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Article

Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents

by
Alexander Zubenko
1,
Victor Kartsev
2,
Anthi Petrou
3,
Athina Geronikaki
3,*,
Marija Ivanov
4,
Jasmina Glamočlija
4,
Marina Soković
4,
Lyudmila Divaeva
5,
Anatolii Morkovnik
5 and
Alexander Klimenko
1
1
North-Caucasian Zonal Research Veterinary Institute, 346406 Novocherkassk, Russia
2
InterBioScreen, 85355 Moscow, Russia
3
Faculty of Pharmacy, School of Health, Aristotle University, 54124 Thessaloniki, Greece
4
Mycological Laboratory, Department of Plant Physiology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
5
Institute of Physical and Organic Chemistry, Southern Federal University, Pr. Stachki 194/2, 344090 Rostov-on-Don, Russia
*
Author to whom correspondence should be addressed.
Antibiotics 2022, 11(11), 1654; https://doi.org/10.3390/antibiotics11111654
Submission received: 25 October 2022 / Revised: 9 November 2022 / Accepted: 15 November 2022 / Published: 18 November 2022
(This article belongs to the Special Issue New Insights into Antimicrobial Discovery)
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Versions Notes

Abstract

:
In this manuscript, we describe the design, preparation, and studies of antimicrobial activity of a series of novel heteroarylated benzothiazoles. A molecular hybridization approach was used for the designing compounds. The in vitro evaluation exposed that these compounds showed moderate antibacterial activity. Compound 2j was found to be the most potent (MIC/MBC at 0.23–0.94 mg/mL and 0.47–1.88 mg/mL) On the other hand, compounds showed good antifungal activity (MIC/MFC at 0.06–0.47 and 0.11–0.94 mg/mL respectively) with 2d being the most active one. The docking studies revealed that inhibition of E. coli MurB and 14-lanosterol demethylase probably represent the mechanism of antibacterial and antifungal activities.

1. Introduction

The growing problem in the community and in hospitals is resistance to pathogenic bacteria. Thus, the search for novel agents to fight against bacterial resistant is very attractive for scientists.
Benzothiazoles and its derivatives attracted the interest of medicinal chemists because of their extensive variety of pharmacological properties, including anti-inflammatory [1,2,3], antimicrobial [4,5,6,7], anticancer [8,9,10], antitubercular [11,12], antidiabetic [13], antioxidant [14,15], antiviral [16,17,18], antileishmanial [19], and others [20,21].
The antimicrobial potential of benzothiazoles is of great importance against the backdrop of the global aggravating problem of antimicrobial resistance and multidrug resistance that cause significant mortality in the world (about 700,000 annual deaths with the prospect of an increase in more than an order of magnitude) [10].
The antimicrobial activity of benzothiazole derivatives is widely presented in the literature. Thus, Singh et al. [22] synthesized and evaluated the antimicrobial activity of several novel benzothiazole based 4-thiazolidinones. Some compounds appeared to be the very potent against E. coli and C. albicans with MIC values in the range of 15.6–125 microg/mL. Haroun et.al. [5] synthesized new benzothiazole based thiazolidinone and found that all synthesized derivatives expressed better activity than ampicillin against most of the studied strains as well as more than streptomycin against several strains. On the other hand, compounds showed very good antifungal activity higher than reference drugs ketoconazole and bifonazole with very low toxicity (LD50 350–1000 mg/kg). Morsy et al. [4] evaluated antimicrobial activity of benzothiazole derivatives with MIC for antibacterial and antifungal one at 25–250 mg/mL. Nishad et al. [6] synthesized substituted N-(benzo[d]thiazol-2-yl)-2-chloroacetamides among which compound B4 was the most potent against all the tested strains with low MIC values.
It is noteworthy that there are many drugs with benzothiazole scaffold, such as Ethoxzolamide, a sulfonamide medication acting as carbonic anhydrize inhibitor against glaucoma and duodenal ulcers being a diuretic agent; Frentizole, an FDA-approved immunosuppressive drug, a novel inhibitor of the Aβ-ABAD interaction; Riluzole, a medication for the treatment of amyotrophic lateral sclerosis; and Zopolrestat, an aldose reductase inhibitor for the treatment of antidiabetic drug. [23]. Additionally, there are many benzothiazole derivatives known to be studied in clinical trials [24] (Figure 1).
On the other hand, phthalazine core is also mentioned in the literature to possess antimicrobial activity. Mourad et al. [25] prepared a series of phthalazine derivatives and studied their antimicrobial activity towards three bacterial strains. It was found that many of the compounds exhibited excellent inhibition against the tested pathogens. Rayes et al. [26] reported antimicrobial activity of phthalazinedion-based derivatives. Moreover, the antitumor approved drug Dasatinib contains phthalazine moiety. Consequently, the design and development of new benzothiazole-based phthalazine derivatives is a promising option in the creation of novel antimicrobial agents.
Taking all these into account, and as a continuation of our outgoing project on search for new compounds with antimicrobial activity, we synthesized novel derivatives incorporating benzothiazole and substituted phthalazine heterocycle through different linkers in the frame of one molecule. It is known that the combination of two or more molecules in one [27] is a promising strategy for enhancing of the activity as well as diminishing the side effects [28].
Herein we report the synthesis, evaluation of antimicrobial activity, as well as molecular docking studies of new heteroarylated benzothiazole derivatives (Figure 2).

2. Results and Discussion

2.1. Chemistry

New heteroarylated benzothiazoles were synthesized according to five routs (Scheme 1, Scheme 2, Scheme 3, Scheme 4 and Scheme 5) and their antimicrobial activity studied against a panel of pathogens.
In these benzothiazole derivatives (structures 2, 3, 5, 6, 8, 10) the heteroaryl group is linked to the mono- or bicyclic scaffold through various linkers such as -(CH2)nCONH(CH2)2- (n = 1,2), -S-, 1-piperidin-4-yl, -CONH-.
The target benzothiazole heteroaryl(aryl)derivatives were prepared by nucleophilic substitution of the chlorine atom in chlorosubstituted (1-methyl-2-chloromethylbenzimidazole for 2a, 1-chloro-4-R-phthalazines for 2b–2o, 1,4-bis(chloromethyl)benzene derivatives—for 3a, 3b, 3-(chloromethyl)-2-tosylpyridine—for 6) or in acid chlorides (tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-8-sulfonyl chloride -for 5), benzo[d]thiazole-6-carboxylic acid for 8) and 4-methyl-1-oxophthalazine-2(1H)-carboxylic acid for 10) various derivatives of benzothiazole in DMF. In this case, the clean products with good yield were obtained. Compounds were characterized by 1H-NMR, 13C-NMR, and elemental analysis. In 1H-NMR, the signals of the benzothiazole ring appeared in the aromatic region of 7.30–7.60 ppm (H-5, H-6), 7.88–8.78 (H-4, H-7). The signal of SCH2 group of compounds 2a, 2i–2o, 3a, 3b was found as a singlet at 4.10–4.47 ppm. In the 13C NMR spectra, the signal of the characteristic C=O group is seen at 166 ppm. All signals of 1H-NMR, 13C-NMR correspond to the proposed structures.

2.2. Biological Evaluation

2.2.1. Antibacterial Activity

Title derivatives were studied for their antibacterial activity against several selected bacterial pathogens by microdilution method. Compounds showed moderate to good potency (MIC/MBC at 0.23 to >3.75 mg/mL and 0.35–>3.75 mg/mL, respectively; Table 1) following the order: 2j > 2c > 2g = 8 > 2d > 2h > 2e > 5 > 2i > 2l > 2k > 3a > 2a > 2b > 2m > 6 > 2o > 2n > 3b > 10 > 2f.
The most potent among compounds tested appeared 2j with MIC and MBC at 0.23–0.94 mg/mL and 0.47–1.88 mg/mL, respectively, while compound 2f was the less potent. Some compounds demonstrate quite high potency against some bacterial strains. Thus, compounds 2b and 2e exhibit good activity against S. typhimurium with MIC 0.23 mg/mL, while compounds 2g and 2j exhibit good activity against E. coli with the same MIC. Compounds 2d, 2k and 8 were potent against B. cereus (MIC 0.23 mg/mL), whereas 2k also exhibit good activity against L. monocytogenes. On the other hand, activity of compounds 2a, 2i and 5 against the same strain was a little bit lower (MIC 0.35 mg/mL). En. cloacae appeared to be very sensitive to these derivatives in the contrast to the resistant S. aureus.
According to structure-activity relationships studies the presence of 4-(3,4-dimethylphenyl)-2-methylphthalazin-1(2H)-one connected to benzothiazole via 2-mercapto-N-methylacetamide linker (2j) is beneficial for antibacterial activity. Replacement of 4-(3,4-dimethylphenyl)-2-methylphthalazin-1(2H)-one as substituent by 1-phenylphthalazine connected to benzothiazole by S as linker (2c) decreased a little the activity. Introduction of 1-phenylpthalazine N,N-dimethylsulfonic amide as substituent gave compound 2g with less potency in comparison with 2c. N,N-diethyl-4-(phthalazin-1-yl)benzamide as substituent was detrimental not only for the group of compounds with S-linker but for all tested compounds. From all mentioned above, it seems that the important role for antibacterial activity play the substituent of benzothiazole ring as well as the linker.

