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. 2025 Feb 28;10(9):9703–9717. doi: 10.1021/acsomega.4c11076

Design, Characterization, Antimicrobial Activity, and In Silico Studies of Theinothiazoloquinazoline Derivatives Bearing Thiazinone, Tetrazole, and Triazole Moieties

Hagar S El-Hema a,*, Sara M Soliman b, Wagdy El-Dougdoug b, Mohamed H M Ahmed b, Abdelmotaal Abdelmajeid b, Eman S Nossier c,d, Modather F Hussein e,f, Ashtar A Alrayes e, Mariam Hassan g,h, Noha A Ahmed g, Amr Sabry i, Adel A-H Abdel-Rahman j,*
PMCID: PMC11904721  PMID: 40092816

Abstract

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The pressing demand for novel antibiotics to counter drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), underscores the serious public health threat posed by antibiotic resistance. To address this issue, novel quinazoline-4-one derivatives were developed, synthesized, and evaluated in vitro against a range of pathogens, including fungi like Aspergillus fumigatus (RCMB 002008), Gram-negative bacteria like Escherichia coli (ATCC 25922), and Gram-positive bacteria like Staphylococcus aureus (ATCC 25923) and MRSA (USA300). Notably, the thieno-thiazolo-quinazoline compounds 4 and 5 demonstrated a strong ability to inhibit and disrupt MRSA USA300 biofilm formation across all tested concentrations. Furthermore, in an in vivo MRSA skin infection model, these compounds effectively reduced bacterial counts compared to both vehicle-treated and untreated control groups. To enhance understanding and provide deeper insights, ADMET and docking simulations were also conducted.

1. Introduction

According to WHO predictions, antibiotic-resistant strains will kill 10 million people globally each year by 2050, surpassing the death toll from AIDS, cancer, and having a significant effect on the world economy.1,2 The stock of effective antibiotics quickly decreases as microbes evolve new resistance mechanisms, posing considerable difficulties to current treatment methods.3,4 The ESCAPE pathogens—Enterococcus faecium, Staphylococcus aureus, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—present a significant challenge in healthcare settings due to their high resistance to multiple drugs.5

Methicillin-resistant Staphylococcus aureus (MRSA) exhibits this problem since it routinely develops resistance to new medications. This resistance complicates treatment options while also imposing a significant fiscal burden on global healthcare systems.6−8 MRSA resistance strategies include changes in target locations, the development of antibiotic-inactivating enzymes, and adjustments to cell membrane permeability, among others. This growing resistance emphasizes the critical need for pharmaceutical innovation to discover and develop novel medicines capable of battling these hardy pathogens.9

Among various antibacterial targets, bacterial type II topoisomerases, including DNA gyrase, have been recognized as crucial therapeutic targets for antibacterial agents.10 These heterotetrametric enzymes are made up of two GyrA and two GyrB subunits (A2B2). In order to prevent positive supercoiling from overtwisting DNA and shattering DNA strands and to preserve equilibrium in bacterial DNA replication, DNA gyrase plays a unique role in negative supercoiling. GyrB provides energy for the enzyme’s catalytic function through ATP hydrolysis, whereas GyrA is mainly engaged in the breaking and reunification of double-stranded DNA.11,12 Therefore, DNA gyrase will remain crucial for bacterial survival.13

Quinazoline and Quinazolinone derivatives were considered as a source of useful pharmacophores for novel drug evolution and still gain enormous attention nowadays14,15 Due to multiple substitutions on this ring system. Moreover, the broad variety of therapeutic properties of quinazolinones have drawn much attention and great application in drug discovery.16 such as sedative,17 hypoglycemic,18 anticonvulsant,19,20 herbicidal,21 antibacterial,22,23 antifungal,24 antileishmanial,25 antioxidant,26 antioxidant,27 diuretic activities,28 anti-inflammatory,29,30 cytotoxicity,31,32 antitumor,33,34 anti-HIV,35 antiviral,32 antituberculosis31 properties, in addition to their inhibitory effects on tyrosine kinase,36−38 thymidylate synthase37,39 and poly(ADP-ribose) polymerase (PARP),17 and other plentiful uses and interesting properties. These examples highlight their widespread presence in bioorganic and medicinal chemistry. In this article, we focus on quinazolinones and their various derivatives with antimicrobial activity.40−43

In searching for novel medications, particularly those related to antibacterial drugs, heterocycles are essential structural motifs.44,45 Incorporating heteroatoms into the cyclic structures of these compounds enhances their interactions with various biological macromolecules, such as DNA, proteins, and enzymes, significantly boosting their biological activity.46,47 Various compounds I-VI in (Figure 1), either with quinazolinone and/or with other nitrogenous moieties such as thiazole or triazole, were shown to have significant antimicrobial activity, including against MRSA.48−53 Additionally, their antimicrobial potency was furnished through inhibition of Staphylococcus aureus DNA gyrase.

Figure 1.

Figure 1

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Various antimicrobial agents, bearing quinazolinone and other nitrogenous moieties as, thiazole, or triazole constituents, with Staphylococcus aureus DNA gyrase inhibition mechanism.

Building on the broad medicinal potential of quinazoline-4-one and inspired by the structural characteristics of compound I, new quinazoline-4-one derivatives were strategically designed and synthesized. This was achieved through molecular hybridization with other pharmacophoric groups, aiming to enhance their biological activity (Figure 2). All derivatives were screened in vitro for their antimicrobial activities versus Staphylococcus aureus (ATCC 25923) and methicillin-resistant Staphylococcus aureus (MRSA, USA300) as Gram-positive bacterial examples, Escherichia coli (ATCC 25922) as a Gram-negative bacterial example, and Aspergillus fumigatus (RCMB 002008) as a fungal example. The promising compounds were further subjected to in vitro antibiofilm activity and an in vivo MRSA skin infection model. Moreover, in silico ADMET assessment and docking simulation were applied to describe their pharmacokinetic characteristics along with their potential as crucial antimicrobial candidates.

Figure 2.

Figure 2

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Designed rationale for quinazolinone-based derivatives 1–12 fused with various nitrogenous moieties as antimicrobial agents targeting inhibition of Staphylococcus aureus DNA gyrase.

