = 19-26 mm). Additionally, compound 25 was active against Proteus vulgaris KUEN 1329 (IZ = 10 mm), but inferior to the standard drug [12].

SAR studies in this series showed that aryl substitution induced better activity compared to hetaryl substitution (Figure 7). Thus, in the aryl substituted derivatives, para substitution (17-20) favorized an overall better activity compared to meta substitution (21-23). The position of R₁ substituent was found to be more important than their nature, as substitution in para with both electron-withdrawing and electron-donating groups yielded similar activities [12]. In the case of compounds 24 and 25, bearing 2-thienyl and 2-furanyl substituents, a broader activity spectrum was observed for 24, which could be attributed to the higher aromaticity of 2-thienyl compared to 2-furanyl substituent, which makes it suitable for the bioisosteric substitution of phenyl rings [12]. No potential target was reported by the authors.

Mansour et al. designed three series of 2-(3-aryl-5-hetaryl-2-pyrazolin-1-yl)-thiazole derivatives (Figure 8), with three points of variation: one is the linking position to the naphthyl ring (a = 1-naphthyl or b = 2-naphthyl) from the third position of 2-pyrazoline ring and the other two are in the fourth (R₁) and fifth positions (R₂) of the thiazole ring [13]. Depending on each case, R₁ can be a para-halogen substituted phenyl ring (26 and 27) or a methyl group (28-33), while R₂ can be either hydrogen (26 and 27) or various acyl substituents (28-30) and arenediazo groups (31-33) (Figure 8) [13].

The compounds were tested for the antimicrobial activity against Gram-positive and Gram-negative bacteria and various fungal strains [13]. Most of the compounds displayed antibacterial activity against S. aureus (IZs = 0.5-2.6 mm) and antifungal activity against A. flavus (IZs = 0.5-2.3 mm), but inferior compared to amoxicillin (IZs = 2.2-3.5 mm) and griseofulvin (IZs = 2.1-3.3 mm). Only compounds 27b and 33a were active against all the tested microbial strains (S. aureus, Bacillus subtilis, K. pneumoniae, P. aeruginosa, A. fumigatus, A. flavus, Syncephalastrum racemosum, Penicillium expansum, and C. albicans) [13].

SAR studies suggest the activity depends on the nature of R₁ and R₂ and the linkage 2-pyrazoline ring to the naphthyl group [13]. Thus, in the 4-(p-halophenyl)-thiazolyl series (26a,b and 27a,b) (Figure 8), bromo substituent (27a and b) inactivated the compounds, while the chloro substituent (26a and b) was responsible for the antibacterial activity, apart from compound 26b, which displayed activity against all tested bacterial and fungal strains. Therefore, chloro and 2-naphthyl substituents (26b) were the best combination for highly active antimicrobials [13].

In the 5-acylthiazolyl series (28a,b, 29a,b, and 30a,b) (Figure 8), the compounds substituted with acetate (29a and 29b) or anilido (30a and 30b) groups were inactive or had a very low activity only against A. flavus (IZ = 0.5 mm) and P. expansum (IZ = 0.8 mm), while acetyl substitution (28a and 28b) yielded a moderate antimicrobial activity (IZs = 0.5-1.2 mm) [13].

Finally, in the 5-arendiazothiazolyl series (31a,b, 32a,b, and 33a,b), the activity depended more on the linkage to the naphthyl group (a or b) [13]. Thus, the best combination was between p-chlorobenzenediazo and 1-naphthyl (33a), which was the most active. Combinations between p-toluenediazo and 1-naphthyl (32a) or benzenediazo and 2-naphthyl (31b) yielded inactive molecules (Figure 8) [13]. No potential target was reported by the authors.

Using a similar scaffold, Masoud et al. [14] reported the synthesis of two more series of 2-(3-aryl-5-hetaryl-2-pyrazolin-1-yl)-thiazole derivatives, with two points of variation: (R) linked to the fifth position of 2-pyrazoline ring (c = 3,4-dimethoxyphenyl and d = 1,3-benzodioxole) and (R₁) from the fifth position of thiazole ring [14]. Depending on each case, R₁ can be various acyl substituents (34-36) or arenediazo groups (37-39) (Figure 8).

The antimicrobial effect was assayed using the same strains and positive controls mentioned by Mansour et al [14]. The most notable results for the antibacterial activity were obtained for compounds 36d, 38d, and 39c against S. aureus (IZs = 0.9-1.2 mm), compounds 34c, 35c, 37c, 38c, and 39c against K. pneumoniae (IZs = 1.2-2.0 mm) and P. aeruginosa (IZs = 1.0-1.8 mm) [14].

In the case of antifungal activity, the most important results were obtained for compounds 37c, 38c, and 39d against C. albicans (IZs = 1.3-2.1 mm), compound 38c against A. fumigatus (IZ = 1.2 mm) and compound 38d against A. flavus (IZ = 2.3 mm) [14].

SAR studies in these compounds suggest that acyl group substitution in position 5 of the thiazole ring (34c,d, 35c,d, and 36c,d) results in only antibacterial active compounds (Figure 8) [14]. Favorable substituents for the antibacterial activity were acetate (34c and d), anilido (35c and d), and acetyl (36c and d), which was the opposite compared to the compounds by Mansour et al [14].

Arendiazo substitution of the thiazole ring (37c,d, 38c,d, and 39c,d) expanded the spectrum against both bacterial and fungal strains. In this case, the main difference in the potence was dictated by whether if the substituent from position 5 of the 2-pyrazoline ring was 3,4-dimethoxyphenyl (c) or 1,3-benzodioxole (d), with the first being more active [14]. No potential target was reported by the authors.

By analyzing the SAR studies in the molecules synthesized by both authors (Figure 8), it seemed that the naphthyl group brought drawbacks to the compounds designed by Mansour et al., as the antimicrobial potential was reduced compared to the compounds designed by Masoud et al, who replaced it with a 3,4-dimethoxyphenyl moiety. Thus, a higher polarity should be considered when designing novel antimicrobial compounds [13,14].