2.2.2. Antifungal Activity

The evaluation of antifungal activity was performed via a microdilution method, with bifonazole and ketoconazole being used as the reference drugs. According to obtained results (Table 2) all compounds demonstrated good antifungal activity except compound 10. The order of activity can be presented as follows: 2d > 3b > 3a > 2o > 2m > 2a > 2i > 2j > 2l > 6 > 2b > 5 > 8 > 2e > 2c > 2g > 2f > 2n > 2h > 10. Compound 2d with MIC/MFC at 0.08–0.17 mg/mL and 0.11–0.23 mg/m, respectively, exhibited the highest potency, whereas compound 10 was the less active.
Several derivatives appeared to be more active than the reference drugs towards some fungal strains. Thus, compounds 2d, 2i, 3b, and 6 showed better potency against T viride compared with ketoconazole and bifonazole with MIC/MFC at 0.06/0.11 mg/mL. Good potency was also expressed in compounds 2a, 2b, 2h, 2i, 2l, 3a, and 5, with minimal inhibitory and fungicidal concentrations at 0.11/0.23 mg/mL, comparable with both reference drugs against T. viride, while 2i, 2m, and 3a were found to be active also against A. niger. On the other side, compounds 2a, 2j, 2m, and 2o were potent against A. versicolor, while 2a was also potent with MIC at 0.11mg/mL against P. cyclopium var. verucosum. It should be mentioned that T. viride demonstrated high sensibility toward our compounds, while A. fumigatus, followed by P. funiculosum. were the most resistant ones.
The structure-activity relationship study showed that the presence of 1-(p-tolyl)phthalazine substituent linked to benzothiazole ring through S-linker (2d) is favorable for antifungal activity. Replacement of 1-(p-tolyl)phthalazine by 2,5-dimethoxy-1,4-phenyl linked to two benzothiazole rings via sulfamethylene linker give less active compound 3b, while introduction of methyl group (3a) instead of methoxy ones (3b) resulted in lesser active compound compared with previous one (3b). It should be mentioned that ten compounds (2b, 2d, 2h, 2i, 2j, 2l, 2m, 2o, 3a, and 6) showed activity better than that of ketoconazole against A. niger mostly, while all compounds exhibited higher activity than ketoconazole against T. viride. Furthermore, derivatives 2b, 2d, 2h, 2i, 2j, 2l, 2m, and 6 were more potent also than bifonazole against T. viride. The general observation is that fungi are more sensitive to tested than bacterial strains. It should be noticed that the response of fungi and bacteria to the compounds tested is different. This behavior is probably due to some differences between bacteria and fungi organization of prokaryotic organisms, organization of DNA genetic material and finally in composition of the cell wall which are made from peptidoglycans (bacteria) and chitin (fungi). Both are prokaryotic organisms, but bacteria are unicellular, while fungi multicellular. On the other hand, despite both containing DNA as genetic material, the genetic material of bacteria is organized in cytoplasm, while in fungi it is organized inside the nucleus. Bacteria do not contain membrane-bound organelles in comparison with fungi which contain membrane-bound. Finally, the cell wall of bacteria is made up of peptidoglycans, whereas the cell wall of fungi is made up of chitin. The only common response of bacteria and fungi to compounds tested was observed for compounds 10 and 2f which were among the less active.

2.3. In Silico Studies—Molecular Docking

2.3.1. In Silico Studies to Antibacterial Targets

Compounds were docked to different antibacterial targets, aiming for a prediction of possible mechanisms of action.
To this direction, we used the following enzymes for docking studies: responsible for the most common mechanisms of activity of antibacterial agents such as E. coli DNA gyrase, Thymidylate kinase, E. coli Primase, E. coli MurA and E. coli MurB enzymes.
According to the results of the docking studies, the lowest Free Energy of Binding was observed to E. coli MurB (Table 3), suggesting inhibition of this enzyme as putative mechanism of antibacterial activity.
One of the most active compounds, 2d, binds E. coli MurB enzyme forming three favorable hydrogen bond interactions. These are between the oxygen atom of COOH group, of compound and residue Ser50 (2.27 Å), and the oxygen atom of the C=O group and Ile173 residue (2.74 Å), and the last one between S atom of the compound and residue Ser116 (3.56 Å). Moreover, hydrophobic interactions between Ile122, Ile110, Ile119, Val52, Ala85 and Ile45 and the compound were detected, contributing to the stability of the complex ligand-enzyme (Figure 3).
It was observed that the most active compounds bind to MurB in a similar way to FAD, interacting with the residues such as Ser50, Arg213, Arg158 and Ser229 (Figure 3). The similarity in binding mode with FAD is probably the reason of comparable to ampicillin potency of these derivatives.
Finally, the docking pose of a known inhibitor of MurB enzyme also co-crystalized with it in the X-ray structure and showed that it binds MurB in a completely different way from our compounds. This inhibitor fit into the binding center of the enzyme away from the binding cavity of substate FAD, while our compounds seem to bind MurB in the FAD cavity of the enzyme, interacting with crucial for the enzyme activity residues (Figure 3 and Figure 4). This observation confirms the better binding energy of our compounds and by extension their higher inhibition over this inhibitor.

2.3.2. In Silico Studies to Antifungal Targets

All the synthesized compounds and the reference drug ketoconazole were docked to lanosterol 14α-demethylase of C. albicans and DNA topoisomerase IV (Table 4) in order to explore the possible mechanism of antifungal activity of compounds.
It was found that the most active compound, 2d, binds the enzyme alongside the heme group, interacting with it throughout its benzene ring forming aromatic and hydrophobic interactions.
The most active compound 2d binds the 14a-lanosterole demethylase enzyme at the side of the heme group, forming aromatic and hydrophobic interactions with its benzene ring. Moreover, hydrophobic interactions between Tyr118, Leu121, Tyr122, Thr311, Leu376, Phe380, Met508 and the compound were detected. Aromatic interaction with the heme group was also observed with the benzene ring of ketoconazole (Figure 5 and Figure 6). This property may account for the good antifungal activity of compound 2d.

2.4. Drug Likeness

The bioavailability and drug-likeness scores of all compounds are shown in Table 5. According to prediction results, the bioavailability score of all compounds was about 0.55. Moreover, all compounds displayed good-to-excellent Drug-likeness scores (−0.60–0.79). Figure 7 presents the bioavailability radar of most active compound 2j. The best in the in-silico predictions results was achieved for compound 5 with a Drug-likeness score of 0.79 and with no violation of any rule. According to predicted results all compounds except 2g, 2h, 2j, 2m, 2n, 3a, and 3b can be orally absorbed since their TPSA are < 120 Å.

3. Materials and Methods

3.1. Chemistry-General Information

NMR 1H spectra of all compounds were recorded on a spectrometer Bruker 400 (400 MHz); for compounds 2a, 2b, 5—on Bruker AC-300 in DMSO-d6 and spectra are presented in Supplementary Material File S1. Chemical shifts of nuclei 1H were measured relatively the residual signals of deuteron solvent (δ = 2.50 ppm). Coupling constants (J) are reported in Hz. Τhe assignment was based on 2D NMR techniques. Melting points were determined using the Fisher-Johns Melting Point Apparatus (Fisher Scientific) and are uncorrected. Elemental analysis was performed by the classical method of microanalysis. The reaction and purity of the obtained compounds were monitored by TLC (plates with Al2O3 III activity grade, eluent CHCl3, development of TLC plates by exposition to iodine vapors in “iodine chamber”). The solvents were purified according to standard procedures. The starting compounds—4-substituted 1-chlorophthalazine (for 2b–2o)—were provided by InterBioscreen Ltd. (Russia); benzo[d]thiazole-2-thiol 1 (for 2a, 3a, 3b), benzo[d]thiazole-6-carboxylic acid 7 (for 8), and 4-methyl-1-oxophthalazine-2(1H)-carboxylic acid 9 (for 10) are commercially available. L, 2-(Piperidin-4-yl)benzo[d]thiazole was obtained similarly to the procedure described in [29,30].