2. Results and Discussion

2.1. Chemistry

The synthetic methods used to produce the intermediate and final compounds are outlined in Schemes 1–5, respectively. In Scheme 1, the desired 4-Phenyl-3a,4-dihydro-5H-thiazolo[3,2-a]quinazoline-1,5(2H)-dione (1) was prepared with 72% yield by reacting the starting material 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one54 (A) with chloroacetic acid in dry 1,4 dioxane under refluxing conditions for 2 h using a Dean–Stark condenser, followed by an efficient transformation with ethyl cyanoacetate, sulfur, and diethylamine in dry DMF at 50 °C for 2 h to yield ethyl 9-amino-5-oxo-6-phenyl-6,6a-dihydro-5H-thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-8-carboxylate (2). The confirmation of the final chemical structures of compounds 1 and 2 was carried out through the analysis of analytical and spectral data, while the purity of the compounds was assessed using thin-layer chromatography (TLC). For instance, in the case of compound 1, the IR spectrum revealed absorption bands at 2936 and 1730 cm–1, corresponding to the CH-aliphatic and C = O (thiazolidin-4-one) groups, respectively. Additionally, in the 1H NMR spectrum, singlet signals at 4.16 and 7.22 ppm were observed, which were attributed to the thiazole protons. Moreover, the 13C NMR spectrum displayed distinct signals at 45.51, 90.00, and 172.37 ppm, corresponding to the triazole CH2, CH, and C = O carbons, respectively. In the case of compound 2, the IR spectrum revealed absorption bands at 3239, 3219, and 1719 cm–1, corresponding to the NH2 and C = O ester groups, respectively, and showed an absence of an absorption band at 1730 cm–1, corresponding to the C = O (thiazolidin-4-one) group. Additionally, in the 1H NMR spectrum, a triplet signal at 1.50 ppm, a quartet signal at 4.20 ppm, and a broad signal at 6.40 ppm were observed, which were attributed the ester and amino protons, respectively, and the absence of a signal at 4.16 ppm, which was attributed to the CH2 protons. Moreover, the 13C NMR spectrum displayed distinct signals at 12.34, 63.65, and 156.06 ppm, corresponding to the CH3, CH2, and C = O carbons, respectively, and the absence of signals at 45.51 and 172.37 ppm, corresponding to the CH2 and C = O (thiazolidin-4-one) carbons.

Scheme 1. Synthesis of Thiazolo[3,2-a]quinazoline-1,5-dione 1 and Ethyl 9-Amino-thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-8-carboxylate 2.

Scheme 1

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Scheme 5. Synthesis of [1,2,4]Triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8-dione 12.

Scheme 5

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In Scheme 2, the desired 1,2-thiazinan-5-one derivative (3) was prepared in 66% yield by reacting 2 with sulfur in dry DMF to yield 6-phenyl-6,6a-dihydro-5H,9H-[1,2]thiazino[4″,3”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(11H)-dione (3), followed by reaction with methane sulfonyl chloride in the presence of triethylamine as a catalyst in dry DMF to yield 11-(methylsulfonyl)-6-phenyl-6,6a-dihydro-5H,9H-[1,2]thiazino[4″,3”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(11H)-dione (4). The confirmation of the final chemical structures of compounds 3 and 4 was achieved through the analysis of both analytical and spectral data. For instance, in the case of compound 3, the IR spectrum revealed absorption bands at 3267, 2977, 2915, and 1722 cm–1 corresponding to the NH, CH-aliphatic, and C = O (thiazinone) groups, respectively, and showed an absence of absorption bands at 3239, 3219, and 1719 cm–1 corresponding to the NH2 and C = O (ester) groups. Additionally, in the 1H NMR spectrum, a broad signal at 4.00 ppm and a singlet signal at 3.13 ppm were observed, which were attributed to the NH and CH2 protons, respectively, and the absence of signals at 1.50, 4.20, and 6.40 ppm, which were attributed to the CH3, CH2 and NH2 protons. Additionally, in the 13C NMR spectrum, signals at 46.09 and 176.54 ppm were observed, which were attributed to the CH2 and C = O (thiazinone) carbons, and the absence of signals at 12.34, 63.65, and 156.06 ppm, which were attributed to the CH3, CH2, and C = O (ester) carbons. For instance, in the case of compound 4, the IR spectrum revealed absorption bands at 2853 and 1315 cm–1 corresponding to the CH-aliphatic and S = O groups, respectively, and showed an absence of an absorption band at 3267 cm–1 corresponding to the NH group. Additionally, in the 1H NMR spectrum, a singlet signal at 2.60 ppm was observed, which was attributed to the CH3 protons, and the absence of signal at 4.00 ppm, which was attributed to the NH proton. Additionally, in the 13C NMR spectrum, a signal at 45.89 ppm was observed, which was attributed to the CH3 carbon. Compound 2 underwent an efficient transformation to yield ethyl 5-oxo-6-phenyl-9-(1H-tetrazol-1-yl)-6,6a-dihydro-5H-thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-8-carboxylate (5). This transformation was accomplished by reacting compound 2 with triethyl orthoformate and sodium azide in glacial acetic acid. The resulting compound 5 was then treated with hydrazine hydrate, leading to the successful synthesis of the cyclized diamino pyrimidinone 6, which was obtained in good yield. The confirmation of the chemical structures of compounds 5 and 6 was achieved through the analysis of both analytical and spectral data. For instance, in the case of compound 5, the IR spectrum revealed absorption bands at 1536 and 1408 cm–1, corresponding to the C = N and N = N groups, and the absence of absorption bands at 3239 and 3219 cm–1, corresponding to the NH2 group. Additionally, in the 1H NMR spectrum, a singlet signal at 9.48 ppm was observed, which was attributed to the CH tetrazole proton, and the absence of a broad signal at 6.40 ppm, which was attributed to the NH2 protons. Additionally, in the 13C NMR spectrum, a signal at 135.05 ppm was observed, which was attributed to the C = N tetrazole carbon. For instance, in the case of compound 6, the IR spectrum revealed absorption bands at 3440, 3388, 1687, and 1631 cm–1, corresponding to the 2NH2, C = O (pyrimidine), and C = N groups, respectively. Additionally, in the 1H NMR spectrum, a broad signal at 6.18 ppm was observed, which was attributed to the 2NH2 group protons, and the absence of signals at 1.85, 4.25, and 9.48 ppm, which were attributed to the CH3, CH2 and CH tetrazole protons. Additionally, in the 13C NMR spectrum, signals at 12.12, 63.07, 135.05, and 156.05 ppm disappeared, which were attributed to the COOCH2CH3 and C = N tetrazole ester carbons, and signals at 150.67 and 168.53 ppm were observed, which were attributed to the C = N and C = O (pyrimidine) carbons.

Scheme 2. Synthesis of Thieno-thiazolo-quinazoline Derivatives 3–6.

