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Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones.

ABSTRACT: 8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis. Synthesis, structural characterization and in vitro testing against Mycobacterium aurum DSM 43999 and M. tuberculosis H₃₇Rv of halogenated 2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-ones lacking a nitro group are reported. X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.

SUBMITTER: Madikizela B

PROVIDER: S-EPMC8192043 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones

Project description:Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antituberculotic drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-D-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites in vivo. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement against electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized a set of various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for all antimycobacterial compounds by enzymatic inhibition assays and protein mass spectrometry analysis.

2024-09-11 | PXD053165 | Pride

Synthesis, spectral studies, antioxidant and antibacterial evaluation of aromatic nitro and halogenated tetradentate Schiff bases.

Project description:Herein, we report the synthesis, characterization, and biological properties of eleven (3a-3k) novel Schiff bases. The spectral data of FT-IR, 1H NMR, 13C NMR, and LC-MS are associated with these synthesized compounds. From the FT-IR analysis, we confirmed the azomethine (-C=N-) group and from 1H NMR data, the phenolic -OH proton is appeared at range δ 13.92-14.09ppm due to hydrogen bonding. The LC-MS analysis agreed with molecular ion peaks of synthesized Schiff bases. To evaluate the antibacterial activity of newly synthesized compounds were screened against b. licheniformis, b. species, e. coli, and s. aureus. Furthermore, the antioxidant activity was investigated by two methods 2,2-diphenyl-1-picryl hydrazyl (DPPH) and hydroxyl radical scavenging methods. The (-NO2,-Cl,-Br,-I) substituted compounds have shown good antibacterial activity against tested organisms. Also, these compounds were exhibited higher antioxidant activity by given methods.

| S-EPMC9192811 | biostudies-literature

Synthesis and evaluation of triazole congeners of nitro-benzothiazinones potentially active against drug resistant <i>Mycobacterium tuberculosis</i> demonstrating bactericidal efficacy.

Project description:With growing concerns regarding target residue mutation hovering over established anti-TB pharmacophores, it is imperative to have reserve chemotypes at our disposal to curb unrestrained spread of tuberculosis. In this context, we herein present the synthesis and bio-evaluation of a library of new nitrobenzothiazinone (BTZ) congeners comprising 2-mercapto/amino-benzothiazinone tethered 1,2,3-triazole hybrids as antitubercular agents. In preliminary screening, 10 out of 37 compounds displayed substantial in vitro potency against Mtb H37Rv (MIC 0.5-8 μg mL-1). Structural optimization of the initial hit 5o (MIC 0.5 μg mL-1) led to identification of linker variants 9a, 9b, 9c, and 9d exhibiting potent anti-TB activity (MIC 0.03-0.12 μg mL-1). When tested against Vero cells to determine their selectivity index (SI), these compounds displayed no appreciable cytotoxicity (SI >80). Further studies on activity against drug resistant (DR) Mtb indicated these compounds to be equally potent (MIC 0.03-0.25 μg mL-1). The in silico covalent docking study suggested a similar polar interaction to that of PBTZ169 with an additional and contrasting side chain interaction at the active site of Mtb DprE1 target protein. Further, the time kill kinetic study found compounds 9a and 9d to be demonstrating bactericidal efficacy, completely eliminating bacilli in 7 days at 10× MIC. The most promising compound 9d, considering its potent anti-TB activity (MIC 0.06 μg mL-1 against drug susceptible Mtb and MIC 0.06-0.25 μg mL-1 against DR Mtb) along with a broad therapeutic index (SI >640) demonstrating a comparable concentration dependent bactericidal efficacy to that of RIF, holds a significant edge to be translated into a potent anti-Mtb agent.

| S-EPMC9132192 | biostudies-literature

Synthesis, biological evaluation, and radioiodination of halogenated closo-carboranylthymidine analogues.

Project description:The synthesis and initial biological evaluation of 3-carboranylthymidine analogues (3CTAs) that are (radio)halogenated at the closo-carborane cluster are described. Radiohalogenated 3CTAs have the potential to be used in the radiotherapy and imaging of cancer because they may be selectively entrapped in tumor cells through monophosphorylation by human thymidine kinase 1 (hTK1). Two strategies for the synthesis of a (127)I-labeled form of a specific 3CTA, previously designated as N5, are described: (1) direct iodination of N5 with iodine monochloride and aluminum chloride to obtain N5-(127)I and (2) initial monoiodination of o-carborane to 9-iodo-o-carborane followed by its functionalization to N5-(127)I. The former strategy produced N5-(127)I in low yields along with di-, tri-, and tetraiodinated N5 as well as decomposition products, whereas the latter method produced only N5-(127)I in high yields. N5-(127)I was subjected to nucleophilic halogen- and isotope-exchange reactions using Na(79/81)Br and Na(125)I, respectively, in the presence of Herrmann's catalyst to obtain N5-(79/81)Br and N5-(125)I, respectively. Two intermediate products formed using the second strategy, 1-(tert-butyldimethylsilyl)-9-iodo-o-carborane and 1-(tert-butyldimethylsilyl)-12-iodo-o-carborane, were subjected to X-ray diffraction studies to confirm that substitution at a single carbon atom of 9-iodo-o-carborane resulted in the formation of two structural isomers. To the best of our knowledge, this is the first report of halogen- and isotope-exchange reactions of B-halocarboranes that have been conjugated to a complex biomolecule. Human TK1 phosphorylation rates of N5, N5-(127)I, and N5-(79/81)Br ranged from 38.0% to 29.6% relative to that of thymidine, the endogenous hTK1 substrate. The in vitro uptake of N5, N5-(127)I, and N5-(79/81)Br in L929 TK1(+) cells was 2.0, 1.8, and 1.4 times greater than that in L929 TK1(-) cells.