3.1.1. General Procedure for the Synthesis of Compounds 2a–o and 3a,b

Sodium hydride (0.29 g, 0.012 mol) was added to a solution of 2-mercaptobenzothiazole 1 (0.01 mol) in of DMF (15 mL) with stirring in a nitrogen atmosphere at 25–30 °C. The mixture was stirred for 30 min, 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (for 2a) or a 4-substituted 1-chlorophthalazine (0.01 mol) was added and kept 1 min while boiling (for 2b–2h), 1 h at 100 °C (for 2i, 2k, 2l), 4 h at 50–55 °C (for 2j), and 30 min at 40–45 °C (for 2m–2o). Then the mixture was cooled, water (40 mL) was added, the precipitate was filtered off, and washed with water (3 × 20 mL).
  • 2-{[(1-Methyl-1H-benzo[d]imidazol-2-yl)methyl]thio}benzo[d]thiazole (2a). Yield 2.99 g (96%), colorless crystals, m.p. 90–92 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.93 (s, 3H, Me), 4.98 (s, 2H, CH2), 7.14–7.25 (m, 2H, H-5′, H-6′), 7.29–7.48 (m, 3H, H-5, H-6, H-4′), 7.58 (d, J 7.6, 1H, H-7′), 7.85–7.88 (m, 2H, H-4, H-7). 13C NMR (100 MHz, DMSO-d6) δ 165.85 (S-C-S), 152.89 (C-12), 150.16 (C-4), 142.28 (C-15), 136.36 (C-14), 135.32 (C-5), 126.89 (C-8), 125.10 (C-7), 122.80 (C-18), 122.38 (C-19), 122.18 (C-6), 121.68 (C-9), 119.21 (C-17), 110.65 (C-20), 30.56 (CH3), 29.46. Found (%): C, 61.45; H, 4.00; N, 13.16; S, 20.72. Calc. for C16H13N3S2 (%): C, 61.71; H, 4.21; N, 13.49; S, 20.59.
  • 2-(4-Methylphthalazin-1-yl)benzo[d]thiazole (2b). Yield 2.47 g (89%), colorless crystals, m.p. 163–165 °C (EtOH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.99 (s, 3H, Me), 7.35–7.56 (m, 2H, H-5, H-6), 8.22–8.38 (m, 2H, H-6′), 8.02–8.15 (m, 3H, H-5′, H-7′, H-8′), 8.22–8.38 (m, 2H, H-4, H-7). 13C NMR (100 MHz, DMSO-d6) δ 161.14, 159.82, 155.43, 152.07 (C-4), 139.85 (C-10), 136.05 (C-5), 134.74 (C-16), 134.33 (C-17), 132.81 (C-14), 129.65 (C-15), 127.51 (C-8), 126.19 (C-19), 125.24 (C-7), 124.48 (C-18), 122.39 (2C, C-6, C-9), 30.24 (CH3). Found (%): C, 68.98; H, 3.68; N, 15.00; S, 11.72. Calc. for C16H11N3S (%): C, 69.29; H, 4.00; N, 15.15; S, 11.56.
  • 2-(4-Phenylphthalazin-1-yl)benzo[d]thiazole (2c). Yield 3.12 g (92%), colorless crystals, m.p. 214–216 °C (methycellosolve). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 7.39–7.59 (m, 2H, H-5, H-6), 7.60–7.85 (m, 5H, H″–H-6″), 7.88–8.20, (m, 2H, 8.22–8.38 (m, 5H, H-7, H-5′–H-8′), 8.35–8.46 (m, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 161.10 (N=C-S), 159.83 (C-13), 155.32 (C-4), 152.01 (C-10), 139.82 (C-20), 136.03 (C-5), 134.72 (C-14), 134.33 (C-16), 132.81 (C-21), 129.60 (2C, C-25, C-6), 127.52 (C-23), 126.21 (2C, C-22, C-24), 125.23 (C-17), 331 124.29 (2C, C-7, C-8), 122.38 (2C, C-9, C-19), 121.79 (2C, C-15, C-18). Found (%): C, 74.10; H, 3.61; N, 12.11; S, 9.72. Calc. for C21H13N3S (%): C, 74.31; H, 3.86; N, 12.38; S, 9.45.
  • 2-(4-(p-Tolyl)phthalazin-1-yl)benzo[d]thiazole (2d). Yield 3.11 g (88%), colorless crystals, m.p. 202–205 °C (DMF:EtOAc). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.91 (s, 6H, Me, H2O), 7.36–7.51 (m, 4H, H-2″, H-3″, H-5″, H-6″), 7.65 (d, 2H, H-5, H-6), 7.91–8.16 (m, 5H, H-5′–H-8′, H-7), 8.31–8.42 (m, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 167.82 (N-C-S), 159.10 (S-C=N), 158.86 (C-14), 148.14 (C-5), 144.38 (2C, C-13, C-21), 134.09 (2C, C-4, C-24), 132.54 (C-19), 130.07 (2C, C-22, C-26), 127.22 (3C, C-1, C-2, C-3), 126.57 (3C, C-12, C-23, C-25), 124.80 (2C, C-17, C-18), 123.10 (C-6), 116.08 (C-20), 18.87 (CH3). Found (%):C, 74.49; H, 4.00; N, 11.48; S, 9.29.Calc. for C22H15N3S (%): C, 74.76; H, 4.28; N, 11.89; S, 9.07.
  • 2-[4-(4-Chlorophenyl)phthalazin-1-yl]benzo[d]thiazole (2e). Yield 3.14 g (84%), colorless crystals, m.p. 195–196 °C (methycellosolve). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 7.42 (td, J 7.5, 1.4, 1H, H-6), 7.50 (td, J 7.5, 1.4, 1H, H-5), 7.63–7.68 (m, 2H, H-3″, H-5″), 7.79 (d, J 7.5, 2H, H-5′, H-8′), 7.92–7.97 (m, 1H, H-7′), 8.02 (d, J 7.9, 1H, H-6), 8.03–8.17 (m, 3H, H-2″, H-6″, H-7), 8.40 (d, 1H, J 7.8, H-4). 13C NMR (100 MHz, DMSO-d6) δ 160.75 (N=C-S), 158.84 (C-13), 155.95 (C-4), 152.01 (C-10), 136.09 (C-20), 135.15 (C-5), 134.51 (C-Cl), 132.32 (3C, C-14, C-21, C-25), 129.21(3C, C-16, C-22, C-24), 127.30 (C-17), 127.02 (C-19), 126.01 (C-8), 125.81 (C-7), 125.08 (C-18), 124.45 (C-15), 122.47 (C-6), 122.39 (C-9). Found (%):C, 67.22; H, 3.01; Cl, 9.72; N, 11.00; S, 8.74. Calc. for C21H12ClN3S (%): C, 67.47; H, 3.24; Cl, 9.48; N, 11.24; S, 8.58.
  • 4-[4-(Benzo[d]thiazol-2-yl)phthalazin-1-yl]-N,N-diethylbenzamide (2f). Yield 2.81 g (64%), colorless crystals, m.p. 180–181 °C (DMF). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.24 (t, J 7.0, 6H, 2CH3), 3.45 (s, 4H, 2CH2), 7.36–7.43 (m, 1H, H-6), 7.44–7.51 (m, 1H, H-5), 7.59 (d, J 7.8, 2H, H-5′, H-8′), 7.83 (d, J 7.9, 2H, H-2″, H-6″), 7.95 (t, J 8.7, 2H, H-6′, H-7′), 8.02–8.19 (m, 3H, H-3″, H-5″, H-7), 8.35–8.42 (m, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 166.63 (C=O), 165.61 (S-C=N), 152.83 (C-14), 142.40 (C-27), 141.68 (C-2), 139.63 (C-17), 136.58 (C-28), 135.21 (C-5), 133.47 (C-23), 132.26 (2C, C-4, C-6), 130.31 (2C, C-3, C-7), 129.58 (C-21), 128.68 (C-18), 127.98 (C-20), 126.84 (C-31), 125.35 (C-19), 124.97 (C-22), 124.20 (C-30), 124.14 (C-29), 122.36 (C-32), 21.35 (2C, CH3). Found (%): C, 71.00; H, 4.82; N, 12.49; S, 7.56. Calc. for C26H22N4OS (%): C, 71.21; H, 5.06; N, 12.78; S, 7.31.
  • 5-(4-(Benzo[d]thiazol-2-yl)phthalazin-1-yl)-N,N,2-trimethylbenzenesulfonamide (2g). Yield 3.41 g (74%), colorless crystals, m.p. 163–165 °C (PrOH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.74 (s, 3H, CH3), 2.83 (s, 6H, N(CH3)2), 7.44 (td, J 7.6, 1.3, 1H, H-6), 7.52 (td, J 7.6, 1.5, 1H, H-5), 7.69 (d, J 7.9, 1H, H-3″), 7.93–7.96 (m, 2H, H-6′, H-7′), 8.02–8.06 (m, 1H, H-4″), 8.09–8.18 (m, 4H, H-4, H-7, H-5′, H-8′), 8.38–8.43 (m, 1H, H-6″. 13C NMR (100 MHz, DMSO-d6) δ 167.20 (N-C-S), 159.42 (S-C=N), 152.60 (C-5), 146.22 (C-14), 137.35 (C-24), 137.12 (C-23), 134.93 (C-4), 133.42 (C-13), 132.63 (C-21), 132.05 (C-25), 130.50 (C-26), 128.92 (C-22), 128.43 (C-12), 128.31 (C-19), 127.66 (C-17), 126.82 (C-18), 126.58 (C-20), 126.42 (C-1), 124.74 (C-2), 121.95 (C-3), 121.02 (C-6), 36.80 (2C, N-(CH3)2), 19.88 (C-CH3). Found (%): C, 62.32; H, 4.12; N, 12.00; S, 14.26. Calc. for C24H20N4O2S2 (%): C, 62.59; H, 4.38; N, 12.16; S, 13.92.
  • 3-{4-[4-(Benzo[d]thiazol-2-ylthio)phthalazin-1-yl]benzoyl}-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (2h). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.01–2.14 (m, 2H, H-5), 2.50–2.57 (m, 1H, H-6, DMSO), 3.00 (s, 2H, H-7), 3.15–3.41 (m, 3H, H-4, H-1), 3.68–3.75 (m, 1H, H-2), 4.05–4.11 (m, 1H, H-2), 6.05 (d, 1H, H-11), 6.33 (dd, J 9.1, 1.3, 1H, H-9), 7.03–7.37 (m, 3H, H-5′, H-6′, H-10), 7.40–7.54 (m, 2H, H-6″, H-7″), 7.72 (d, J 7.8, 2H, H-5″, H-8″), 7.95 (d, J 8.0, 1H, H-5‴), 8.03 (d, J 7.9, 1H, H-3‴), 8.07–8.16 (m, 3H, H-4′, H-2‴, H-6‴), 8.40–8.42 (m, 1H, H-10). 13C NMR (100 MHz, DMSO-d6) δ 175.96 (2C, C=O, C-2), 156.54 (C=O), 153.10 (C-7), 147.82 (2C, C-14, C-19), 144.93 (C-4), 140.62 (C-27), 136.71 (C-24), 134.79 (C-21), 134.54 (C-26), 130.06 (3C, C-15, C-33, C-34), 129.18 (3C, C-31, C-32, C-39), 127.77 (2C, C-35, C-40), 126.52 (2C, C-17, C-36), 125.29 (2C, C-41, C-42), 122.75 (2C, C-28, C-38), 122.61 (C-37), 109.99 (C-25), 56.70 (C-22), 53.17 (2C, C-16, C-20), 40.65 (C-8), 32.37 (C-18), 21.58 (C-23). Found (%): C, 67.12; H, 4.20; N, 11.69; S, 11.22. Calc. for C33H25N5O2S2 (%): C, 67.44; H, 4.29; N, 11.92; S, 10.91.
  • 4-[3-(Benzo[d]thiazol-2-ylthio)-4-methylphenyl]-2-methylphthalazin-1(2H)-one (2i). Yield 3.82 g (89%), colorless crystals, m.p. 111–112 °C (DMF). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.57 (s, 3H, CH3), 3.79 (s, 3H, NCH3), 4.74 (s, 1H, CH2), 7.30–7.44 (m, 4H, H-5′, H-5″, H-6″, H-8), 7.50–7.61 (m, 2H, H-6′, H-7), 7.67 (d, J 7.9, 1H, H-2′), 7.71–7.82 (m, 2H, H-6, H-7′), 7.83–7.88 (m, 1H, H-9), 8.36 (d, J 7.9, 1H, H-7″). 13C NMR (100 MHz, DMSO-d6) δ 166.13 (C-1), 158.62 (C=O), 153.01 (C-5), 145.86 (C-18), 138.40 (C-13), 135.19 (C-6), 134.94 (C-16), 133.56 (C-12), 132.91 (C-14), 132.18 (C-28), 131.14 (C-17), 131.10 (C-27), 129.29 (C-20), 128.90 (C-29), 127.75 (C-19), 126.86 (C-26), 126.73 (C-9), 126.71 (C-15), 125.08 (C-10), 122.31 (C-8), 121.69 (C-7), 39.50 (C-25), 35.33 (C-11), 19.23 (CH3). Found (%): C, 66.72; H, 4.18; N, 9.53; S, 15.27. Calc. for C24H19N3OS2 (%): C, 67.11; H, 4.46; N, 9.78; S, 14.93.