Bhandare et al. reported the synthesis of some 2-(2-pyrazolin-1-yl)-thiazoles in which the fourth position of the thiazole ring was linked via a methylene bridge to various thiol- and tioether-containing azoles (1,3,4-oxadiazole and 1,2,4-triazole) (Figure 9) [15].

The compounds were tested for their antibacterial activity against Gram-positive and Gram-negative strains and for their antifungal activity against Candida sp. and Aspergillus sp. strains [15]. Overall, all compounds displayed a significant antimicrobial potential. Compounds 42, 46, 48, and 49 showed similar activity (MICs = 0.5-8 µg/mL) against S. aureus ATCC 11632, S. faecalis ATCC 14506, K. pneumoniae ATCC 10031, E. coli ATCC 10536, P. aeruginosa ATCC 10145, compared to ciprofloxacin (MICs between ≤1 and >5 µg/mL) [15].

Regarding the antifungal activity, the same compounds showed similar activity against C. tropicalis ATCC 1369 and A. niger ATCC 6275, compared to fluconazole (MICs ≤ 1 µg/mL) [15].

SAR studies pointed out that the heterocyclic tetrad induced promising overall antibacterial and antifungal activities (Figure 9) [15]. The additional aryl substituent (42-46 and 48-51) in the thioether series was essential for the activity. Switching to a hetaryl substituent, 3-pyridinyl (47), decreased the activity. The substituents on aryl were also an important factor in determining the antibacterial and antifungal strengths. Thus, a small halogen substituent, like 4-fluoro (46 and 49), induced excellent activity, while larger substituents, such as 2-trifluoromethyl (44), 4-trifluoromethoxy (45), 4- or 5-chloro (43 and 50), and 4-bromo (51) significantly decreased the activity. Noteworthy, unsubstituted rings (42 and 48) also displayed important activity (Figure 9) [15].

These compounds could potentially target DNA gyrase, important for the replication of genetic material in bacteria, and Cytochrome P450 14 α-sterol demethylase, important for the synthesis of ergosterol from lanosterol, for the antifungal activity, based on the molecular docking studies [15].

Abdel-Wahab et al. designed a series of 2-(5-(3-(1,2,3-triazol-4-yl)-pyrazol-4-yl)-2-pyrazolin-1-yl)-thiazole (Figure 10) [16]. These compounds are para substituted on the phenyl ring from the third position of the 2-pyrazoline ring (R₁) and have an additional substituent in the fourth position of the thiazole ring (R₂).

The compounds were tested for the antimicrobial activity against Gram-positive and Gram-negative bacteria and C. albicans NRRL Y-477 [16]. Compounds 52 and 53 showed inferior activity (MIC = 50 µg/mL) against S. aureus ATCC 29213 and K. pneumoniae ATCC 13883, compared to ciprofloxacin (MIC = 25 µg/mL) [16].

Only compound 54 was active against C. albicans (MIC = 200 µg/mL), but the activity was inferior compared to clotrimazole (MIC = 25 µg/mL) [16].

SAR studies in these compounds suggest that identic substitution (52 and 53) of both 2-pyrazoline and 1,3-thiazole moieties could be responsible for the antibacterial activity (Figure 10). Compound 54, containing an additional 1-(p-tolyl)-5-methyl-1,2,3-triazol-4-yl moiety, may induce a closer resemblance to fluconazole than the rest of the compounds, by containing two triazole moieties in its structure, hence the better antifungal activity against C. albicans [16]. No potential target was reported by the authors.

Bondock and Fouda designed some 2-(N-allyl)-5-(2-pyrazolin-3-yl)-thiazole derivatives with various substituents in the first position of the 2-pyrazoline ring (55-60) (Figure 11) [17].

The compounds were tested for the antimicrobial activity against Gram-positive and Gram-negative bacteria and fungal strains [17]. All selected compounds showed similar activities (MICs = 0.03-7.81 µg/mL) against S. pneumoniae RCMB 010010 and S. epidermidis RCMB 010024, compared to ampicillin (MICs = 0.6-0.24 µg/mL). Compounds 55, 57, and 60 showed similar activity (MICs = 0.03-7.81 µg/mL) against E. coli RCMB 010052, P. vulgaris RCMB 010085, and K. pneumoniae RCMB 010093, compared to gentamycin (MICs = 0.03-1.95 µg/mL) [17].

In terms of antifungal activity, which was similar to amphotericin B (MICs = 0.12-7.81 µg/mL), compounds 56-58 and 60 showed results against A. fumigatus RCMB 02568 (MICs = 0.12-7.81 µg/mL), while only compounds 57 and 60 were active against S. racemosum RCMB 05922 (MICs = 0.24-7.81 µg/mL) [17].

According to SAR studies, substitution of 2-pyrazoline ring with a thiocarbamido group (57) favorized the overall antibacterial and antifungal activities (Figure 11), while phenylthiocarbamido group (58) only induced good activity against Gram-positive bacteria and A. fumigatus [17]. Substitution with a phenyl ring (56) induced a moderate antifungal activity (Figure 11). Further expansion of the molecule with a phenylthiazolyl moiety (59 and 60) yielded overall medium antibacterial and antifungal activities. The 4-fluorophenyl derivative (60) was more potent against S. epidermidis RCMB 010024, P. vulgaris RCMB 010085, A. fumigatus RCMB 02568, and S. racemosum RCMB 05922, compared to the compound with unsubstituted phenyl (59) [17]. No potential target was reported by the authors.

To conclude the results observed in the analyzed papers (Figure 12), clubbing thiazole with 2-pyrazoline to obtain novel antimicrobials should be considered when aiming for compounds active against Gram-positive bacterial strains, especially against S. aureus. Moderate results were observed against Gram-negative bacterial strains, except against K. pneumoniae, where the results were promising [13,14,15,16,17].