Scheme 2

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The fusion of compound 6 with two types of aromatic aldehydes, specifically 4-dimethylaminobenzaldehyde and furfuraldehyde, in an oil bath at 180 °C resulted in the formation of the desired triazolo-N,N-dimethylaniline and furan dihydrotriazole derivatives (7) and (8) (Scheme 3).The confirmation of the chemical structures of compounds 7 and 8 was achieved through the analysis of both analytical and spectral data. For instance, in the case of compound 7, the IR spectrum revealed absorption bands at 3138, 2990, and 2947 cm–1, corresponding to the NH and CH-aliphatic groups, respectively, and the absence of absorption bands at 3440 and 3388 cm–1, corresponding to the NH2 group. Additionally, in the 1H NMR spectrum, singlet signals at 2.52 and 3.04 ppm were observed, which were attributed to the CH3 and NH protons, and the absence of a signal at 6.18 ppm, which was attributed to the NH2 protons. Additionally, the MS spectrum showed a molecular ion peak at m/z 563 [M+], corresponding to C29H21N7O2S2, which aligns with the molar mass of the proposed structure. The primary fragmentation occurred at m/z 429, resulting from the loss of a C8H10N2 group, corresponding to a (134 Da) mass loss, m/z = 365, indicating the loss of a C2N2O group (68 Da) and gaining 4 hydrogens, m/z = 293, indicating the loss of a C2H2NS group (72 Da), m/z = 227, indicating the loss of a -C3S group (68 Da) and gaining 2 hydrogens, m/z = 170, indicating the loss of a C2H3NO group (57 Da), m/z = 110 indicating the loss of a C5 group (60 Da), m/z = 94 indicating the loss of a CH4 group (16 Da) and m/z = 81, indicating the loss of a CH group (13 Da) with 100% abundance as a base peak. In the case of compound 8, the IR spectrum revealed an absorption band at 3186 cm–1, corresponding to the NH group, and the absence of absorption bands at 3440 and 3388 cm–1, corresponding to the NH2 group. Additionally, in the 1H NMR spectrum, singlet signals at 2.08 and 8.37 ppm were observed, which were attributed to NH and CH furfural protons. Additionally, the MS spectrum revealed a molecular ion peak at m/z 510 [M+], corresponding to C25H14N6O3S2 and in agreement with the molar mass of the suggested structure. The primary fragmentation occurred at m/z = 487 due to the loss of a CO group, corresponding to a (28 Da) mass loss and gaining 5 hydrogens, m/z = 440, indicating the loss of a CH4O2 group (48 Da), m/z = 339, indicating the loss of a C5N3 group (102 Da) and gaining 1 hydrogen, m/z = 227 indicating the loss of a C4H4N2S group (112 Da) with 100% abundance as a base peak, m/z = 120, indicating the loss of a C6H3S group (107 Da) and m/z = 57 indicating the loss of a C5H3 group (63 Da). Upon heating compound 6 with diethylmalonate, the ethyl acetate ester (9) was formed. The IR spectrum of compound 9 displayed prominent absorption bands at 3242, 2988, 2949, 2919, 2860, and 1788 cm–1 due to NH, CH aliphatic, and ester C = O groups, and the absence of absorption bands at 3440 and 3388 cm–1, corresponding to the NH2 group. In the 1H NMR spectrum, broad and triplet signals appeared at 2.07 and 2.58 ppm, which were ascribed to the NH and methyl protons, singlet and quartet signals appeared at 3.15 and 4.20 ppm, which were ascribed to the two CH2 protons, and there was an absence of signal at 6.18 ppm, which was attributed to the NH2 protons. In the 13C NMR spectrum, a signal at 15.39 ppm appeared, which was ascribed to the methyl carbon; 44.63 and 62.29 ppm appeared, which were ascribed to the 2CH2 carbons; and 169.08 ppm appeared, which was ascribed to the C = O (ester) carbon. The MS spectrum revealed a molecular ion peak at 530 m/z [M+], corresponding to C25H18N6O4S2 and in agreement with the molar mass of the suggested structure. The primary fragmentation occurred at m/z = 475 due to the loss of a C2O2 group, corresponding to a (55 Da) mass loss and gaining 1 hydrogen, m/z = 340, indicating the loss of a C7H5NO2 group (135 Da), m/z = 274, indicating the loss of a C3H2N2 group (66 Da) with 100% abundance as a base peak, m/z = 230, indicating the loss of a CS group (44 Da), m/z = 146, indicating the loss of a C3H2NS group (84 Da), and m/z = 69, indicating the loss of a C4HN2 group (77 Da). The synthesis of the triazolo propanone derivative (10) was successfully achieved with a satisfactory yield by reacting compound 6 with ethyl acetoacetate at 180 °C. The IR spectrum of compound 10 displayed prominent absorption bands at 3111, 2956, 2921, and 1740 cm–1 due to NH, CH aliphatic, and acetyl C = O groups, and the absence of absorption bands at 3440 and 3388 cm–1, corresponding to the NH2 group. In the 1H NMR spectrum, broad, singlet signals appeared at 2.07, 2.58, and 4.31 ppm, which were ascribed to the NH, CH3, and CH2 protons, and there was an absence of signal at 6.18 ppm, which was attributed to the NH2 protons. In the 13C NMR spectrum, 27.20, 40.00, and 202.00 ppm appeared, which were ascribed to the CH3, CH2, and C = O carbons.

Scheme 3. Synthesis of [1,2,4]Triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8-diones 7–10.

Scheme 3

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In Scheme 4, the desired 4-ethylmorpholine derivative 11 was prepared in 80% yield by reacting 8 with formaldehyde and morpholine in dry DMF to yield 11-(furan-2-yl)-12-(morpholinomethyl)-6-phenyl-6,6a-dihydro[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(12H)-dione (11). The confirmation of the chemical structure of compound 11 was accomplished through the analysis of both analytical and spectral data. For example, in the case of compound 11, the IR spectrum revealed absorption bands at 2992 and 2892 cm–1 corresponding to the CH-aliphatic group and the absence of an absorption band at 3186 cm–1, corresponding to the NH group. Additionally, in the 1H NMR spectrum, triplet signals at 2.31, 3.50, and 3.58 ppm were observed, which were attributed to the 4CH2 morpholine protons, respectively, and a singlet signal at 4.24 ppm was observed, which was attributed to the CH2 protons, and the absence of a signal at 2.08 ppm, which was attributed to the NH proton. Additionally, in the 13C NMR spectrum, signals at 55.57, 55.95, 59.50, and 67.20 ppm were observed, which were attributed to the 5CH2 carbons.

Scheme 4. Synthesis of [1,2,4]Triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8-dione 11.

Scheme 4

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In Scheme 5, the desired benzyl derivative 12 was prepared in high yields by the reaction of 10 with benzyl chloride in the presence of triethylamine in dry DMF to yield 12-Benzyl-11-(2-oxopropyl)-6-phenyl-6,6a-dihydro-5H-[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(12H)-dione (12). The confirmation of the chemical structure of compound 12 was achieved through the analysis of both analytical and spectral data. For instance, in the case of compound 12, the IR spectrum showed absorption bands at 2989, 2945, 2921, and 1744 cm–1 corresponding to the CH-aliphatic and C = O groups, respectively, and the absence of an absorption band at 3111 cm–1, corresponding to the NH group. Additionally, in the 13C NMR spectrum, a signal at 34.56 ppm was observed, which was attributed to the CH2–Ph ring carbon. Additionally, the MS spectrum revealed a molecular ion peak at 590 m/z [M+], corresponding to C31H22N6O3S2 and in agreement with the molar mass of the suggested structure. The primary fragmentation occurred at m/z = 454 due to the loss of a C5N2O3 group, corresponding to a (136 Da) mass loss, m/z = 227, indicating the loss of a C16H7N2 group (227 Da), m/z = 183, indicating the loss of a CS group (44 Da), m/z = 156, indicating the loss of a C2H3 group (27 Da), m/z = 113, indicating the loss of a C3H7 group (43 Da), and m/z = 62, indicating the loss of a C2H2 group (51 Da) with 100% abundance as a base peak.