  • 2-(Benzo[d]thiazol-2-ylthio)-N-[2-methyl-5-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)benzyl]acetamide (2j). Yield 4.09 g (84%), colorless crystals, m.p. 201–202 °C (DMF). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.41 (s, 3H, CH3), 3.77 (s, 3H, NCH3), 4.10 (s, 2H, SCH2), 4.43 (d, J 5.7, 2H, NCH2) 7.21–7.32 (m, 4H, H-5, H-6, H-3′, H-6″), 7.46 (d, J 1.7, H-7‴), 7.59–7.69 (m, 2H, H-7, H-6′), 7.72–7.77 (m, 3H, H-4, H-4, H-8″), 8.27–8.37 (m, 1H, H-5″), 8.56 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 167.17 (S-C-N), 166.46 (C=O), 158.55 (C=O), 152.66 (C-23), 146.23 (C-25), 137.36 (C-5), 137.00 (C-11), 134.95 (C-4), 133.42 (C-24), 132.65 (C-16), 132.07 (C-18), 130.51 (C-19), 128.95 (C-17), 128.42(C-3), 128.29 (C-2), 127.64 (C-30), 126.85 (C-6), 126.56 (C-31), 126.40 (C-33), 124.73 (C-32), 121.98 (C-20), 121.04 (C-21), 41.24 (CH2-NH), 36.81 (2C, N-CH3), 18.98 (C-CH3). Found (%): C, 64.00; H, 4.22; N, 11.18; S, 13.54. Calc. for C26H22N4O2S2 (%): C, 64.18; H, 4.56; N, 11.51; S, 13.18.
  • 2-(Benzo[d]thiazol-2-ylthio)-1-[4-(4-phenylphthalazin-1-yl)piperazin-1-yl]ethan-1-one (2k). Yield 3.68 g (74%), colorless crystals, m.p. 162–163 °C (EtOH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.53 (s, 2H, 2H-2′), 3.65 (s, 2H, 2H-6′), 3.88 (s, 2H, H-3′), 3.97 (s, 2H, H-5′), 4.57 (s, 2H, SCH2), 7.31 (t, J 7.6, H-4‴), 7.42 (t, J 7.6, H-6), 7.51–7.60 (m, 3H, H-5, H-3‴, H-5‴), 7.62–7.69 (m, 2H, H-6″, H-7″), 7.59–7.69 (m, 2H, H-7, H-6′), 7.99–7.80 (m, 5H, H-7, H-2‴, H-6‴,H-8″), 8.22 (d, J 8.2, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 161.14(S-C=N), 159.82 (C=O), 155.43 (C-20), 152.07 (2C, C-5, C-23), 139.85 (C-30), 136.05 (C-4), 134.74 (C-22), 134.33 (C-33), 132.81 (2C, C-11, C-28), 129.65 (4C, C-16, C-18, C-25, C-31), 127.51 (2C, C-27, C-2), 126.19 (C26), 125.24 (2C, C-1, C-29), 124.48 (2C, C-32, C-34), 122.39 (2C, C-19, C-15), 121.56 (3C, C-3, C-6, C-21). Found (%): C, 65.00; H, 4.39; N, 13.86; S, 12.99. Calc. for C27H23N5OS2 (%): C, 65.17; H, 4.66; N, 14.07; S, 12.88.
  • 2-(Benzo[d]thiazol-2-ylthio)-1-(4-(4-(p-tolyl)phthalazin-1-yl)piperazin-1-yl)ethan-1-one (2l). Yield 3.53 g (69%), colorless crystals, m.p. 155–156 °C (CH3CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.02 (s, 3H, CH3), 3.51 (s, 2H, 2H-2′), 3.63 (s, 2H, 2H-6′), 3.87 (s, 2H, H-3′), 3.97 (s, 2H, H-5′), 4.57 (s, 2H, SCH2), 7.27–7.47 (m, 4H, H-3‴, H-4‴, H-5‴, H-6‴), 7.52–7.58 (m, 2H, H-5, H-6), 7.78–8.01 (m, 5H, H-7, H-5″–H-8″), 8.21 (d, J 8.1, 1H, H-4). 13C NMR (100 MHz, DMSO-d6) δ 166.50 (S-C-S), 165.94 (C=O), 155.37 (C-10), 152.95 (C-13), 147.79 (C-31), 139.59 (C-22), 135.21 (C-20), 134.37 (C-32), 131.49 (C-14), 129.79 (C-16), 127.77 (2C, C-24, C-25), 126.85 (C-17), 124.98 (C-18), 123.32 (C-15), 122.96 (C-35), 122.32 (3C, C-21, C-23, C-19), 121.51 (2C, C-33, C-34), 118.48 (C-36), 38.24 (4C, C-4, C-6, C-8, C-9), 20.20 (2C, C-2, CH3). Found (%): C, 65.48; H, 4.69; N, 13.46; S, 12.74. Calc. for C28H25N5OS2 (%): C, 65.73; H, 4.93; N, 13.69; S, 12.53.
  • 2-(Benzo[d]thiazol-2-ylthio)-N-(3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)phenyl)acetamide (2m). Yield 3.74 g (72%), colorless crystals, m.p. 235–237 °(DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.91 (s, 3H, Me), 4.38 (s, 2H, CH2), 7.27–7.36 (m, 1H, H-4″), 7.37–7.51 (m, 2H, H-5, H-6), 7.80–7.92 (m, 4H, H-7′–H-10′), 8.00 (t, J 7.6, 1H, H-5″), 8.17 (d, J 7.9, 2H, H-4, H-7), 8.61 (d, J 7.9, 1H, H-6″), 8.67 (d, J 2.0, 1H, H-2″), 10.48 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 166.50 (S-C=N), 165.95 (C=O), 155.37 (C-27), 152.95 (C-11), 147.79 (C-CH3), 143.79 (N-C-N), 139.58 (C-18), 135.21 (C-28), 134.37 (C-2), 131.49 (C-1), 129.79 (C-4), 127.77 (C-16), 127.43 (C-14), 126.85 (C-3), 124.98 (C-31), 123.32 (2C, C-6, C-15), 122.97 (C-17), 122.90 (C-5), 122.33 (C-32), 121.51 (C-33), 121.02 (C-30), 118.48 (C-19), 38.23 (CH2-C=O), 20.21 (CH3). Found (%): C, 62.00; H, 3.41; N, 17.21; S, 13.04. Calc. for C25H18N6OS2 (%): C, 62.22; H, 3.76; N, 17.41; S, 13.29.
  • 2-(Benzo[d]thiazol-2-ylthio)-N-(2-methyl-5-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)phenyl)acetamide (2n). Yield 3.87 g (78%), colorless crystals, m.p. 251–253 °C (DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.36 (s, 3H, Me), 2.87 (s, 6H, Me, DMSO), 4.39 (s, 2H, CH2), 7.32–7.42 (m, 3H, H-5, H-6, H-5″), 7.84–7.89 (m, 3H, H-7, H-8′, H-9′), 7.96–8.03 (m, 1H, H-7), 8.13–8.18 (m, 2H, H-7′, H-10′), 8.61 (d, J 8.0, 1H, H-4″), 8.69 (s, 1H, H-2″), 9.67 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 166.53 (S-C=N), 165.92 (C=O), 155.35 (C-27), 152.92 (C-11), 147.80 (C-7), 143.77 (C-10), 139.56 (C-18), 135.18 (C-28), 134.35 (C-16), 131.46 (C-17), 129.80 (C-2), 127.76 (C-1), 127.32 (C-4), 126.91 (C-14), 124.95 (C-3), 123.30 (C-31), 122.99 (2C, C-6, C-32), 122.91 (C-15), 122.34 (C-5), 121.50 (C-33), 121.07 (C-30), 118.46 (C-19), 38.24 (C-23), 24.51 (CH3), 20.19 (CH3). Found (%): C, 62.56; H, 4.40; N, 17.11; S, 13.15. Calc. for C26H20N6OS2 (%): C, 62.88; H, 4.06; N, 16.92; S, 12.91.
  • 2-(Benzo[d]thiazol-2-ylthio)-N-(5-(p-tolyl)benzo[4,5]imidazo[2,1-a]phthalazin-9-yl)acetamide (2o). Yield 4.68 g (88%), colorless crystals, m.p. 248–250 °C (DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.52 (s, 3H, Me), 4.40 (s, 2H, CH2), 7.33–7.44 (m, 3H, H-3″, H-5″, H-10′), 7.57–7.69 (m, 3H, H-2″, H-6″, H-11′), 7.76–8.03 (m, 6H, H-5, H-6, H-1′–H-4′), 8.26 (d, J 1.8, 1H, H-8′), 8.74–8.78 (m, 2H, H-4, H-7), 10.47 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 166.59 (S-C=N), 165.60 (2C, N=C-N, C=O), 152.98 (C-33), 142.42 (C-8), 141.68 (C-16), 139.63 (C-24), 136.57 (C-17), 135.21 (C-19), 133.47 (C-34), 132.25 (C-22), 130.20 (2C, C-23, C-25), 129.61 (2C, C-26, C-27), 128.68 (C-11), 127.97 (C-12), 126.86 (C-9), 125.35 (C-10), 124.97 (C-13), 124.21 (C-36), 124.12 (C-37), 122.35 (C-20), 121.51 (C-35), 116.21 (C-38), 111.51 (C-14), 109.66 (2C, C-18, C-21), 38.34(CH2-C=O), 21.44 (CH3). Found (%): C, 67.42; H, 4.21; N, 13.54; S, 12.36. Calc. for C30H21N5OS2 (%): C, 67.77; H, 3.98; N, 13.17; S, 12.06.
  • 2,2′-{[(2,5-Dimethyl-1,4-phenylene)bis(methylene)]bis(sulfanediyl)}bis(benzo[d]thiazole) (3a). Yield 90%, colorless crystals, m.p. 170–171 °C (methylcellosolve), 1H NMR (200 MHz, DMSO-d6, δ, ppm): 2.32 (s, 6H, 2Me), 4.54 (s, 4H, 2CH2), 7.26 (s, 2H, H-3″, H-5″), 7.34–7.37 (m, 2H, H-5, H-5′), 7.43–7.47 (m, 2H, H-6, H-6′), 7.86 (d, J 1.1, H-7), 7.88 (d, J 1.1, H-7′), 7.92 (d, J 1.3, H-4), 7.93 (d, J 1.3, H-4′). 13C NMR (100 MHz, DMSO-d6) δ 166.60 (S-C=N), 165.72 (S-C-S), 152.92 (C-5), 142.40 (C-23), 141.62 (C-14), 136.56 (C-17), 135.23 (C-4), 133.24 (C-22), 130.20 (2C, C-13, C-16), 129.63 (2C, C-12, C-15), 127.97 (C-1), 126.86 (C-2), 125.35 (C-27), 124.97 (C-26), 124.23 (2C, C-3, C-25), 124.11 (2C, C-6, C-28), 37.15 (2C, C-11, C-18), 21.42 (2C, CH3). Found (%): C, 62.36; H, 4.56; N, 6.34; S, 27.81. Calc. for C24H20N2S4 (%): C, 62.03; H, 4.34; N, 6.03; S, 27.60.
  • 2,2′-{[(2,5-Dimethoxy-1,4-phenylene)bis(methylene)]bis(sulfanediyl)}bis(benzo[d]thiazole) (3b). Yield 95%, colorless crystals, m.p. 184–186 °C (DMFA). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 3.79 (s, 6H, 2OMe), 4.56 (s, 4H, 2CH2), 7.18 (s, 2H, H-3″, H-6″), 7.30–7.36 (m, 2H, H-5, H-5′), 7.41–7.47 (m, 2H, H-6, H-6′), 7.84–7.92 (m, 4H, H-4, H-4′, H-7, H-7′). 13C NMR (100 MHz, DMSO-d6) δ 166.59 (S-C=N), 166.45 (S-C-S), 159.14 (2C, C-OCH3), 152.66 (C-5), 148.82 (C-23), 137.53 (C-4), 136.67 (C-22), 133.48 (C-15), 132.65 (C-12), 132.05 (2C, C-1, C-17), 128.44 (2C, C-2, C-26), 127.65 (2C, C-3, C-25), 124.78 (2C, C-6, C-28), 121.05 (2C, C-13, C-16), 53.28 (2C, O-CH3), 36.84 (2C, C-11, C-18). Found (%): C, 58.40; H, 4.29; N, 5.26; S, 25.49. Calc. for C24H20N2O2S4 (%): C, 58.04; H, 4.06; N, 5.64; S, 25.82.