The antifungal activity was much lower compared to the antibacterial activity. Thus, this scaffold may not be suitable for designing potent antifungals.

Finally, it is worth mentioning that the 2-(2-pyrazolin-1-yl)-thiazole scaffold was the most common and is responsible for the majority of results concerning the antimicrobial activity of hybrid compounds containing thiazole and 2-pyrazoline heterocycles [11,12,13,14,15,16].

2.2.2. Thiazolyl-Pyrazolin-3-one Hybrid Compounds

3-Pyrazolinone is an important scaffold for designing antimicrobial molecules [18], as presented further.

Abu-Melha obtained some N-(4-pyrazolin-3-one)-2-thiazolyl-hydrazonomethyl-phenoxyacetamides, with various substituents in the fourth and fifth positions of the thiazole ring (Figure 13), through a multi-step synthesis between N-(4-antipyrinyl)-2-chloroacetamide, p-hydroxybenzaldehyde, thiosemicarbazide, and various α-halogenocarbonyl compounds [19].

The compounds were tested for their antibacterial activity against Gram-positive and Gram-negative strains and for their antifungal activity [19]. Compounds 61-63 showed superior antibacterial activity (MICs = 28-168 µg/mL) on S. aureus ATCC 25923, Salmonella typhimurium ATCC 14028, and E. coli ATCC 25922, compared to chloramphenicol (MICs = 143-152 µg/mL) and cephalothin (MICs = 135-229 µg/mL) [19].

In terms of antifungal activity, compounds 62 and 63 showed superior activity (MICs = 168-172 µg/mL) on C. albicans ATCC 10231, compared to cycloheximide (MIC = 254 µg/mL) [19].

Additionally, the compounds can target the penicillin binding proteins 4 (PBP4) from S. aureus and E. coli for the antibacterial activity, based on the molecular docking studies [19].

2.2.3. Thiazolyl-Pyrazole Hybrid Compounds

Pyrazole bears significant antimicrobial, anthelmintic, and anticancer properties, which makes this heterocycle an important motif when designing novel antimicrobial compounds [20]. Herein, we present the structure-activity relationship in thiazole clubbed with pyrazole compounds with promising antimicrobial potential, in order to establish how clubbing these two heterocycles influences the biological activity.

Based on the found structures, it can be concluded that there were two types of scaffolds used: one in which the thiazole and pyrazole rings are clubbed through a linker, which is a methylylidenehydrazinyl, and the other where both rings are linked directly. For the second type of scaffold, there were two possible linking positions to the pyrazole ring: one in the first position and the other in the third position of the pyrazole ring (Figure 14).

Gondru et al. [21] and Patil et al. [22] synthesized some series of 2-(pyrazol-4-yl)-methylylidenehydrazinyl-thiazoles (Figure 15). These compounds were substituted in the fourth position of thiazole ring with various aryl and hetaryl substituents (R₁), in the second position of 2-pyrazoline ring with a benzothiazole or phenyl ring (R₂), and in the fifth position with a coumarin (64-69) or a substituted phenyl ring (70-81) (R₃) (Figure 15).

The compounds were assayed for their antibacterial activity against both Gram-positive and Gram-negative strains and for their antifungal activity against Candida sp. and Aspergillus sp. strains [21,22]. Compounds 64, 65, 67, and 69 showed inferior activities (MICs = 1.9-7.8 µg/mL) on S. aureus MTCC 96 and MTCC 2940, Micrococcus luteus MTCC 2470, K. planticola MTCC 530, E. coli MTCC 739, and P. aeruginosa MTCC 2453, compared to ciprofloxacin (MIC = 0.9 µg/mL). Compounds 70-81 showed superior activities (MICs = 3.9-18.5 µg/mL) on S. aureus, E. coli, and P. aeruginosa, compared to chloramphenicol (MICs = 24.6-32.8 µg/mL) [21,22].

Concerning the antifungal activity, compounds 64, 66, 67, and 69 showed similar activities (MICs = 7.8 µg/mL) on C. albicans MTCC 3017 compared to miconazole (MIC = 7.8 µg/mL). Compounds 70-81 showed superior activities on A. niger and C. albicans (MICs = 3.9-11.3 µg/mL) [21,22].

Additionally, the antibiofilm activity was evaluated on S. aureus and K. planticola biofilms [21]. Compound 69 presented a promising biofilm inhibition against S. aureus MTCC 96 (IC₅₀ = 1.8 µM), while compound 67 inhibited the biofilm formation of S. aureus MTCC 2940 (IC₅₀ = 12 µM) and K. planticola MTCC 530 (IC₅₀ = 14 µM).

According to the structure-activity relationship study, inserting a strong electron-withdrawing group, particularly nitro, in the para position of the phenyl ring in R₁ (70, 73, 76, and 79) resulted in an increased overall antibacterial and antifungal activity, while meta substitution was not as favorable (71, 74, 77, and 80) (Figure 15). The presence of benzothiazole moiety (64-69), which is known for its toxicity, could halt any future progress towards leader molecules [21,22].

Compounds 64-69 could target dehydrosqualene synthase of S. aureus, important for staphyloxanthin biosynthesis, a virulence factor. Based on the molecular docking studies, the coumarin moiety is important for binding to the Lys20 residue, through hydrogen bonds [21].

Abdel-Aziem et al. [23] and Kumar et al. [24] designed some 5-(coumarin-3-yl)-2-(pyrazol-1-yl)-thiazoles. These compounds were halo-substituted in the sixth position of coumarin ring (R₁) and variously substituted in the third and fourth positions of the pyrazole ring (R₂ and R₃) (Figure 16).