2.2. Biological Activity

2.2.1. Antimicrobial Efficiency

The newly synthesized thiazolo-quinazoline derivatives 1–12 were evaluated in vitro for their antimicrobial activity. The evaluation targeted several pathogens versus Staphylococcus aureus (ATCC 25923) and methicillin-resistant Staphylococcus aureus (MRSA, USA300) as Gram-positive bacterial examples, Escherichia coli (ATCC 25922) as a Gram-negative bacterial example, and Aspergillus fumigatus (RCMB 002008) as a fungal example. The antimicrobial activity was initially screened using the agar diffusion method.55−58 Ketoconazole and gentamicin were employed as reference drugs for antifungal and antibacterial activity, respectively. The results were recorded as the average diameters of inhibition zones (IZ) in millimeters, indicating the extent of bacterial or fungal growth suppression around the discs. These inhibition zone diameters were recorded based on a preliminary test, which is shown in Table S1 and Figure S1.

The obtained results showed that all screened derivatives exhibited no fungal activity against Aspergillus fumigatus. They produced moderate to mild inhibition zones against S. aureus (ATCC 25923) and E. coli (ATCC 25922) compared with gentamycin as a positive control. Regarding MRSA USA300, all compounds revealed no activity except 4 and 5 (IZ= 14 ± 0.22 and 17 ± 0.10 mm, respectively).

By calculation of MIC values for the promising derivatives as depicted in Table 1, it was noted that derivatives 4 and 5 revealed promising activity against S. aureus (ATCC 25923) and MRSA (USA300), however, compounds 2, 3, and 12 displayed potential potency against E. coli (ATCC 25922).

Table 1. MIC Values of the Promising Thiazolo-quinazoline Analogs in μMa.
MIC (Mean ± SEM) (μM)
  Gram + ve Bacteria
 Gram -ve Bacteria
Compd. No. S. aureus(ATCC 25923) MRSA (USA 300) E. coli(ATTC 25922)
Gentamycin 2.5 ± 0.10 2.00 ± 0.15 3.2 ± 0.15
2 – – 5.90 ± 0.22
3 – – 2.95 ± 0.13
4 4.97 ± 0.24 5.90 ± 0.13 –
5 2.44 ± 0.17 3.32 ± 0.18 –
12 – – 4.23 ± 0.25
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a

–: No activity.

Structure–Activity Relationship (SAR)

The existence of the thieno-thiazolo-quinazoline scaffold in 2, fused with the thiazine moiety in 3 or with the 12-benzyl-11-(2-oxopropyl)-triazolo-pyrimidine moiety in 12, potentiates potency against E. coli (MIC = 5.90, 2.95, and 4.23 μM, respectively) compared with gentamycin (MIC = 3.2 μM). Substitution of the thiazine moiety in 3 with the methyl sulfonyl fragment in 4 altered activity toward S. aureus (ATCC 25923) and MRSA (USA300) (MIC = 4.97 and 5.90 μM, respectively) in comparison with the reference (MIC = 2.50 and 2.00 μM, respectively). Furthermore, superior potency was achieved against the latter strains upon substitution of thieno-thiazolo-quinazoline in 2 with a tetrazole moiety at p-9 in 5 (MIC = 2.44 and 3.32 μM, respectively). Enlargement of thieno-thiazolo-quinazoline through fusion or substitution with other moieties drastically decreased potency against all screened strains.

2.2.2. Effect of Compounds 4 and 5 on MRSA USA300 Biofilm Activity

The antibiofilm activity of the promising compounds 4 and 5 was investigated following the reported methodology.59−61 Both compounds significantly inhibited and detached MRSA USA300 biofilm formation at all tested concentrations (two-way ANOVA, Tukey’s posthoc test, P < 0.05) (Figure 3A&B). Compound 5 was more effective than compound 4 in MRSA biofilm inhibition activity with mean IC50 values of 0.263 and 0.786 μM, respectively. Regarding MRSA biofilm detachment activity, the same pattern was observed with mean DC50 values of 0.488 and 0.392 μM for compounds 4 and 5, respectively.

Figure 3.

Figure 3

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Antibiofilm activity: The effect of various subminimum bactericidal concentrations (MBC) (1.25–0.0390625 μg/mL) of compounds 4 and 5 on MRSA USA300 biofilm was evaluated. The results are presented as the mean biofilm inhibition percentage (A) ± standard error and the mean biofilm detachment percentage (B) ± standard error.

2.2.3. In-Vivo MRSA Skin Infection Model

The MRSA skin infection model62,63 was used to assess the in vivo antibacterial activity of thiazolo-quinazoline 4 and 5. Both derivatives significantly reduced MRSA USA300 bacterial count compared to vehicle and negative control groups (one-way ANOVA, Tukey’s posthoc test, P < 0.0001). Compound 5 had slightly higher in vivo activity than compound 4, but there was no significant difference. The bacterial count recovered was 3.009 and 3.066 logs from the compound 4 group and 3.585 and 3.642 logs from the compound 5 group, lower than those of the untreated (negative control) and vehicle control (DMSO) groups, respectively (Figure 4A&B).

Figure 4.

Figure 4

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Efficacy of compounds 4 and 5 in an in vivo murine model of MRSA skin infection: Twenty-eight BALB/C mice were divided into four groups (n = 7). A: Photographic image showing the efficacy of different treatment groups on MRSA skin infection on the posterior backs of mice at the end of the experiment. B: Efficacy of different treatment groups on bacterial load in the murine model of MRSA skin infection. Each data point represents a mouse. Results are expressed as mean ± standard error. **** indicates a significant difference at p < 0.0001 (one-way ANOVA, Tukey’s posthoc test).2.2.4. In-vitro assay against S. aureus DNA gyrase.

The promising thiazolo-quinazolines 4 and 5 were further evaluated for their inhibitory activities against S. aureus DNA gyrase to predict their mechanism of action, comparing them with the standard ciprofloxacin. The obtained results, expressed as IC50 values in μM, were collected for analysis in Table 2 and Figure S2.

Table 2. Evaluation of the Inhibitory Activities of the Selected Thiazolo-quinazolines 4 and 5, in Comparison with Ciprofloxacin, Against S. aureus DNA Gyrasea.
  IC50(μM) (mean ± SEM)
Compd. No. S. aureusDNA gyrase supercoiling
4 11.72 ± 0.47
5 7.13 ± 0.28
Ciprofloxacin 19.3 ± 0.73
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a

IC50: The compound concentration required to inhibit 50% of the enzyme activity, represented by the standard error of the mean (SEM). Each value corresponds to the average of three readings.