3.1.2. Synthesis of 9-((4-(Benzo[d]thiazol-2-yl)piperidin-1-yl)sulfonyl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (5)

Compound 5 was obtained from 2-(piperidin-4-yl)benzo[d]thiazole 4 and 4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-9-sulfonyl chloride according to a modified procedure [31].
Yield 2.71 (54%), colorless crystals, m.p. 164–166 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.81–1.96 (m, 2H, 1H-3″, 1H-5″), 2.17–2.26 (m, 2H, 1H-3″, 1H-5″), 2.35 (s, 3H, Me), 2.84–2.93 (m, 2H, H-7), 3.01–3.10 (m, 5H, H-2″, H-4″, H-6″), 3.32 (s, 2H, H-8), 3.78–3.82 (m, 2H, H-5), 4.06 (s, 3H, OMe), 6.05 (s, 2H, H-2), 7.33–7.48 (m, 2H, H-5′, H-6′), 7.88–7.96 (m, 2H, H-4′, H-7′). 13C NMR (100 MHz, DMSO-d6) δ 169.34 (N=C-S), 168.86 (C-O), 159.42 (C-26), 145.81 (C-3), 144.37 (2C, C-2, C-25), 130.18 (2C, C-29, C-30), 119.22 (2C, C-28, C-31), 113.57 (2C, C-4, C-5), 112.99 (C-6), 94.14 (O-C-O), 74.04 (C-34), 40.90 (3C, C-7, C-9, C-35), 36.65 (2C, C-18, C-22), 31.11 (C-20), 28.15 (2C, C-19, C-21), 19.54 (C-10). Found (%): C, 57.18; H, 5.29; N, 8.15; S, 12.41. Calc. for C30H21N5OS2 (%): C, 57,47; H, 5.43; N, 8.38; S, 12.78.

3.1.3. Synthesis of 2-{1-[(2-Tosylpyridin-3-yl)methyl]piperidin-4-yl}benzo[d]thiazole (6)

A mixture of 2-(piperidin-4-yl)benzo[d]thiazole 4 (2.18 g, 0.01 mol), 3-(chloromethyl)-2-tosylpyridine (2.82g, 0.01 mol), and NaHCO3 (1.68 g, 0.02 mol) in DMF (20 mL) was stirred 24 h at 20–25 °C, water (40 mL) was added, the precipitate was filtered off and washed with water (3 × 15 mL).
Yield 3.61 g (78%), colorless crystals, m.p. 153–155 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.90–1.98 (m, 2H, 1H-3‴, 1H-5‴), 2.11–2.16 (m, 2H, 1H-3‴, 1H-5‴), 2.33–2.40 (m, 2H, 1H-2‴, 1H-6‴), 2.46 (s, 3H, Me), 2.93–2.97 (m, 2H, 1H-2‴, 1H-6‴), 3.10–3.22 (m, 1H, H-4‴), 4.07 (s, 2H, CH2), 4.34–4.48 (m, 4H, H-5, H-6, H-3′, H-5′), 7.54–7.58 (m, 1H, H-5″), 7.80–7.86 (m, 2H, H-2′, H-6′), 7.89–7.94 (m, 2H, H-4, H-7), 8.22 (d, J 7.7, 1H, H-4″), 8.38–8.42 (m, 1H, H-6″). 13C NMR (100 MHz, DMSO-d6) δ 175.96 (S-C-N), 156.54 (C=N), 153.10 (C-5), 147.82 (C-20), 144.93 (C-29), 140.62 (C-26), 136.71 (C-4), 134.79 (C-18), 134.54 (C-17), 130.06 (2C, C-28, C-30), 129.18 (2C, C-27, C-31), 127.77 (C-1), 126.52 (C-2), 125.29 (C-19), 122.75 (C-6), 122.61 (C-3), 56.70 (C-16), 53.17 (2C, C-12, C-14), 40.65 (C-10), 32.37 (2C, C-11, C-15), 21.58 (CH3). Found (%): C, 64.48; H, 5.16; N, 9.15; S, 13.60. Calc. for C25H25N3O2S2 (%): C, 64.77; H, 5.44; N, 9.06; S, 13.83.

3.1.4. Synthesis of N-[6-(4-Bromo-1H-pyrazol-1-yl)pyridin-3-yl]benzo[d]thiazole-6-carboxamide (8)

A mixture of benzo[d]thiazole-6-carboxylic acid 7 (1.80 g, 0.01 mol), SOCl2 (1.43 g, 0.87 mL, 0.012 mol), CHCl3 (20 mL) and DMF (0.05 mL) was refluxed until gas evolution stops, cooled, and the resulting solution of benzo[d]thiazole-6-carbonyl chloride was added dropwise at 0 °C to the solution of 6-(4-bromo-1H-pyrazol-1-yl)pyridin-3-amine (2.39 g, 0.01 mol) in CHCl3 (20 mL) and Et3N (2.02 g, 2.79 mL, 0.02 mol). In 10 min, a solution of NaHCO3 (2.52 g, 0.03 mol) and water (50 mL) were added. The organic layer is separated and dried, and the solvent is distilled off in a vacuum at 35–40 °C. Furthermore, precipitate was filtered off and washed with water (3 × 15 mL).
Yield 3.12 g (78%), colorless crystals, m.p. 247–248 °C (EtOH). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 7.74 (s, 1H, H-2′), 7.91 (d, J 8.9, 1H, H-4′), 8.17–8.21 (m, 2H, H-4, H-5), 8.43 (dd, J 8.9, 2.5, 1H, H-5′), 8.62 (s, 1H, H-7), 8.78 (s, 1H, H-5″), 8.88 (d, J 2.5, 1H, H-3″), 9.46 (d, J 1.6, 1H, H-2), 10.58 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 165.81(C=O), 159.91 (S-CH2-N), 155.48 (C-5), 146.32 (C-16), 142.53 (C-22), 140.24 (C-14), 135.33 (C-4), 134.20 (C-20), 131.74 (C-13), 131.25 (C-2), 127.53 (C-18), 126.22 (C-1), 123.32 (C-3), 123.23 (C-6), 112.24 (C-17), 96.09 (C-Br). Found (%): C, 48.32; H, 2.68; Br + S, 27.64; N, 17.21. Calc. for C16H10BrN5OS (%): C, 48.01; H, 2.52; Br, 19.96; N, 17.50; S, 8.01.

3.1.5. Synthesis of N-(6-Bromobenzo[d]thiazol-2-yl)-2-(4-methyl-1-oxophthalazin-2(1H)-yl) acetamide (10)

A mixture of 2-(4-methyl-1-oxophthalazin-2(1H)-yl)acetic acid 9 (2.18 g, 0.01 mol), SOCl2 (1.43 g, 0.87 mL, 0.012 mol), CHCl3 (15 mL) and DMF (0.05 mL) was refluxed until gas evolution stops, cooled and the resulting solution of 2-(4-methyl-1-oxophthalazin-2(1H)-yl)acetyl chloride was added dropwise at 0 °C to a solution of 6-bromobenzo[d]thiazol-2-amine (2.29 g, 0.01 mol) in DMF (15 mL) and piridine (2.23 mL, 0.03 mol). Then the mixture was stirred 0.5 h, NaHCO3 (9.5 g), water (100 mL) and petroleum (20 mL) were added. The precipitate was filtered off and washed with water (3 × 15 mL).
Yield 2.23 g (52%), colorless crystals, m.p. 271–272 °C (DMF). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.60 (s, 3H, CH3), 5.07 (s, 1H, CH2), 7.51 (dd, J 8.6, 2.0, 1H, H-4), 7.65 (d, J 8.6, 1H, H-5), 7.83–7.88 (m, 1H, H-7′), 7.93–7.95 (m, 1H, H-6′), 8.09 (d, J 2.0, 1H, H-7), 8.32 (d, J 7.7, H-8′), 12.65 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ 167.85 (C=O), 159.11 (C=O), 158.87 (C-8), 148.14 (C-5), 144.39 (C-17), 134.09 (2C, C-4, C-24), 130.07 (C-18), 127.22 (2C, C-1, C-19), 126.57 (2C, C-23, C-26), 124.80 (2C, C-3, C-25), 116.08 (2C, C-2, C-6), 54.17 (CH2-C=O), 18.87(CH3). Found (%): C, 50.12; H, 2.86; Br + S, 26.31; N, 13.05. Calc. for C18H13BrN4O2S (%): C, 50.36; H, 3.05; Br, 18.61; N, 13.05; S, 7.47.