The compounds were evaluated for their antibacterial activity, using the agar well diffusion method or MIC assay, against both Gram-positive and Gram-negative strains and for their antifungal activity against Candida sp. strains [23,24]. Compounds 82-85 showed superior activity on Enterococcus faecalis ATCC 29212, compared to chloramphenicol, while compounds 84 and 85 showed superior active P. aeruginosa ATCC 27853, compared to cephalotin [23]. Both compounds 86 and 87 showed superior activity (MICs = 15.67-31.25 µM) against S. aureus MTCC 3160, S. pyogenes MTCC 442, and E. faecalis MTCC 439, compared to kanamycin (MICs = 31.25-62.50 µM) [24].

Regarding the antifungal activity, compounds 86 and 87 showed inferior activity (MIC = 61.25 µM) against C. albicans NCPF 400034, C. keyfer NCPF 410004, C. krusei NCPF 44002, and C. parapsilosis NCPF 450002, compared to amphotericin B (MICs = 0.78-12.50 µM) [24].

SAR studies showed that small substituents, like methyl (82) and hydroxy (83), were important for the activity against E. faecalis, while the larger substituents, like trifluoromethyl (84), against P. aeruginosa (Figure 16). Moreover, only the compounds with both R₁ and R₃ substituents being electron-withdrawing groups (86 and 87) displayed an overall improved antibacterial and antifungal activity. No potential target was reported by the authors [23,24].

Mahmoodi and Ghodsi designed some 2-pyrazolium-thiazol-4-yl salts substituted in the fourth position of the thiazole ring with a coumarin, in the third position of pyrazolium ring with various substituted coumarins (R₂-R₄), and in the fifth position with various aryl and hetaryl substituents (R₁) (Figure 17) [25].

The compounds were tested, using the zone inhibition method, for their antibacterial activity against both Gram-positive and Gram-negative strains and for their antifungal activity against Aspergillus sp. strains [25]. Compounds 88-94 and 96 showed inferior activities (IZs = 12-17 mm) against S. aureus, E. coli and M. luteus compared to gentamycin (IZs = 18-21 mm) [25].

Only compound 93 was active (IZs = 16-17 mm) against on A. niger and A. flavus, but inferior to fluconazole (IZ = 25 mm), in terms of antifungal activity [25].

Nevertheless, the heterogeneity of the results and the lack of activity in MIC terms make it difficult to draw conclusions about potential structure-activity relationships. No potential target was reported by the authors [25].

Nalawade et al. designed a series of 2-phenyl-5-(4-hetaryl-pyrazol-3-yl)-thiazoles (Figure 18) [26].

The compounds were tested, using the well diffusion method, for the antibacterial activity against Gram-positive and Gram-negative strains and for the antifungal activity against three types of strains [26]. All tested compounds (99-115) showed inferior activity (IZs = 9.6-14.4 mm) against E. coli and S. epidermidis, compared to streptomycin (IZs = 18.52-25.0 mm). In terms of antifungal activity, all compounds were active (IZs = 13.0-22.3 mm) against C. albicans NCIM 3100, A. niger ATCC 504, and Rhodotorula glutinis NCIM 3168, but inferior to fluconazole (IZs = 18.35-25.30 mm) and ravuconazole (IZs = 20.15-28.64 mm).

The antifungal activity was further evaluated through MIC screening [26]. Eleven compounds (99-119) emerged as promising anti A. niger agents (MICs = 31.25 µg/mL), with similar activity compared to ravuconazole (MICs = 7.81-31.25 µg/mL). Twelve compounds (100, 102-106, 110-115) were moderately active against R. glutinis (MICs = 62.5 µg/mL) and only one (101) against C. albicans (MIC = 62.5 µg/mL), but with inferior activity compared to fluconazole (MIC = 7.81 µg/mL) and ravuconazole.

Structure-activity relationship in these compounds implies that the best activity against A. niger was in the presence of methyl (101-103) or fluoro (104-108 and 111) as substituents on the phenyl ring directly linked to thiazole, while bulkier substituents, such as chloro (108, 112, and 113) and bromo (109, 110, and 113-115), were associated with a lower activity (Figure 18). This was opposite in the case of anti R. glutinis activity.

The antifungal activity of these compounds can be attributed to their capacity to target lanosterol 14α-demethylase, based on the molecular docking studies. No potential target was reported by the authors for the antibacterial activity [26].

To conclude the results observed in the analyzed papers (Figure 19), clubbing thiazole with pyrazole to obtain novel antimicrobials seems to expand the activity spectrum, compared to 2-pyrazoline. Pyrazole-containing compounds displayed antibacterial activity against Gram-positive and Gram-negative strains, while the antifungal activity got increasingly better. However, it should be noted that additional structural elements, such as a hydrazine linker or a supplementary heterocycle, like coumarin or 1,2,3-triazole, could significantly influence the antimicrobial activity. For example, coumarin-containing compounds were only active against Gram-positive bacterial and fungal strains, while 1,2,3-triazole-containing compounds were potent antifungal agents.

Based on the provided results, the general structure-activity relationship studies of antimicrobial 3-(2-(pyrazol-1-yl)-thiazol-4-yl)-coumarins and 2-pyrazolium-thiazol-4-yl salts could be formulated as follows: a halogen atom, bromo or chloro, in the sixth position of the coumaryl moiety enhances, but is not essential (as observed in the pyrazolium series, Figure 17), the antimicrobial potential, while the nature of the substituents from pyrazole or pyrazolium moieties influences the spectrum. Thus, compounds containing electron-withdrawing groups had a larger span of activity compared to those containing electron-donating groups, covering both Gram-positive and Gram-negative bacterial strains, as well as fungal strains.

Nevertheless, clubbing pyrazole with 1,3-thiazole is a promising research hypothesis when designing novel antifungals.

2.2.4. Thiazolyl-Imidazole Hybrid Compounds

Imidazole is frequently present in various bioactive compounds. Besides the potent activity against fungal strains, imidazole is found in compounds with various effects, such as antibacterial, antituberculosis, antiviral, antiparasitic or anticancer [27].