Both derivatives 4 and 5 demonstrated excellent and superior inhibitory potency against S. aureus DNA gyrase compared to the reference ciprofloxacin, with IC50 values of 11.72 ± 0.47, 7.13 ± 0.28, and 19.3 ± 0.73 μM, respectively

2.3. Computational Studies

2.3.1. Docking Application

Based upon the amazing in vitro inhibitory potencies against S. aureus DNA gyrase, a docking simulation of potential thiazolo-quinazolines 4 and 5 was conducted using Auto Dock Vina 4.2 software to determine the anticipated binding affinities with Staphylococcus aureus DNA gyrase (PDB ID: 2XCT).64 The X-ray crystallographic structure of S. aureus DNA gyrase and its natural ligand, ciprofloxacin, was obtained by accessing a protein data bank. We first redocked the original ligand ciprofloxacin inside its receptor to validate the docking procedure. This resulted in a small RMSD value of 0.85 Å between the docked pose and the cocrystallized ligand, as well as an energy score of −11.58 kcal/mol.

With high energy scores of −10.93 and −11.25 kcal/mol, respectively, thiazolo-quinazolines 4 and 5 were well placed within S. aureus DNA gyrase, as seen in Figures 5 and 6. Sulfur of the thiazine moiety and sulfonyl oxygens in 4 afforded four H-bonding with His1081, Val511, Asp512, and Arg1033 (distances: 3.06, 2.53, 2.67, and 1.95 Å, respectively). Also, molecule 4 shared hydrophobic contacts with Asp510, Tyr580, Lys581, Pro1080, and His 1081 (Figure 5A&B).

Figure 5.

Figure 5

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A and B patterns display the two- and three-dimensional binding poses of the promising thiazolo-quinazoline 4 within the active pocket of Staphylococcus aureus DNA gyrase (PDB ID: 2XCT).

Figure 6.

Figure 6

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A and B views illustrate the two- and three-dimensional binding poses of thiazolo-quinazoline 5 in the active pocket of Staphylococcus aureus DNA gyrase (PDB ID: 2XCT).

On the other hand, the nitrogen of tetrazole and the carbonyl oxygen of ethyl carboxylate in derivative 5 displayed H-bond acceptors with Arg1033 and His1081 (distances: 2.46 and 1.99 Å, respectively). Additional hydrophobic interactions were observed with Asp508, Asp510, Val511, and Asp512 (Figure 6A&B).

According to previous findings, the thieno-thiazolo-quinazoline core that was attached to the thiazine-methylsulfonyl fragment in 4 or tetrazole-ethyl carboxylate in 5 enabled fitting within S. aureus DNA gyrase active site by H-bonding with essential amino acids Arg1033 and His1081.

2.3.2. In Silico Prediction of ADMET

Using the free Web sites SwissADME and admetSAR 1.0, the appealing thieno-thiazolo-quinazolines 4 and 5 were further investigated for their expected pharmacokinetic, physicochemical, and toxicological characteristics.32,65−69

The optimal medication choice can be determined by analyzing the ADMET properties (absorption, distribution, metabolism, excretion, and toxicity) of the targeted drugs.Veber and Lipinski’s principles could identify the best drug to take orally. The thieno-thiazolo-quinazolines 4 and 5 only violated the Veber rule once (TPSA > 140), while derivative 4 additionally displayed a violation of Lipinski’s principle (MW > 500) (Table 3).

Table 3. Calculated Physicochemical Characteristics of Attractive Thieno-thiazolo-quinazolines 4 and 5.
Compd. MWa TPSA (Å2)b nRBc nHBAd nHBDe MLogPf Violationsg
Rule ≤500 ≤140 ≤10 ≤10 ≤5 ≤4.15 -
4 501.62 165.22 2 4 0 2.00 1 (Lipinski) MW > 500; 1 (Veber) TPSA > 140
5 476.53 146.99 5 6 0 3.72 0 (Lipinski) 1 (Veber) TPSA > 140
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a

Molecular weight.

b

Topological polar surface area.

c

Number of rotatable bonds.

d

Number of hydrogen bond acceptors.

e

Number of hydrogen bond donors.

f

Calculated lipophilicity (MLog Po/w).

g

Violations from Lipinski and Veber rules.

The evaluated thieno-thiazolo-quinazolines 4 and 5 fall within the ideal range (pink zone) for key features (solubility, lipophilicity, flexibility, and size) on the bioavailability radar map (Figure 7), except for polarity and saturation.

Figure 7.

Figure 7

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Bioavailability radar map of the significant thieno-thiazolo-quinazolines 4 and 5. The pink region represents the optimal values for each component of oral bioavailability, while the red lines indicate the expected values for the studied targets.

An admet SAR 1.0 analysis of ADMET associated with potential thieno-thiazolo-quinazolines 4 and 5 is shown in Table S2. These substances had no chance of passing through the blood-brain barrier and had a limited likelihood of gastrointestinal absorption. As a result, they could be used to treat peripheral illnesses without triggering central problems. Transporter for drug efflux P-glycoprotein, or P-gp, serves in the responsibility of eliminating medications from cells and may influence drug tolerance. Since they are not P-gp substrates, the tested thieno-thiazolo-quinazolines 4 and 5 show minimal discharge from cells with the greatest activity. In the mitochondria, both are also dispersed and concentrated.

Research has shown that blocking more CYP enzymes raises the risk that a drug would interact with other active molecules in drug–drug interactions (DDI).70,71 It was therefore expected that the majority of CYPs would not be significantly affected by these medications.

With no Ames toxicity, target 4 failed to block the potassium channel associated with the human ether-a-go-go gene (hERG) as expected. This suggests that there may not be much of a risk for genotoxicity or cardiotoxicity, which are common concerns during clinical trials for pharmaceutical candidates, but 5 did not.

Furthermore, based on estimates of acute oral toxicity, thieno-thiazolo-quinazolines 4 and 5 yielded readings of 634.6 and 656.8 mg.kg–1, respectively. These results were classified as harmless compounds since they fell into the third group (500 mg.kg–1 < LD50 ≤ 5000 mg.kg–1).

According to their carcinogenicity descriptor (CARC) values, which are 606.6 and 513.3 mg/kg–1 body weight per day, respectively, these compounds may also be classified as noncarcinogenic and nonrequired. When derivative 5’s ability to decompose in the environment was evaluated, it was anticipated that it would be considered nonbiodegradable, but derivative 4 would not.

2.3.3. Quantum Chemical Calculation

Quantum chemical properties of the 12 synthetic compounds are described in the data in Table S3, with particular attention paid to the energy gap (ΔE), HOMO, and LUMO energies. When evaluating their stability, reactivity, and possible biological activity.