3.2. Biological Evaluation

3.2.1. Antibacterial Activity

The following Gram-negative bacteria: Escherichia coli (ATCC 35210), Enterobacter cloacae (clinical isolate), Salmonella typhimurium (ATCC 13311), as well as Gram-positive bacteria: Listeria monocytogenes (NCTC 7973), Bacillus cereus (clinical isolate), and Staphylococcus aureus (ATCC 6538) were used. The organisms were obtained from the Mycological Laboratory, Department of Plant Physiology, Institute for Biological Research “Siniša Stankovic”, Belgrade, Serbia. The minimum inhibitory (MIC) and minimum bactericidal (MBC) concentrations were determined by the modified microdilution method as previously reported [32,33].

3.2.2. Antifungal Activity

The evaluation of the antifungal activity against the fungi used was performed as detailed described earlier [5,34,35].

3.3. Docking Studies

AutoDock 4.2® software was used for the in silico studies and detailed procedure is reported in our previous paper [36].

3.4. Drug Likeness

Five filters were used to predict Drug-likeness [37,38,39,40] by the Molsoft software (San Diego, CA, USA) and SwissADME program (http://swissadme.ch, accessed on 25 October 2022) via the ChemAxon’s Marvin JS structure drawing tool.

4. Conclusions

This work presents the synthesis and study of antibacterial and antifungal activities against a panel of bacterial and fungal pathogens of twenty-one new benzohiazole derivatives. The antibacterial activity of tested compounds revealed that they have moderate activity with minimal inhibitory concentration being 0.23–2.5 mg/mL and minimal bactericidal at 0.47–0.75 mg/mL. Compounds appeared to be very active against En. cloacae but not against S. aureus.
All compounds exhibited good antifungal potency, with an MIC in range of 0.06–0.47 mg/mL and MFC at 0.11–0.94 mg/mL. Compound 2d demonstrated the best activity among all tested with MIC/MFC at 0.008–0.17/0.11–0.23 mg/mL, respectively. The most sensitive fungal to compounds tested was T. viride, while A. fumigatus was the most resistant one. The behavior of bacteria and fungi toward our compounds was different probably due to the differences in organization of their genetic material as well as a consistence of the cell wall.
According to docking results it seems that inhibition of the MurB enzyme is a putative mechanism of antibacterial activity, whereas inhibition of CYP51 reductase is suggested to be responcible for antifungal activity of the compounds.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/antibiotics11111654/s1, File S1: 1H-NMR and 13C-NMR of compounds.