| S-EPMC3257809 | biostudies-literature

Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

Project description:Fifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values against Mycobacterium tuberculosis (Mtb) ranged from 2 to 32 μg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound 4 showed the strongest bactericidal activity with an MIC of 2 μg/mL. The selectivity index of compound 4 is more than 10, indicating that the compound has low toxicity to animal cells and has the potential to become a drug. Molecular docking indicates that compound 4 can bind firmly to the Mtb KatG active site. The experimental results showed that compound 4 inhibited Mtb KatG and caused the accumulation of ROS in Mtb cells. We speculate that compound 4 causes the accumulation of ROS by inhibiting KatG, and ROS produces oxidative destruction, leading to the death of Mtb. This study provides a new idea for the development of novel anti-Mtb drugs.

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Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.

Project description:New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.

| S-EPMC3128490 | biostudies-literature

Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents.

Project description:Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R² = Me; 2i: R² = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-ylbenzamides with hydroxy substitution (2b: R² = 2-OH; 2d: R² = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.

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3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation.

Project description:A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 ?g·mL-1. Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 ?M, and Staphylococcus epidermidis with MIC = 15.62 ?M. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors.

| S-EPMC6155222 | biostudies-literature

Synthesis, Characterization, and Antifungal Property of Hydroxypropyltrimethyl Ammonium Chitosan Halogenated Acetates.

Project description:Hydroxypropyltrimethyl ammonium chitosan halogenated acetates were successfully synthesized from six different haloacetic acids and hydroxypropyltrimethyl ammonium chloride chitosan (HACC) with high substitution degree, which are hydroxypropyltrimethyl ammonium chitosan bromacetate (HACBA), hydroxypropyltrimethyl ammonium chitosan chloroacetate (HACCA), hydroxypropyltrimethyl ammonium chitosan dichloroacetate (HACDCA), hydroxypropyltrimethyl ammonium chitosan trichloroacetate (HACTCA), hydroxypropyltrimethyl ammonium chitosan difluoroacetate (HACDFA), and hydroxypropyltrimethyl ammonium chitosan trifluoroacetate (HACTFA). These chitosan derivatives were synthesized by two steps: first, the hydroxypropyltrimethyl ammonium chloride chitosan was synthesized by chitosan and 3-chloro-2-hydroxypropyltrimethyl ammonium chloride. Then, hydroxypropyltrimethyl ammonium chitosan halogenated acetates were synthesized via ion exchange. The structures of chitosan derivatives were characterized by Fourier transform infrared spectroscopy (FTIR), ¹H Nuclear magnetic resonance spectrometer (¹H NMR), 13C Nuclear magnetic resonance spectrometer (13C NMR), and elemental analysis. Their antifungal activities against Colletotrichum lagenarium, Fusarium graminearum, Botrytis cinerea, and Phomopsis asparagi were investigated by hypha measurement in vitro. The results revealed that hydroxypropyltrimethyl ammonium chitosan halogenated acetates had better antifungal activities than chitosan and HACC. In particular, the inhibitory activity decreased in the order: HACTFA > HACDFA > HACTCA > HACDCA > HACCA > HACBA > HACC > chitosan, which was consistent with the electron-withdrawing property of different halogenated acetates. This experiment provides a potential idea for the preparation of new antifungal drugs by chitosan.

| S-EPMC6165101 | biostudies-literature

Synthesis and antiplasmodial and antimycobacterial evaluation of new nitroimidazole and nitroimidazooxazine derivatives.

Project description:The synthesis and antiplasmodial and antimycobacterial evaluation of two new series of nitroimidazole and nitroimidazooxazine derivatives is described. The majority of these compounds, especially hybrids 9d, 9f, and 14b, exhibited potent activity against the chloroquine-resistant K1 strain of Plasmodium falciparum. Furthermore, a notable number from the tetrazole series were significantly more active against M. tuberculosis than kanamycin, a standard TB drug.

| S-EPMC4027538 | biostudies-other

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