The HOMO–LUMO energy gap (ΔE) is a crucial quantum parameter. The ease of electron transmission is indicated by ΔE, which is the difference between the HOMO and LUMO energy levels. Higher reactivity is suggested by smaller ΔE values because electronic excitation is simpler. The distribution of electron density across the molecule is seen in ESP maps. Low-density regions (positive ESP) are conducive to nucleophilic attack, whereas regions with high electron density (negative ESP) indicate places vulnerable to electrophilic attack. To increase their antibacterial potency, compounds with different ESP distributions may bind to microbial cell components like proteins or DNA in a specific manner. From the table that we discovered, Compound 5 has the minimum ΔE of 0.01893 eV, which indicates great chemical reactivity, and Compound 1 exhibits the greatest ΔE of 0.06387 eV, indicating comparatively lesser reactivity.

Compounds with smaller ΔE values are more likely to interact with biological targets, such as enzymes or cell membranes, potentially disrupting microbial processes. Compounds 5 and 7 are particularly notable due to their low ΔE, which might translate into stronger antimicrobial activity.

Smaller ΔE values increase the likelihood that a compound may interact with biological targets, like cell membranes or enzymes, and may interfere with microbiological functions. Because of their low ΔE, which may indicate higher antibacterial activity, compounds 5 and 7 stand out.

The following insights for antimicrobial prediction are obtained from the combined examination of HOMO, LUMO, ΔE, and ESP: Low ΔE Compounds: High reactivity is probably exhibited by compounds 5, 7, and 4, allowing for effective interaction with microbial targets like membrane proteins or enzymes. These interactions may cause antimicrobial effects by interfering with metabolic processes or disrupting the formation of microbial cell walls. Compounds with moderate LUMO values (e.g., Compounds 6, 8, 10) could act as inhibitors by binding electron-rich microbial enzymes.

High HOMO values, such as in Compound 5, may allow interaction with oxidative stress sites, leading to microbial cell damage. Potential for Selective Toxicity: If available, ESP maps can forecast which microbial targets will bind more selectively than mammalian cells, potentially lowering cytotoxicity.

Because of their low ΔE values and advantageous HOMO–LUMO properties, compounds 5 and 7 are the most promising antimicrobial candidates. To confirm these predictions and ascertain the compounds’ specificity and potency, additional research is required, including molecular docking and in vitro antimicrobial assays (Figure 8).

Figure 8.

Figure 8

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DFT-optimized structures and HOMO/LUMO (Highest Occupied Molecular Orbital/Lowest Unoccupied Molecular Orbital) diagrams of compounds 5 and 7.

3. Conclusions

Novel quinazoline-4-one derivatives were designed, synthesized, and evaluated for their in vitro antimicrobial activity against a variety of pathogens, including Gram-negative bacteria (Escherichia coli ATCC 25922), Gram-positive bacteria (Staphylococcus aureus ATCC 25923 and methicillin-resistant Staphylococcus aureus [MRSA, USA300]), and fungi (Aspergillus fumigatus RCMB 002008). Among the derivatives, the thieno-thiazolo-quinazoline compounds 4 and 5 demonstrated significant activity, effectively inhibiting and disrupting MRSA USA300 biofilm formation across various concentrations.

To assess their effectiveness further, an in vivo MRSA skin infection model was utilized, highlighting the potential of these derivatives against MRSA. To provide deeper insights into their mode of action, ADMET profiling and molecular docking simulations were performed to investigate the binding interactions between the promising compounds and Staphylococcus aureus DNA gyrase, the target enzyme.

4. Experimental Section

4.1. Chemistry

All details of apparatuses used in spectral analyses were mentioned in the supplementary file.

4-Phenyl-3a,4-dihydro-5H-thiazolo[3,2-a]quinazoline-1,5(2H)-dione (1)

A solution of A (2.54 g, 10 mmol) in 1,4-dioxane (20 mL) was refluxed with chloroacetic acid (0.6 mL, 10 mmol) for 2 h. The reaction mixture was cooled and then poured in ice water. The solid product was filtered, washed, and recrystallized from ethanol to get 1 as a pale pink powder in a (72%) yield, mp 240–242 °C. IR (KBr) cm–1 ν max: 3063 cm–1 (ν CH-Ar), 2936 cm–1 (ν CH aliphatic), 1730, 1648 cm–1 (ν C = O amide), 1618 cm–1 (C = C Ar). 1H NMR (DMSO-d6, 400 MHz,) δ= 4.16 (s, 2H, CH2), 7.22 (s, 1H, CH-S), 7.23–7.48 (m, 9H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ = 45.51 (1C, CH2), 90.00 (1C, CH-S), 114.31–139.88 (11C, C–Ar), 150.20 (1C, C–N), 172.37, 162.33 (2C, 2C = O) ppm.

Ethyl 9-Amino-5-oxo-6-phenyl-6,6a-dihydro-5H thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-8-carboxylate (2)

Sulfur (0.32 g, 10 mmol) was added slowly over 15 min to a mixture of compound 1 (2.96 g, 10 mmol) in DMF (20 mL), ethyl cyanoacetate (1.1 mL, 10 mmol), and diethylamine (1 mL, 10 mmol). The reaction mixture was stirred under reflux at 70 °C for 3 h. After cooling, the separated solid was filtered off, and the filtrate was evaporated under reduced pressure. The remaining residue was recrystallized from acetone to yield compound 2 as a gray powder in a 79% yield, mp 298–300 °C. IR (KBr) cm–1 ν max: 3239, 3219 cm–1 (ν NH2), 3064, 3028 cm–1 (ν CH-Ar), 1719, 1663 cm–1 (ν 2C = O), 1622 cm–1 (C = C Ar). 1H-NMR (DMSO-d6, 400 MHz,) δ= 1.50 (t, J = 2.8 Hz, 3H, CH3), 4.20 (q, J = 4.6 Hz, 2H, CH2), 7.26 (s, 1H, CH-S), 6.40 (br, 1H, NH2 exchangeable), 7.27–8.02 (m, 9H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ = 12.34 (1C, CH3), 63.65 (1C, CH2), 91.95 (1C, CH-S), 111.08–144.44 (15C, Ar–C), 156.06, 163.92 (2C, 2C = O), 160.00 (1C, C-NH2) ppm.

Phenyl-6,6a-dihydro-5H,9H-[1,2]thiazino[4″,3”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(11H)-dione (3)

A solution of 2 (4.23 g, 10 mmol) in DMF (20 mL) was refluxed with sulfur (2.56 g, 10 mmol) for 8 h. The reaction mixture was cooled and then poured in ice water. The solid product was filtered, washed, and recrystallized from methanol to get 3 as a gray powder in a (66%) yield, mp 255–257 °C. IR (KBr) cm–1 ν max: 3267 cm–1 (ν NH), 3042 cm–1 (ν CH-Ar), 2977, 2915 cm–1 (ν CH aliphatic), 1722, 1668 cm–1 (ν 2C = O), 1631 cm–1 (C = C Ar). 1H NMR (DMSO-d6, 400 MHz,) δ= 4.00 (br, 1H, NH exchangeable), 3.13 (s, 2H, CH2), 7.30 (s, 1H, CH-S), 7.32–7.98 (m, 9H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ= 46.09 (1C, CH2), 92.06 (1C, CH-S), 114.80–160.29 (16C, Ar–C), 162.69, 176.54 (2C, 2C = O) ppm.