Nikalje et al. reported the synthesis of some 2-(2,4,5-triphenyl-imidazol-1-yl)-thiazoles, variably substituted in the second position of imidazole ring (Figure 20) [28]. The general structure of these series was rationally designed by using the thiazole heterocycle from abafungin, isavuconazole, and ravuconazole, the imidazole heterocycle and the two phenyl rings from clotrimazole, flutrimazole, and bifonazole.

The compounds were tested for their antifungal activity against multiple strains. The activity was quantified using MIC₈₀, which is the minimal inhibitory concentration for 80% inhibition of growth. Among the synthesized compounds, those containing either electron-donating groups (116-119) or nitro (120) on the aryl showed superior activity, in most cases, against C. albicans NCIM 3471 and C. glabrata NCYC 388 (MIC₈₀ = 0.2-0.35 µg/mL), Fusarium oxysporum NCIM 1332 (MIC₈₀ = 20-35 µg/mL), A. flavus NCIM 539 (MIC₈₀ = 35-50 µg/mL), A. niger NCIM 1196 (MIC₈₀ = 40-45 µg/mL), and C. neoformans NCIM 576 (MIC₈₀ = 5-10 µg/mL), compared to miconazole and fluconazole (MIC₈₀ between 0.5 µg/mL and >64 µg/mL). The antifungal activity of these compounds can be attributed to their capacity to target lanosterol 14α-demethylase, based on the molecular docking studies [28].

2.2.5. Thiazolyl-Thiazolidin-4-one Hybrid Compounds

Thiazolidin-4-one is another versatile five-membered heterocycle, used in designing novel antibacterial compounds, one important direction being the development of antituberculosis compounds [29].

Othman et al. designed a series of novel 2-(thiazol-2-yl)-N-thiazolidin-4-ones, variably substituted in the second position of thiazolidin-4-one ring (Figure 21) [30].

The compounds were tested for their antibacterial activity against sensitive (ATCC 25177 H37Ra), MDR (multidrug resistant, ATCC 35822), and XDR (extended drug resistant, RCMB 2674) strains of Mycobacterium tuberculosis and various bronchitis causing bacteria [30]. Five compounds (121-125) showed equal or inferior activity against the sensitive strain, compared to isoniazid (MIC = 0.12 µg/mL). Three compounds (121, 123, and 125) showed activity against the MDR strain (MICs = 1.95-7.81 µg/mL), and one (123) against the XDR strain (MIC = 7.81 µg/mL). Concerning the antibacterial activity, all five compounds showed similar activity (MICs = 0.48-7.81 µg/mL) against Mycoplasma pneumoniae ATCC 15531, S. pneumoniae ATCC 1659, and K. pneumoniae ATCC 43816, while four compounds (123 and 125-127) showed similar activity against Bordetella pertussis ATCC 9340 (MICs = 1.95-7.81 µg/mL), compared to azithromycin (MICs = 0.49-7.81 µg/mL).

SAR studies showed that the activity on M. tuberculosis sensitive strain was favorably influenced by the presence in para position of halo-substituents (123 and 125) or methoxy substituents (121, 122, and 124). Monosubstitution (121, 123, and 125) was associated with MDR antituberculosis activity. Supplementary, the presence of a voluminous halogen in the fourth position (123) was associated with XDR antituberculosis activity, most likely due to increased molecular lipophilicity (Figure 21) [30].

Concerning the activity against bronchitis causing bacteria, SAR studies showed that the best antibacterial activity was associated with the grafting of methoxy groups in meta position (122 and 124) (Figure 21) [30].

Molecular docking studies showed that the compounds can target the enoyl-acyl carrier protein reductase InhA of M. tuberculosis, important for the type II fatty acids biosynthesis. The inhibition is enhanced by the substituent from the fourth position of the thiazole, the carbonyl of the ester group binding to the target through an accepting hydrogen bond. The inhibitory activity on InhA was further confirmed by in vitro studies [30].

Abo-Ashur et al. reported the synthesis of a series of 2-(thiazol-2-yl)-imino-thiazolidin-4-ones (Figure 22) [31].

The compounds were tested for their antituberculosis activity, with six compounds (128-133) presenting similar activity (MICs = 0.78-3.12 µg/mL) to isoniazid (MIC = 0.78 µg/mL), against M. tuberculosis RCMB 010126 [31].

The antibacterial activity was also tested against Gram-positive and Gram-negative strains [31]. Three compounds (130, 131, and 134) showed excellent activity against S. aureus RCMB 010028 and P. aeruginosa RCMB 010043 (MICs = 0.49-0.98 µg/mL) and six compounds (130-134) against E. coli RCMB 010052 (MICs = 0.49-0.98 µg/mL), compared to ciprofloxacin (MICs = 1.95-3.90 µg/mL) [31].

With respect to the antifungal activity, which was tested against Candida and Aspergillus strains, two compounds showed superior activity (130 and 134) against A. fumigatus (MICs = 0.49 µg/mL), and four compounds (127, 130, 131, and 134) against C. albicans (MICs = 0.49 µg/mL), compared to amphotericin B (MICs = 0.98-1.95 µg/mL) [31].

SAR studies in these series suggest that a halogen (126 and 129) or methoxy (127, 131, and 132) substituent grafted on the phenyl ring (R₂) is essential for the antituberculosis, antibacterial, and antifungal activities (Figure 22). Advantageous for these activities were also the bioisosteric substitution of the phenyl ring with a 3-pyridinyl (134) and the grafting of an additional morpholinyl ring (128 and 130) [31]. No potential target was reported by the authors.

2.2.6. Thiazolyl-Thiazolidindione Hybrid Compounds

Widely known for the antidiabetic activity in glitazones, the thiazolidinedione heterocycle was also used in designing new antibacterial, antifungal, antiretroviral, antituberculosis, and anticancer compounds [32].