Author Contributions

Conceptualization, V.K. and A.G.; methodology, A.Z.; software, A.P.; validation, A.P.; formal analysis, L.D., A.M. and A.K.; investigation, M.I., J.G. and M.S.; data curation, A.G., and M.I.; writing—original draft preparation, A.Z., A.G. and M.I.; writing—review and editing, A.G. and M.I.; visualization, V.K.; supervision, A.G. and A.Z.; funding acquisition, A.Z. and M.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work has been supported by Ministry of Science and Higher Education of the Russian Federation (Southern Federal University, 2020, project FENW-2020-0031), Fundamental Scientific Research of the State Academies of Sciences for 2014–2021 (grant no. 0710-2019-0044) and by the Serbian Ministry of Education, Science and Technological Development for financial support (project No. 451-03-68/2020-14/200007).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Antibiotics 11 01654 g001 550
Figure 1. Benzothiazole- and phthalazine-based approved drugs.
Figure 1. Benzothiazole- and phthalazine-based approved drugs.
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Antibiotics 11 01654 g002 550
Figure 2. Compounds design based on bibliography [4,5,22,25,26].
Figure 2. Compounds design based on bibliography [4,5,22,25,26].
Antibiotics 11 01654 g002
Antibiotics 11 01654 sch001a 550Antibiotics 11 01654 sch001b 550
Scheme 1. Synthesis of heteroarylderivatives benzothiazole 2. Reagents and conditions: (i) NaH, DMF, nitrogen atmosphere, 20–25 °C, 0.5 h; (ii) 5 min, 1 h at 100 °C (for 2i, k, l), 40–45 °C (for 2a, m–o) or 4 h at 50–55 °C (for 2j).
Scheme 1. Synthesis of heteroarylderivatives benzothiazole 2. Reagents and conditions: (i) NaH, DMF, nitrogen atmosphere, 20–25 °C, 0.5 h; (ii) 5 min, 1 h at 100 °C (for 2i, k, l), 40–45 °C (for 2a, m–o) or 4 h at 50–55 °C (for 2j).
Antibiotics 11 01654 sch001aAntibiotics 11 01654 sch001b
Antibiotics 11 01654 sch002 550
Scheme 2. Synthesis of benzothiazole 3. Reagents and conditions: (i) NaH, DMF, nitrogen atmosphere, 25–30 °C, 0.5 h; (ii) 15–20 °C, then at 40–45 °C, 0.5 h.
Scheme 2. Synthesis of benzothiazole 3. Reagents and conditions: (i) NaH, DMF, nitrogen atmosphere, 25–30 °C, 0.5 h; (ii) 15–20 °C, then at 40–45 °C, 0.5 h.
Antibiotics 11 01654 sch002
Antibiotics 11 01654 sch003 550
Scheme 3. Synthesis of benzothiazole derivatives 5, 6. Reagents and conditions: (i), CHCl3, Et3N, 20–25 °C, 10 h; (ii) 2NaHCO3, DMF, 20–25 °C, 2 h.
Scheme 3. Synthesis of benzothiazole derivatives 5, 6. Reagents and conditions: (i), CHCl3, Et3N, 20–25 °C, 10 h; (ii) 2NaHCO3, DMF, 20–25 °C, 2 h.
Antibiotics 11 01654 sch003
Antibiotics 11 01654 sch004 550
Scheme 4. Synthesis of 5-substituted benzothiazole 8. Reagents and conditions: (i) SOCl2, DMF, CHCl3, boiling; (ii), Et3N, CHCl3, 0–2 °C, NaHCO3.
Scheme 4. Synthesis of 5-substituted benzothiazole 8. Reagents and conditions: (i) SOCl2, DMF, CHCl3, boiling; (ii), Et3N, CHCl3, 0–2 °C, NaHCO3.
Antibiotics 11 01654 sch004
Antibiotics 11 01654 sch005 550
Scheme 5. Synthesis of oxophthalazines benzothiazole derivative 10. Reagents and conditions: (i) SOCl2, DMF, boiling; (ii) pyridine, 20–25 °C, NaHCO3.
Scheme 5. Synthesis of oxophthalazines benzothiazole derivative 10. Reagents and conditions: (i) SOCl2, DMF, boiling; (ii) pyridine, 20–25 °C, NaHCO3.
Antibiotics 11 01654 sch005
Antibiotics 11 01654 g003 550
Figure 3. (A) Superposition of compound 2j (magenta) and FAD (blue) in E. coli MurB. (B) Docked conformation of the most active compound 2j in E. coli MurB. Red dotted arrows indicate H-bond and yellow spheres hydrophobic interactions.
Figure 3. (A) Superposition of compound 2j (magenta) and FAD (blue) in E. coli MurB. (B) Docked conformation of the most active compound 2j in E. coli MurB. Red dotted arrows indicate H-bond and yellow spheres hydrophobic interactions.
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Antibiotics 11 01654 g004 550
Figure 4. (A) Superposition of Naphthyl Tetronic Acid inhibitor (red) and FAD (blue) in E. coli MurB. (B) Docked conformation of Naphthyl Tetronic Acid inhibitor in E. coli MurB. Red dotted arrows indicate H-bond and yellow spheres hydrophobic interactions.
Figure 4. (A) Superposition of Naphthyl Tetronic Acid inhibitor (red) and FAD (blue) in E. coli MurB. (B) Docked conformation of Naphthyl Tetronic Acid inhibitor in E. coli MurB. Red dotted arrows indicate H-bond and yellow spheres hydrophobic interactions.
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Antibiotics 11 01654 g005 550
Figure 5. Docked conformation of the most active compound 2d in lanosterol 14α-demethylase of C. albicans (CYP51ca). Blue arrows aromatic interactions and yellow spheres hydrophobic interactions.
Figure 5. Docked conformation of the most active compound 2d in lanosterol 14α-demethylase of C. albicans (CYP51ca). Blue arrows aromatic interactions and yellow spheres hydrophobic interactions.
Antibiotics 11 01654 g005
Antibiotics 11 01654 g006 550
Figure 6. Docked conformation of ketoconazole in lanosterol 14α-demethylase of C. albicans (CYP51ca).
Figure 6. Docked conformation of ketoconazole in lanosterol 14α-demethylase of C. albicans (CYP51ca).
Antibiotics 11 01654 g006
Antibiotics 11 01654 g007 550
Figure 7. Bioavailability Radar and Drug-likeness model diagram of compound 2j. The pink area represents the optimal range for each property for oral bioavailability, (Lipophilicity (LIPO): XLOGP3 between −0.7 and +5.0, Molecular weight (SIZE): MW between 150 and 500 g/mol, Polarity (POLAR) TPSA between 20 and 130 Å2, Solubility (INSOLU): log S not higher than 6, Saturation (INSATU): fraction of carbons in the sp3 hybridization not less than 0.25, and Flexibility (FLEX): no more than 9 rotatable bonds.
Figure 7. Bioavailability Radar and Drug-likeness model diagram of compound 2j. The pink area represents the optimal range for each property for oral bioavailability, (Lipophilicity (LIPO): XLOGP3 between −0.7 and +5.0, Molecular weight (SIZE): MW between 150 and 500 g/mol, Polarity (POLAR) TPSA between 20 and 130 Å2, Solubility (INSOLU): log S not higher than 6, Saturation (INSATU): fraction of carbons in the sp3 hybridization not less than 0.25, and Flexibility (FLEX): no more than 9 rotatable bonds.
Antibiotics 11 01654 g007
Table
Table 1. Antibacterial activity of heteroaryl derivatives of benzothiazole (mg/mL).
Table 1. Antibacterial activity of heteroaryl derivatives of benzothiazole (mg/mL).
No. S.a.B.c.L.m.E.c.S.t.En.cl.
2aMIC1.88 ± 0.000.94 ± 0.000.94 ± 0.000.35 ± 0.080.70 ± 0.190.70 ± 0.19
MBC3.75 ± 0.001.88 ± 0.001.88 ± 0.000.47 ± 0.000.94 ± 0.000.94 ± 0.00
2bMIC1.41 ± 0.380.47 ± 0.000.47 ± 0.00>3.750.23 ± 0.000.47 ± 0.00
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.00>3.750.47 ± 0.000.94 ± 0.00
2cMIC0.70 ± 0.190.70 ± 0.190.70 ± 0.190.70 ± 0.190.70 ± 0.190.70 ± 0.19
MBC0.94 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.00
2dMIC1.41 ± 0.380.35 ± 0.080.70 ± 0.190.70 ± 0.190.70 ± 0.190.70 ± 0.19
MBC1.88 ± 0.000.47 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.00
2eMIC1.41 ± 0.380.94 ± 0.000.70 ± 0.190.47 ± 0.000.23 ± 0.000.47 ± 0.00
MBC1.88 ± 0.001.88 ± 0.000.94 ± 0.000.94 ± 0.000.47 ± 0.000.94 ± 0.00
2fMIC2.50 ± 0.881.41 ± 0.380.94 ± 0.000.70 ± 0.191.41 ± 0.382.50 ± 0.88
MBC3.75 ± 0.001.88 ± 0.001.88 ± 0.000.94 ± 0.001.88 ± 0.003.75 ± 0.00
2gMIC1.41 ± 0.380.70 ± 0.190.70 ± 0.190.23 ± 0.000.70 ± 0.190.70 ± 0.19
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.000.47 ± 0.000.94 ± 0.000.94 ± 0.00
2hMIC0.94 ± 0.000.70 ± 0.190.70 ± 0.190.70 ± 0.190.47 ± 0.000.70 ± 0.19
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.00
2iMIC1.41 ± 0.380.70 ± 0.190.70 ± 0.190.35 ± 0.080.70 ± 0.190.94 ± 0.00
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.000.47 ± 0.000.94 ± 0.001.88 ± 0.00
2jMIC0.94 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.35 ± 0.080.47 ± 0.00
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.000.47 ± 0.000.47 ± 0.000.94 ± 0.00
2kMIC0.94 ± 0.000.23 ± 0.000.35 ± 0.08>3.75>3.750.23 ± 0.00
MBC1.88 ± 0.000.47 ± 0.000.47 ± 0.00>3.75>3.750.47 ± 0.00
2lMIC1.41 ± 0.380.94 ± 0.000.70 ± 0.190.70 ± 0.190.70 ± 0.190.94 ± 0.00
MBC1.88 ± 0.001.88 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.001.88 ± 0.00
2mMIC1.41 ± 0.38>3.750.70 ± 0.190.47 ± 0.000.35 ± 0.080.70 ± 0.19
MBC1.88 ± 0.00>3.750.94 ± 0.000.94 ± 0.000.47 ± 0.000.94 ± 0.00
2nMIC1.41 ± 0.380.70 ± 0.190.70 ± 0.19>3.750.47 ± 0.000.70 ± 0.19
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.00>3.750.94 ± 0.000.94 ± 0.00
2oMIC1.41 ± 0.380.70 ± 0.190.70 ± 0.19>3.750.47 ± 0.000.47 ± 0.00
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.00>3.750.94 ± 0.000.94 ± 0.00
3aMIC0.94 ± 0.000.47 ± 0.000.70 ± 0.190.70 ± 0.190.47 ± 0.000.70 ± 0.19
MBC3.75 ± 0.001.88 ± 0.001.88 ± 0.000.94 ± 0.000.94 ± 0.001.88 ± 0.00
3bMIC1.41 ± 0.380.70 ± 0.190.70 ± 0.19>3.750.70 ± 0.190.70 ± 0.19
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.00>3.750.94 ± 0.000.94 ± 0.00
5MIC1.41 ± 0.380.47 ± 0.000.70 ± 0.190.35 ± 0.080.70 ± 0.191.41 ± 0.38
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.000.47 ± 0.000.94 ± 0.001.88 ± 0.00
6MIC0.94 ± 0.000.70 ± 0.190.70 ± 0.19>3.750.70 ± 0.190.47 ± 0.00
MBC1.88 ± 0.000.94 ± 0.000.94 ± 0.00>3.750.94 ± 0.000.94 ± 0.00
8MIC2.50 ± 0.881.41 ± 0.381.41 ± 0.000.70 ± 0.190.70 ± 0.190.94 ± 0.00
MBC3.75 ± 0.001.88 ± 0.001.88 ± 0.000.94 ± 0.000.94 ± 0.001.88 ± 0.00
10MIC1.41 ± 0.380.23 ± 0.000.70 ± 0.190.70 ± 0.190.23 ± 0.000.70 ± 0.19
MBC1.88 ± 0.000.47 ± 0.000.94 ± 0.000.94 ± 0.000.47 ± 0.000.94 ± 0.00
StreptomycinMIC0.10 ± 0.000.02 ± 0.000.15 ± 0.000.10 ± 0.000.10 ± 0.000.02 ± 0.00
MBC0.20 ± 0.010.05 ± 0.000.30 ± 0.010.20 ± 0.000.20 ± 0.010.05 ± 0.00
AmpicillinMIC0.10 ± 0.000.10 ± 0.000.15 ± 0.000.15 ± 0.000.10 ± 0.000.10 ± 0.00
MBC0.15 ± 0.000.15 ± 0.000.30 ± 0.020.20 ± 0.010.20 ± 0.000.15 ± 0.01