(Methylsulfonyl)-6-phenyl-6,6a-dihydro-5H,9H-[1,2]thiazino[4″,3”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(11H)-dione (4)

A solution of 3 (4.23 g, 10 mmol) in DMF (20 mL) was stirred with methane sulfonyl chloride (0.8 mL, 10 mmol) in the presence of triethylamine (3 drops) for 24 h. The reaction mixture was cooled, then the solid product was filtered, washed, and recrystallized from ethanol to get 4 as a black crystals in (88%) yield, mp 220–222 °C. IR (KBr) cm–1 ν max: 3099, 3057 cm–1 (ν CH-Ar), 2998, 2853 cm–1 (ν CH aliphatic), 1740, 1674 cm–1 (ν 2C = O), 1620 cm–1 (ν C = N), 1599 cm–1 (C = C Ar), 1315 cm–1 (ν S = O). 1H NMR (DMSO-d6, 400 MHz,) δ= 2.60 (s, 3H, CH3), 3.10 (s, 2H, CH2), 7.22 (s, 1H, CH-S), 7.24–7.97 (m, 9H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ= 45.89 (2C, CH2, CH3), 90.00 (1C, CH-S), 114.78–160.29 (16C, Ar–C), 162.70, 176.52 (2C, 2C = O) ppm.

Ethyl 5-Oxo-6-phenyl-9-(1H-tetrazol-1-yl)-6,6a-dihydro-5H-thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-8-carboxylate (5)

Triethyl orthoformate (38 mL, 230 mmol) and sodium azide (3.9 g, 60 mmol) were added to a solution of 2 (21 g, 50 mmol) in glacial acetic acid (30 mL) and agitated under reflux for 2 h. After cooling the reaction mixture, 7 mL of HCl were added. After filtering out the solid product, the filtrate was evaporated at a lower pressure. To obtain 5 as a pale yellow powder, the leftover residue was recrystallized, cleaned, and then recrystallized from ethanol in a (76%) yield, mp 280–282 °C. IR (KBr) cm–1 ν max: 3051 cm–1 (ν CH-Ar), 2914 cm–1 (ν CH aliphatic), 1726, 1651 cm–1 (ν 2C = O), 1536 cm–1 (ν C = N), 1469 cm–1 (ν C = C Ar), 1408 cm–1 (ν N = N). 1H NMR (DMSO-d6, 400 MHz,) δ= 1.85 (t, J = 6.8 Hz, 3H, CH3), 4.25 (dd, J = 2.8 Hz, 2H, CH2), 7.25 (s, 2H, CH-S), 7.37–8.15 (m, 9H, Ar–H), 9.48 (s, 1H, CH tetrazole) ppm. 13C NMR (DMSO-d6, 100 MHz) δ = 12.12 (1C, CH3), 63.07 (1C, CH2), 95.19 (1C, CH-S), 114.31–128.92 (14C, Ar–C), 135.05 (1C, C = N), 145.04 (1C, C–N), 151.00 (1C, C–S), 156.05, 163.02 (2C, 2C = O) ppm.

9,10-Diamino-6-phenyl-6,6a-dihydro-5H-pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(9H)-dione (6)

A solution of 5 (4.76 g, 10 mmol) in EtOH (20 mL) was refluxed with hydrazine hydrate (1.25 mL, 25 mmol) for 8 h. The reaction mixture was cooled and then poured in ice water. The solid product was filtered, washed, and recrystallized from chloroform to get 6 as a pale brown in (89%) yield, mp 216–218 °C. IR (KBr) cm–1 ν max: 3440, 3388 cm–1 (ν 2NH2), 3130 cm–1 (ν CH-Ar), 1687, 1631 cm–1 (ν 2C = O, C = N), 1525 cm–1 (C = C Ar). 1H NMR (DMSO-d6, 400 MHz,) δ= 6.18 (br, 2H, 2NH2 exchangeable), 7.20 (s, 1H, CH), 7.33–8.86 (m, 9H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ = 93.99 (1C, CH-S), 114.79–140.30 (16C, Ar–C), 150.67 (1C, C = N), 168.53, 160.29 (2C, C = O) ppm.

11-[4-(Dimethylamino)phenyl]-6-phenyl-6,6a-dihydro-5H-[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(12H)-dione (7)

A mixture of 6 (4.34 g, 10 mmol) and dimethylaminobenzaldehyde (2.98 g, 20 mmol) was heated in an oil bath at 180 °C for 1 h. The reaction mixture was cooled, and 10 mL EtOH was added to the solidified mass. The solid product was filtered, washed, and recrystallized from ethanol to get 7 as a white powder in a (66%) yield, mp >300 °C. IR (KBr) cm–1 ν max: 3138 cm–1 (ν NH), 3082, 3060 cm–1 (ν CH-Ar), 2990, 2947 cm–1 (ν CH aliphatic), 1690, 1670 cm–1 (ν 2C = O), 1618 cm–1 (ν C = N), 1602 cm–1 (C = C Ar). EI-MS: m/z (C29H21N7O2S2) calcd = 562.9 [M+]. 1H NMR (DMSO-d6, 400 MHz,) δ= 2.52 (s, 6H, 2CH3), 3.04 (br, 1H, 1NH exchangeable), 7.05 (s, 1H, CH-S), 7.32–9.05 (m, 13H, Ar–H) ppm.

11-(Furan-2-yl)-6-phenyl-6,6a-dihydro-5H-[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(12H)-dione (8)

A mixture of 6 (4.34 g, 10 mmol) and furfuraldehyde (1.65 mL, 20 mmol) was heated in an oil bath at 180 °C for 1 h. The reaction mixture was cooled, and 10 mL EtOH was added to the solidified mass. The solid product was filtered, washed, and recrystallized from ethanol to get 8 as a gray powder in a (71%) yield, mp >300 °C. IR (KBr) cm–1 νmax: 3186 cm–1 (ν NH), 3061 cm–1 (ν CH-Ar), 2977 cm–1 (ν CH aliphatic), 1701, 1664 cm–1 (ν 2C = O), 1619 cm–1 (ν C = N), 1522 cm–1 (C = C Ar). EI-MS: m/z (C25H14N6O3S2) calcd = 510.2 [M+]. 1H NMR (DMSO-d6, 400 MHz,) δ = 2.08 (br, 1H, 1NH exchangeable), 7.15 (s, 1H, CH-S), 7.18–8.13 (m, 11H, Ar–H), 8.37 (s, 1H, CH furfural) ppm.