Alegaon et al. designed a series of antimicrobial 2-(thiazolidin-2,4-dion-3-yl)-N-(thiazol-2-yl)acetamides (Figure 23). The active methylene from the fifth position of the thiazolidin-2,4,-dione ring was derivatized (R) with various aromatic and heteroaromatic aldehydes through Knoevenagel condensations [33].

The compounds were tested for their antibacterial activity against Gram-positive and Gram-negative strains and for their antifungal activity against various fungal strains [33]. Five compounds (135-139) showed inferior activity (MICs = 4-32 µg/mL) against S. aureus ATCC 25923, E. faecalis ATCC 35550, E. coli ATCC 35218, and P. aeruginosa ATCC 25619, compared to ciprofloxacin (MICs = 2 µg/mL) [33].

Concerning the antifungal activity, the same compounds showed inferior activity against C. albicans ATCC 2091, A. flavus NCIM 524, A. niger ATCC 6275, and C. neoformans (clinical isolate), compared to ketoconazole (MICs = 1-2 µg/mL) [33].

SAR studies underlined that the substitution of the arylidene moiety from the fifth position of thiazolidin-2,4-dione ring with electron-donating groups, especially methoxy (136-138), enhanced the overall antibacterial and antifungal activities (Figure 23). Bioisosteric substitution of the phenyl ring with 2-furanyl (139) also favorized the antibacterial and antifungal activities. The substitution with electron-withdrawing groups, such as nitro or cyano, almost abolished both activities [33].

These compounds could potentially target the ATP binding domain of bacterial DNA gyrase B and the fungal lanosterol 14α-demethylase, according to the molecular docking studies [33].

2.2.7. Thiazolyl-1,3,4-Thiadiazole Hybrid Compounds

The versatility of 1,3,4-thiadiazole heterocycle comes from its ability to act as a hydrogen binding domain, as a two-electron donor system and as a bioisosteric replacement of thiazole. Thus, it is a valuable moiety for designing novel antimicrobial, anticancer, and antiprotozoal compounds [34].

Using the artificial intelligence, Stokes et al. repurposed an antidiabetic compound, SU-3327, which acts as a c-Jun N-terminal protein kinase (JNK) inhibitor, into a promising antibacterial molecule called halicin. Structurally, halicin (140) contains a 5-nitrothiazole and a 2-amino-1,3,4-thiadiazole, linked in the 2,5’ positions by a thioether group (Figure 24) [35,36].

Halicin displayed broad antibacterial activity against E. coli (MIC = 2 µg/mL), M. tuberculosis, carbapenem-resistant Enterobacteriaceae and A. baumanii, but no activity against P. aeruginosa [35]. Further studies for the assessment of the antibacterial potential were reported by other authors as well [36,37].

Booq et al. tested halicin with significant results against S. aureus ATCC BAA-977 (MIC = 16 µg/mL), E. coli ATCC 25922 (MIC = 32 µg/mL), A. baumanii ATCC BAA-747 (MIC = 128 µg/mL), and A. baumanii MDR isolate (MIC = 256 µg/mL) bacterial strains [36]. Hussain et al. obtained promising results when assayed halicin against strains of E. faecalis and E. faecium (MICs = 4-8 µg/mL) [37]. Moreover, halicin showed proof of antibiofilm potential, alone and also in synergism with other molecules, as reported by some authors [38,39]. Currently, there are no ongoing clinical trials for testing halicin on humans.

The unique mechanism of action, which implies the disruption of membrane electrochemical gradient, pH modification and upregulation of iron acquisition genes, makes it difficult to acquire resistance. It is also possible that halicin may act as a siderophore prior to pH alteration [35].

2.2.8. Thiazolyl-1,2,3-Triazole Hybrid Compounds

1,2,3-Triazole is the most stable among heterocycles with three adjacent nitrogen atoms and it can be found in variable bioactive compounds, including antibacterial, antifungal, antimalarial, and anticancer agents [40]. Herein, we present the structure-activity relationship in thiazole clubbed with 1,2,3-triazole compounds with promising antimicrobial potential, to establish how clubbing these two heterocycles could potentially influence the biological activity.

Based on the found structures, it can be concluded that there were two types of scaffolds used: one in which the thiazole and 1,2,3-triazole rings are linked directly, but with different linking positions (a-b) [41,42], and the other one in which the rings are clubbed through various linkers and variable linking positions (c-e) [43,44,45] (Figure 25).

Shinde et al. reported the design of novel antituberculosis 5-(1,2,3-triazol-4-yl)-thiazoles, substituted in the second position of the thiazole ring with various aryl substituents (Figure 26) [41].

The antituberculosis activity was tested against M. tuberculosis H37Ra (ATCC 25177), using rifampicin (IC₅₀ = 0.002 µg/mL and MIC₉₀ = 0.75 µg/mL) as reference. The activity of the compounds was quantified using both IC₅₀ and MIC₉₀. While most of the compounds were very active in terms of IC₅₀ values (0.58-8.23 µg/mL) [41], only two compounds (141 and 142) were active in terms of MIC₉₀ values (2.22 µg/mL and 4.71 µg/mL), the activity being inferior to rifampicin [41].

SAR studies show that fluoro substitution of the benzyl group linked to 1,2,3-triazole is responsible for the antituberculosis activity (Figure 26) [41]. However, this boost in the activity only took place when the other phenyl ring was either unsubstituted (141) or 3-methyl substituted (142). Double halogen substitution was associated with a decrease in the activity [41].

These compounds can potentially target enoyl acyl carrier protein reductase, which is an important enzyme in the fatty acid biosynthesis and growth of mycobacteria, based on the molecular docking studies [41].

Mahale et al. synthesized a series of 2-(1,2,3-triazol-4-yl)-thiazole derivatives, substituted on the first position of 1,2,3-triazole ring (R₁) and the fifth position of thiazole ring (R₂) with aryl substituents (Figure 27) [42].