S.a.—Staphylococcus aureus, B.c Bacillus cereus, l.m.—Listeria monocytogenes, E.c.—Escherichia coli, S.t.—Salmonella typhimurium, En.c.—Enterobacter cloacae, Relative standard deviations were all < 2.0. Amp.: Ampicillin, Strept.: Streptomycin. This experiment was performed in duplicate.
Table
Table 2. Antifungal activity of heteroaryl derivatives of benzothiazole (mg/mL).
Table 2. Antifungal activity of heteroaryl derivatives of benzothiazole (mg/mL).
No. A.f.A.n.A.v.P.f.T.v.P.v.c.
2aMIC0.23 ± 0.000.23 ± 0.000.11 ± 0.000.35 ± 0.080.11 ± 0.000.11 ± 0.00
MFC0.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.000.23 ± 0.000.23 ± 0.00
2bMIC0.23 ± 0.000.23 ± 0.000.23 ± 0.000.23 ± 0.000.11 ± 0.000.23 ± 0.00
MFC0.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
2cMIC0.23 ± 0.000.23 ± 0.000.23 ± 0.000.35 ± 0.080.23 ± 0.000.23 ± 0.00
MFC0.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.00
2dMIC0.17 ± 0.050.11 ± 0.000.17 ± 0.050.17 ± 0.050.08 ± 0.000.17 ± 0.05
MFC0.23 ± 0.000.23 ± 0.000.23 ± 0.000.23 ± 0.000.11 ± 0.000.23 ± 0.00
2eMIC0.23 ± 0.000.23 ± 0.000.35 ± 0.080.35 ± 0.080.17 ± 0.050.35 ± 0.08
MFC0.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
2fMIC0.47 ± 0.000.23 ± 0.000.23 ± 0.000.23 ± 0.000.17 ± 0.050.23 ± 0.00
MFC0.94 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
2gMIC0.47 ± 0.000.17 ± 0.050.23 ± 0.000.35 ± 0.080.17 ± 0.050.35 ± 0.08
MFC0.94 ± 0.000.23 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
2hMIC0.47 ± 0.000.23 ± 0.000.35 ± 0.080.35 ± 0.080.11 ± 0.000.70 ± 0.19
MFC0.94 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.94 ± 0.00
2iMIC0.23 ± 0.000.11 ± 0.000.23 ± 0.000.23 ± 0.000.06 ± 0.000.23 ± 0.00
MFC0.47 ± 0.000.23 ± 0.000.47 ± 0.000.47 ± 0.000.11 ± 0.000.47 ± 0.00
2jMIC0.23 ± 0.000.23 ± 0.000.11 ± 0.000.23 ± 0.000.11 ± 0.000.23 ± 0.00
MFC0.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
2kMIC0.23 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
MFC0.47 ± 0.000.94 ± 0.000.94 ± 0.000.94 ± 0.000.47 ± 0.000.94 ± 0.00
2lMIC0.23 ± 0.000.17 ± 0.050.23 ± 0.000.23 ± 0.000.11 ± 0.000.23 ± 0.00
MFC0.47 ± 0.000.23 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
2mMIC0.17 ± 0.050.11 ± 0.000.11 ± 0.000.23 ± 0.000.17 ± 0.050.35 ± 0.08
MFC0.23 ± 0.000.23 ± 0.000.23 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
2nMIC0.47 ± 0.000.23 ± 0.000.23 ± 0.000.35 ± 0.080.23 ± 0.000.35 ± 0.08
MFC0.94 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.00
2oMIC0.17 ± 0.050.17 ± 0.050.11 ± 0.000.23 ± 0.000.17 ± 0.050.23 ± 0.00
MFC0.23 ± 0.000.23 ± 0.000.23 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
3aMIC0.17 ± 0.050.11 ± 0.000.23 ± 0.000.17 ± 0.050.11 ± 0.000.23 ± 0.00
MFC0.23 ± 0.000.23 ± 0.000.47 ± 0.000.23 ± 0.000.23 ± 0.000.47 ± 0.00
3bMIC0.23 ± 0.000.23 ± 0.000.17 ± 0.050.17 ± 0.050.06 ± 0.000.17 ± 0.05
MFC0.47 ± 0.000.47 ± 0.000.23 ± 0.000.23 ± 0.000.11 ± 0.000.23 ± 0.00
5MIC0.23 ± 0.000.35 ± 0.080.23 ± 0.000.23 ± 0.000.11 ± 0.000.23 ± 0.00
MFC0.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.23 ± 0.000.47 ± 0.00
6MIC0.23 ± 0.000.35 ± 0.080.23 ± 0.000.23 ± 0.000.06 ± 0.000.23 ± 0.00
MFC0.47 ± 0.000.47 ± 0.000.47 ± 0.000.47 ± 0.000.11 ± 0.000.47 ± 0.00
8MIC3.75 ± 0.003.75 ± 0.003.75 ± 0.003.75 ± 0.003.75 ± 0.003.75 ± 0.00
MFC>3.75>3.75>3.75>3.75>3.75>3.75
10MIC1.88 ± 0.000.47 ± 0.000.70 ± 0.0191.41 ± 0.380.70 ± 0.192.50 ± 0.88
MFC3.75 ± 0.000.94 ± 0.000.94 ± 0.001.88 ± 0.000.94 ± 0.003.75 ± 0.00
BifonazoleMIC0.15 ± 0.000.15 ± 0.000.10 ± 0.000.20 ± 0.000.15 ± 0.000.10 ± 0.00
MFC0.20 ± 0.000.20 ± 0.000.20 ± 0.000.25 ± 0.000.20 ± 0.000.20 ± 0.00
KetoconazoleMIC0.20 ± 0.000.20 ± 0.000.20 ± 0.000.20 ± 0.001.00 ± 0.010.20 ± 0.00
MFC0.50 ± 0.000.50 ± 0.000.50 ± 0.000.50 ± 0.001.50 ± 0.000.30 ± 0.010
A.f.—A. fumigatus, A.n.—A. niger, A.v.—A. versicolor, P.f.—P. funiculosum, T.v.—T. viride, P.v.c.—P. cyclopium var. verucosum. Relative standard deviations were all < 2.20. This experiment was performed in duplicate.
Table
Table 3. Molecular docking free binding energies (kcal/mol) to antibacterial targets.
Table 3. Molecular docking free binding energies (kcal/mol) to antibacterial targets.
Comp.Est. Binding Energy (kcal/mol)I-H
E. coli MurB		Residues
E. coli MurB
E. coli Gyrase
1KZN		Thymidylate Kinase
4QGG		E. coli Primase
1DDE		E. coli MurA JV4TE. coli MurB 2Q85
2a−4.52--−3.62−8.031Ser229
2b−5.28-−1.23−4.27−7.861Arg158
2c−4.39−2.55-−5.19−10.132Ser50, Ser229
2d−5.19−1.03−2.26−6.52−9.642Arg158, Arg213
2e−4.55-−1.39−5.24−9.612Arg213, Ser229
2f−4.37--−5.37−6.531Arg213
2g−5.37−1.54−2.33−6.72−10.022Arg158, Arg213
2h−4.19--−5.68−9.712Arg213, Ser229
2i−5.63−1.28−1.30−5.22−9.342Ser50, Ser229
2j−5.27--−6.34−10.753Ser50, Ser116, Ile173
2k−4.23--−4.53−8.761Ser229
2l−4.96-−2.38−6.59−9.112Ser50, Ser229
2m−5.23--−4.56−7.801Arg158
2n−4.31−1.85-−3.11−7.301Arg213
2o−3.62--−2.54−7.351Arg213
3a−4.35--−3.64−8.451Ser229
3b−2.32−1.68-−4.52−7.181Arg158
5−5.12-−1.30−5.57−9.532Arg213, Ser229
6−3.66--−2.50−7.421Arg213
8−5.10−1.52−2.46−6.22−9.902Arg158, Arg213
10−4.28--−3.55−6.921Arg213
Naphthyl Tetronic Acid inhibitor----−8.82-Asn233
Table
Table 4. Molecular docking free binding energies (kcal/mol) to antifungal targets.
Table 4. Molecular docking free binding energies (kcal/mol) to antifungal targets.
Est. Binding Energy(kcal/mol)Residues Involved in H-Bond FormationResidues Involved in Hydrophobic InteractionsResidues Involved in Aromatic InteractionsInteractions with HEM601
N/NDNA TopoIV
1S16		CYP51 of C. albicans
5V5Z
2a−1.38−9.85Tyr132Tyr118, Leu121, Thr311, Phe380, Met508, Hem601Hem601Hydrophobic, aromatic
2b−3.59−8.82Tyr132Tyr118, Tyr122, Ile304, Thr311, Hem601Tyr118Hydrophobic
2c−2.64−8.03-Tyr118, Thr311, Leu376, Met508, Hem601Hem601Hydrophobic, aromatic
2d−3.57−11.32-Tyr118, Leu121, Tyr122, Thr311, Leu376, Phe380, Met508, Hem601Tyr118, Hem601Hydrophobic, aromatic
2e−3.15−8.50Tyr118Tyr118, Leu376, Met508, Hem601Tyr118Hydrophobic
2f−1.29−7.46-Met508, Hem601Hem601Hydrophobic, aromatic
2g-−7.93-Ile304, Thr311, Met508, Hem601-Hydrophobic
2h−2.44−7.21-Tyr118, Leu376, Met508, Hem601Tyr118Hydrophobic
2i-−9.82Tyr132Tyr118, Phe380, Met508, Hem601-Hydrophobic
2j−3.83−9.56-Tyr118, Tyr122, Thr311, Leu376, Met508, Hem601Tyr118, Hem601Hydrophobic, aromatic
2k-−7.39-Tyr118, Met508, Hem601-Hydrophobic
2l−1.279.52-Tyr118, Tyr122, Leu376, Met508, Hem601Tyr122, Hem601Hydrophobic, aromatic
2m−3.21−10.02Tyr64Tyr118, Tyr122, Thr311, Leu376, Phe380, Hem601Tyr118Hydrophobic
2n-−7.25-Tyr118, Leu376, Met508, Hem601-Hydrophobic
2o−2.50−10.25-Tyr118, Leu121, Tyr122, Thr311, Hem601Hem601Hydrophobic, aromatic
3a−2.75−10.31-Tyr118, Leu121, Leu376, Phe380, Met508, Hem601Hem601Hydrophobic, aromatic
3b−3.23−10.87-Tyr118, Tyr122, Thr311, Leu376, Met508, Hem601Tyr118, Hem601Hydrophobic, aromatic
5-−8.62-Tyr118, Tyr122, Thr311, Met508, Hem601Hem601Hydrophobic, aromatic
6−2.45−9.10-Tyr118, Tyr122, Ile304, Thr311, Leu376, Hem601Ile131, Hem601Hydrophobic, aromatic
8−2.06−8.21-Tyr118, Tyr122, Ile131, Leu376, Met508, Hem601-Hydrophobic
10−2.41−7.20-Tyr118, Leu376, Met508, Hem601Tyr118Hydrophobic
ketoconazole-−8.23Tyr64Tyr118, Ile131, Tyr132, Leu300, Ile304, Leu376, Met508, Hem601Hem601Hydrophobic, aromatic
Table
Table 5. Drug likeness predictions of tested compounds.
Table 5. Drug likeness predictions of tested compounds.
No.MWNumber of HBA aNumber of HBD bLog Po/w
(iLOGP) c		Log S dTPSA eBBB Permeant fLipinski, Ghose, Veber, Egan, and Muegge ViolationsBioavailability ScoreDrug-Likeness Model Score
2a311.42202.81Poorly soluble84.25No00.55−0.08
2b309.41303.19Poorly soluble92.21No00.55−0.19
2c371.48303.69Poorly soluble92.21No00.55−0.35
2d385.50303.86Poorly soluble92.21No00.55−0.12
2e405.92304.03Poorly soluble92.21No00.550.20
2f470.61404.30Poorly soluble112.52No2 *0.550.65
2g492.64604.13Poorly soluble137.97No3 **0.55−0.22
2h587.71504.65Insoluble134.52No2 ***0.170.37
2i429.56303.65Poorly soluble101.32No00.550.06
2j486.61413.73Poorly soluble130.42No00.550.43
2k497.63404.36Poorly soluble115.76No00.550.21
2l511.66404.31Poorly soluble115.76No00.550.42
2m482.58513.61Poorly soluble138.61No00.550.32
2n496.61514.14Poorly soluble138.61No00.550.34
2o531.65414.38Poorly soluble125.72No2 ***0.17−0.03
3a464.69204.75Poorly soluble132.86No00.55−0.05
3b496.69404.87Poorly soluble151.32No00.550.43
5501.62803.85Poorly soluble117.82No00.550.79
6463.61503.56Poorly soluble99.78No00.550.49
8400.25412.93Poorly soluble100.94No00.55−0.60
10429.29412.65Poorly soluble105.12No00.550.44
a number of hydrogen bond acceptors; b number of hydrogen bond donors; c lipophilicity; d Water solubility (SILICOS-IT [S = Soluble]); e topological polar surface area (Å2); f Blood Brain Barrier permeant; * Ghose 2 violations: WLOGP > 5.6, MR > 130, ** Ghose 3 violations: MW > 480, WLOGP > 5.6, MR > 130, *** Lipinski: 2 violations: MW > 500, MLOGP > 4.15.
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Zubenko, A.; Kartsev, V.; Petrou, A.; Geronikaki, A.; Ivanov, M.; Glamočlija, J.; Soković, M.; Divaeva, L.; Morkovnik, A.; Klimenko, A. Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents. Antibiotics 2022, 11, 1654. https://doi.org/10.3390/antibiotics11111654

AMA Style

Zubenko A, Kartsev V, Petrou A, Geronikaki A, Ivanov M, Glamočlija J, Soković M, Divaeva L, Morkovnik A, Klimenko A. Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents. Antibiotics. 2022; 11(11):1654. https://doi.org/10.3390/antibiotics11111654

Chicago/Turabian Style

Zubenko, Alexander, Victor Kartsev, Anthi Petrou, Athina Geronikaki, Marija Ivanov, Jasmina Glamočlija, Marina Soković, Lyudmila Divaeva, Anatolii Morkovnik, and Alexander Klimenko. 2022. "Experimental and In Silico Evaluation of New Heteroaryl Benzothiazole Derivatives as Antimicrobial Agents" Antibiotics 11, no. 11: 1654. https://doi.org/10.3390/antibiotics11111654

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