Ethyl 2-(5,8-Dioxo-6-phenyl-6,6a,8,12-tetrahydro-5H-[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazolin-11-yl)acetate (9)

A suspension of 6 (4.34 g, 10 mmol) in diethylmalonate (1.63 g, 10 mmol) was refluxed for 6 h. The reaction mixture was cooled, then the solid product was filtered, washed, and recrystallized from ethanol to get 9 as a dark red powder in (74%) yield, mp 278–280 °C. IR (KBr) cm–1 νmax: 3242 cm–1 (ν NH), 3049, 3024 cm–1 (ν CH-Ar), 2988, 2949, 2919, 2860 cm–1 (ν CH aliphatic), 1788, 1694, 1653 cm–1 (ν 3C = O), 1619 cm–1 (ν C = N), 1554 cm–1 (C = C Ar). EI-MS: m/z (C25H18N6O4S2) calcd = 531.4 [M+]. 1H NMR (DMSO-d6, 400 MHz,) δ= 2.01 (br, 1H, 1NH exchangeable), 1.50 (t, J = 2.6 Hz, 3H, CH3), 3.15 (s, 2H, CH2), 4.20 (q, J = 2.2 Hz, 2H, CH2), 7.06 (s, 1H, CH-S), 7.26–8.02 (m, 9H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ = 15.39 (1C, CH3), 44.63, 62.29 (2C, 2CH2), 9.09 (1C, CH-S), 114.79–140.08 (166C, Ar–C), 158.67 (2C, 2C = N), 161.54, 163.33, 169.08 (3C, 3C = O).

6–11-(2-Oxopropyl)-6-phenyl-6,6a-dihydro-5H-[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(12H)-dione(10)

A suspension of 6 (4.34 g, 10 mmol) in ethyl acetoacetate (1.3 mL, 10 mmol) was refluxed for 6 h. The reaction mixture was cooled, then the solid product was filtered, washed, and recrystallized from ethyl acetate to get 10 as an orange powder in (46%) yield, mp >300 °C. IR (KBr) cm-1 νmax: 3111 cm–1 (ν NH), 3069, 3024 cm–1 (ν CH-Ar), 2956, 2921 cm–1 (ν CH aliphatic), 1740, 1671, 1613 cm–1 (ν 3C = O), 1587 cm–1 (ν C = N), 1487 cm–1 (C = C Ar). 1H NMR (DMSO-d6, 400 MHz,) δ= 2.07 (br, 1H, 1NH exchangeable), 2.58 (s, 3H, CH3), 4.31, 4.39 (s, 2H, CH2), 7.15 (s, 1H, CH-S), 7.18–8.13 (m, 9H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ= 27.20 (1C, CH3), 40.00 (1C, CH2–CO), 95.57 (1C, CH-N), 111.01–140.00 (15C, Ar–C), 150.58, 151.00, 151.99 (3C, 3C = N), 162.02, 162.99, 202.00 (3C, 3C = O).

11-(Furan-2-yl)-12-(morpholinomethyl)-6-phenyl-6,6a-dihydro-5H-[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(12H)-dione (11)

A solution of 8 (5.10 g, 10 mmol) in DMF (15 mL) was refluxed with formaldehyde (0.36 mL, 10 mmol) and morpholine (0.86 mL, 10 mmol) for 15 h. The reaction mixture was poured onto ice. The formed precipitate was filtered off, washed, and recrystallized from DMF to get 11 as an off-white powder in (48%) yield, mp >300 °C. IR (KBr) cm–1 νmax: 3050 cm–1 (ν CH-Ar), 2992, 2892 cm–1 (ν CH aliphatic), 1696, 1658 cm–1 (ν 2C = O), 1608 cm–1 (ν C = N), 1586 cm–1 (C = C Ar). 1H NMR (DMSO-d6, 400 MHz,) δ = 2.31 (t, J = 6.4 Hz, 4H, 2CH2–N), 3.50, 3.58 (t, J = 3.00 Hz, 4H, 2CH2–O), 4.24 (s, 2H, CH2), 7.07 (s, 1H, CH-S), 7.19–8.58 (m, 12H, Ar–H) ppm. 13C NMR (DMSO-d6, 100 MHz) δ = 55.57, 55.95 (2C, 2CH2–N), 59.50 (1C, CH2), 67.20 (2C, 2CH2–O), 95.95 (1C, CH-S), 111.08–144.44 (21C, Ar–C), 156.06 (1C, C–S pyrimidine), 161.00, 161.29 (2C, 2C = O).

12-Benzyl-11-(2-oxopropyl)-6-phenyl-6,6a-dihydro-5H-[1,2,4]triazolo[1”’,5”’:1″,2”]pyrimido[5″,4”:4′,5′]thieno[2′,3′:4,5]thiazolo[3,2-a]quinazoline-5,8(12H)-dione (12)

A solution of 10 (5 g, 10 mmol) in DMF (20 mL) was stirred with benzyl chloride (1.15 mL, 10 mmol) in the presence of triethylamine (3 drops) overnight. The reaction mixture was poured into ice water. The solid product was filtered, washed, and recrystallized from ethanol to get 12 as a gray powder in a (46%) yield, mp >300 °C. IR (KBr) cm–1 νmax: 3046 cm–1 (ν CH-Ar), 2989, 2945, 2921 cm–1 (ν CH aliphatic), 1744, 1684, 1667 cm–1 (ν 3C = O), 1619 cm–1 (ν C = N), 1553 cm–1 (C = C Ar). EI-MS: m/z (C31H22N6O3S2) calcd = 590.68 [M+].

4.2. Biological Activity

The supplemental data contained detailed descriptions of every in vitro and in vivo study.

4.3. In Silico Studies

4.3.1. Molecular Docking Study

The rationalization of biological observations has been aided by computational docking simulation. Using Auto Dock Vina 4.2 software, the fortunate thieno-thiazolo-quinazolines 4 and 5 were docked into the active pocket of Staphylococcus aureus DNA gyrase (PDB ID: 2XCT). Details can be found in the supporting file.

4.3.2. Quantum Chemical Calculation

Density Functional Theory (DFT) computations were performed using the B3LYP functional, a hybrid exchange-correlation functional that combines the gradient-corrected correlation functional of Lee, Yang, and Parr (LYP) with Becke’s three-parameter exchange functional. By addressing integration concerns, this method has advantages over pure DFT techniques.

Gaussian 09 was used to fully optimize all molecular geometries at the B3LYP/6-311G++(d,p) level of theory. The energy gap (ΔE), global electrophilicity (ω), softness (σ), electronegativity (χ), hardness (η), and ionization potential (I) were then determined using frontier molecular orbital (FMO) analysis.

Using the optimized geometries, calculations were carried out at the B3LYP/6-31G level of theory in order to visualize the molecular electrostatic potential (MEP). The MEP maps reveal information about the molecules’ electrophilic and nucleophilic areas.72

Acknowledgments

Thanks to Al-Jouf, Menoufia, and Benha University for participating in completing the research work.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c11076.

  • Everything related to information about the devices and tools that were used; biological evaluation; enzyme assessment of DNA gyrase; molecular docking study; HOMO; LUMO of the assembled molecules; 1H,13C NMR, IR; mass spectra of the synthesized compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao4c11076_si_001.pdf (3.9MB, pdf)

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