The compounds were tested for their antibacterial activity against Gram-positive and Gram-negative strains and for their antifungal activity against Candida sp. and Aspergillus sp. strains [42]. Compounds 144, 146, 148, and 150-154 were equally active (MIC = 0.5 µg/mL) against E. coli ATCC 25922 and S. aureus ATCC 25923, compared to streptomycin (MIC = 0.5 µg/mL).

Concerning the antifungal activity, compounds 143-145, 147, 149, and 150 were equipotent (MIC = 0.5 µg/mL) against C. albicans MTCC 2977 and A. niger MCIM 545, compared to griseofulvin (MIC = 0.5 µg/mL) [42].

SAR studies suggest that substitution with predominantly electron-withdrawing groups, like nitro and halogen atoms, provide an antibacterial effect to the molecules, while the antifungal effect can be achieved using electron-donating, such as methyl and methoxy, and electron-withdrawing groups in both positions (Figure 27). No potential target was reported by the authors [42].

Jagadale et al. designed a series of 1-(thiazol-5-yl)-2-(1,2,3-triazol-1-yl)-ethanol derivatives, substituted in the second position of the thiazole ring (R₁) and the fourth position of the 1,2,3-triazole ring (R₂) with various aryl substituents (Figure 28) [43].

The compounds were tested for the antibacterial activity against Gram-positive and Gram-negative strains and for the antifungal activity against various strains [43]. Compounds 156-158 showed inferior activity (MIC = 62.5 µg/mL) against S. epidermidis NCIM 2178, compared to streptomycin (MIC = 7.81 µg/mL) [43].

Regarding the antifungal activity, compounds 155 and 159-162 were inferior against A. niger (ATCC 504) compared to fluconazole (MIC = 7.81 µg/mL), but similar to ravuconazole (MIC = 31.25 µg/mL). Additionally, compound 158 displayed activity against R. glutinis (MIC = 62.5 µg/mL) too, but inferior to both reference compounds [43].

SAR studies suggest that substitution with 4-chloro (160-162) and 4-fluoro (159) in R₁, as well as unsubstituted phenyl (155) are responsible for the activity against A. niger (Figure 28). Fluoro substitution of only one (156-157, and 160) or both (158) of the phenyl rings was associated with antibacterial activity against S. epidermidis. Double 4-fluorophenyl substitution induced activity against S. epidermidis, A. niger, and R. glutinis, as seen in compound 158. No potential target was reported by the authors [43].

Poonia et al. designed some 2-(1,2,3-triazol-1-yl)-N-(thiazol-2-yl)-acetamides and 2-(1,2,3-triazol-1-yl)-N-(benzothiazol-2-yl)-acetamides, para-substituted on the phenyl-ureidomethyl moiety, linked to the fourth position of 1,2,3-triazole ring (Figure 29) [44].

The compounds were tested for their antibacterial activity against Gram-positive and Gram-negative strains and for their antifungal activity against Candida sp. and Rhizopus sp. strains [44]. All compounds (163-174) showed superior activity (MICs = 0.0074-0.0333 µmol/mL) against C. albicans MTCC 183 and Rhizopus oryzae MTCC, compared to fluconazole (MIC = 0.0408 µmol/mL) [44].

Concerning the antibacterial activity, four compounds (165, 170, 173, and 174) showed noteworthy activity. Compounds 165 and 170 showed inferior activity (MICs = 0.0287-0.0299 µmol/mL) against E. coli MTCC 1654 and S. aureus MTCC 3160, compared to ciprofloxacin (MIC = 0.0094 µmol/mL). Compounds 170 and 173 showed inferior activity (MICs = 0.0257-0.0299 µmol/mL) against P. fluorescens MTCC 664, compared to the reference drug, while compound 174 showed superior activity (MIC = 0.0071 µmol/mL). Lastly, compound 171 was the most active against Bacillus endophyticus (MIC = 0.0257 µmol/mL), but still inferior to the reference drug [44].

Based on the SAR studies, the insertion of thiazole or benzothiazole rings increased the antifungal activity, compared to the phenylureidopropargyl precursors and fluconazole (Figure 29) [44]. For the antibacterial activity, bromo (165, 169, and 173) and methoxy (166, 170, and 171) substitutions, as well as the annulation of the thiazole ring (171-174) were the most important [44].

These compounds act as antifungals by targeting sterol 14-α demethylase, according to the molecular docking studies [44].

Gondru et al. reported the synthesis of two series of 2-(1,2,3-triazol-4-yl-methoxybenzylidenehydrazinyl)-thiazoles, substituted on the fourth position of thiazole ring with aryl and hetaryl substituents (Figure 30) [45]. They used para-hydroxybenzaldehyde as starting material, of which the phenolic hydroxyl group was etherified with a substituted 1,2,3-triazole moiety, while the carbonylic group was derivatized to the corresponding hydrazonothiazoles [45].

The compounds were tested for their antibacterial activity against Gram-positive and Gram-negative strains and for their antifungal activity against various Candida sp. and Issatchenkia sp. strains [45]. Compounds 175-181 showed inferior activity (MICs = 2.8-15.7 µM) against S. aureus MTCC-96, S. aureus MLS16 (MTCC 2940), M. luteus MTCC 2470, K. planticola MTCC 530, E. coli MTCC 739, and P. aeruginosa MTCC 2453, compared to ciprofloxacin (MIC = 2.7 µM) [45].

Concerning the antifungal activity, compounds 176-180 showed superior activity (MICs = 5.9-14.2 µM) against C. albicans MTCC 183, MTCC 854, and MTCC 3018, C. aaseri MTCC 1962, C. glabrata MTCC 3019, and Issatchenkia hanoiensis MTCC 4755, compared to miconazole (MIC = 18.7 µM) [45].

According to the SAR studies, 4-methoxyphenyl (175), benzo[f]coumarinyl (176), and 8-methoxycoumarinyl (177), 6-bromo-8-methoxycoumarinyl (178), and 8-bromocoumarinyl (179) substitutions were associated with antibacterial activity against S. aureus (Figure 30) [45]. The presence of the coumarin heterocycle was important for the antifungal activity, especially against C. albicans MTCC 183 strain. By replacing the methoxy group from the coumarin ring with an ethoxy group or introducing electron-withdrawing groups, like chloro and nitro, in both 6- and 8- positions of the coumarin, cancelled the antibacterial effect, but not the antifungal one. No potential target was reported by the authors [45].

In conclusion, 1,2,3-triazole heterocycle is a versatile moiety for designing novel antimicrobial compounds with broad activity spectrum. As observed in the presented studies, clubbing with thiazole resulted in potent compounds against a large variety of pathogen strains, including mycobacteria.

A prominent feature of the presented compounds was the presence of substituted phenyl rings, linked directly to the heterocycles or through a linker. Thus, the difference between compounds’ activity were mostly attributed to these substituents. By far, the most used substituents in these compounds were halogens, methyl and methoxy groups [41,42,43,44,45]. A summary of the structure-activity relationships in antimicrobial 1,3-thiazole clubbed with 1,2,3-triazole hybrid compounds is presented in Figure 31.

2.2.9. Thiazolyl-1,3,4-Oxadiazole Hybrid Compounds

Similarly to the previously mentioned heterocycles containing three heteroatoms, the 1,3,4-oxadiazole ring can be found in a plenitude of compounds with various biological activities, including anticancer, antibacterial, antifungal, and antiviral effects. This heterocycle can act as bioisostere for the carbonyl group and can be used in the structure of a molecule as a flat aromatic linker to ensure an adequate orientation [46].

As reported in the literature, the 5-thioxo-1,3,4-oxadiazole heterocycle can be found in a series of anticancer and antimicrobial compounds [47,48,49], thus making this heterocycle an important contender for designing novel antimicrobials.

Some series of 2-thiazolyl-5-mercapto-1,3,4-oxadiazoles, either linked through a methylene linker between the fourth position of thiazole ring and the second position of 1,3,4-oxadiazole ring (Figure 33), or directly linked between the fifth position of thiazole ring and the second position of 1,3,4-oxadiazole ring (Figure 34), were synthesized [50,51].

The compounds exist in two tautomeric forms (Figure 32). The existing data [52] show that the thione tautomer (II) is more stable in the solid state, while in solution the thiol tautomer (I) is predominant. The existence of thiol-thione tautomerism was valorized by obtaining the corresponding thioether derivatives (Figure 33) and Mannich bases (Figure 34) [50,51].

Figure 32. The thiol-thione tautomerism [52].

Figure 32. The thiol-thione tautomerism [52].

Figure 33. SAR studies in 1,3-thiazole clubbed in 2-(thiazol-4-yl)-methylene-5-thio-1,3,4-oxadiazoles urease inhibitors, reported by Athar Abasi et al. [50].

Figure 33. SAR studies in 1,3-thiazole clubbed in 2-(thiazol-4-yl)-methylene-5-thio-1,3,4-oxadiazoles urease inhibitors, reported by Athar Abasi et al. [50].

Figure 34. SAR studies in antimicrobial 2-(thiazol-5-yl)-5-mercapto-1,3,4-oxadiazoles, reported by Desai et al. [51].

Figure 34. SAR studies in antimicrobial 2-(thiazol-5-yl)-5-mercapto-1,3,4-oxadiazoles, reported by Desai et al. [51].

Athar Abbasi et al. described the synthesis of 2-(thiazol-4-yl)-5-thio-1,3,4-oxadiazoles, capable of urease inhibition, thus offering an alternative potential treatment to Helicobacter pylori infections (Figure 33) [50].

The inhibitory activity was tested using thiourea (IC₅₀ = 21.11 ± 0.12 µM) as reference. Based on the results (IC₅₀ = 2.17 ± 0.41 µM) and molecular docking studies, compound 182 (Figure 33) presented the best binding affinity (-8.40 kcal/mol), among all synthesized and tested compounds, and was able to bind to the active site of the enzyme [50].

By integrating all the obtained information, it could be concluded that the fluorine atom forms two halogen-metal bonds with the nickel active center of urease. The potential inhibition of urease was influenced by the type and position of the halogen atom, on the benzyl moiety linked to the sulfur atom. The fluorine atom in para position (182) was the most advantageous for the inhibition. For chlorine, meta position was favorable, while for bromine was either ortho or para position. One more important aspect observed was that an unsubstituted benzyl moiety yielded the weakest inhibitory capacity, therefore the presence of a halogen substituent was essential for urease inhibition [50].

Desai et al. designed a series of 2-(thiazol-5-yl)-5-mercapto-1,3,4-oxadiazole Mannich bases. These compounds are variably substituted on the anilino moiety linked to the fourth position of the 1,3,4-oxadiazole ring, through a methylene bridge (Figure 34) [51].

The compounds were tested for their antibacterial activity against Gram-positive and Gram-negative bacterial strains and for their antifungal activity against Candida sp. and Aspergillus sp. strains [51]. Compounds 183, 184, and 187 showed superior activity against E. coli MTCC 443, P. aeruginosa MTCC 1688, and S. pyogenes MTCC 442, compared to ampicillin (MICs = 100-250 µg/mL) [51].

Concerning the antifungal activity, compounds 185 and 186 showed superior activity (MICs = 25-50 µg/mL) against C. albicans (MTCC 227) and A. niger (MTCC 282), compared to griseofulvin (MICs = 100-500 µg/mL) [51].

SAR studies implied that the most active antibacterial compounds had electron-withdrawing groups, such as nitro (187) and fluoro (183-184), while the most active antifungal compounds had electron-donating groups, such as methoxy (185-186) (Figure 34). No potential target was reported by the authors [51].

3. Conclusions

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