Mycobacterium Tuberculosis H37Rv Strain Research Articles

Noncovalent inhibitors of DprE1 for tuberculosis treatment: design, synthesis, characterization, in vitro and in silico studies of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamides

In this study, we present a novel series of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamide derivatives, which exert their inhibitory effect on decaprenylphosphoryl-β-D-ribose 2’-epimerase (DprE1) via the establishment of non-covalent interactions with the pivotal Cys387 residue located within the enzyme’s active site. These compounds underwent scrutiny for their efficacy in combatting the Mycobacterium tuberculosis H37Rv strain, and compounds T8 and T13 exhibited promising antitubercular activity, boasting a minimal inhibitory concentration (MIC) of 7.99 and 8.27 µM respectively. Additionally, three compounds, T2, T3 and T12, showcased substantial antibacterial activity whereas compounds T12 and T13 exhibited pronounced antifungal efficacy. Remarkably, all active compounds demonstrated negligible cytotoxicity, and none posed harm to normal cells. To attain a more profound comprehension of the attributes of these compounds, we conducted in silico investigations to evaluate their Absorption, Distribution, Metabolism and Excretion properties. Additionally, molecular docking analyses were executed to elucidate their interactions with the DprE1 enzyme. Finally, Density Functional Theory studies were leveraged to explore the electronic characteristics of these compounds, thereby providing insights into their potential utility in the realm of pharmaceuticals.

Ionic liquid promoted facile one-pot synthesis of phenothiazine-thiazolidin-4-ones as potent antitubercular agents via mycobacterial ATP synthase inhibition

The mycobacterial ATP synthase is responsible for the optimal growth, metabolism and viability of mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the facile and efficient one-pot three component synthesis of 2-(10H-phenothiazin-3-yl)-3-substituted thiazolidin-4-one derivatives by using ionic liquid, 1-butyl-3-methylimidazolium bromide [Bmim]Br and their inhibitory potency against mycobacterium tuberculosis H37Rv strain (ATCC-27294). Compound T27 exhibited the highest inhibition activity with an MIC of 0.78 μg/mL, which is twofold and fourfold superior (in terms of the MIC values) to the standard first-line TB drugs isoniazid (MIC: 1.56 μg/mL) and pyrazinamide (MIC: 3.12 μg/mL) respectively. Two other compounds (T25 and T30) are equipotent as the isoniazid. The SAR studies revealed that insertion of 1,2,3-traizole and thiozolidine-2-one rings enhance the anti-TB activity in most of the tested compounds. Also, compound T27 was screened for mycobacterial ATP synthase inhibition activity and it exhibited an IC50 of 0.735 µM in M. smegmatis IMVs. Further, toxicity evaluation against VERO cell lines confirmed null cytotoxicity (selectivity index > 70) of the potent analogues. The title compounds are highly specific towards to the M. tb strain, i.e., most of the compounds exhibited moderate inhibitory potency against the tested bacterial strains (MIC ≥ 6.25 μg/mL). In addition, molecular docking was employed against the active site of the ATP synthase enzyme to validate the binding mechanism and in vitro activity profile of the phenothiazine derivatives. Furthermore, in silico ADME and pharmacokinetic parameters’ prediction indicated good oral bioavailability.

Antimycobacterial Activity of Essential Oils from Bulgarian Rosa Species Against Phylogenomically Different Mycobacterium tuberculosis Strains

In this study, we aimed to assess the activity of the essential oils from four Bulgarian oil-bearing roses Rosa damascena Mill., R. alba L., R. centifolia L., and R. gallica L., on the reference strain Mycobacterium tuberculosis H37Rv and clinical M. tuberculosis strains of the Beijing and Latin-American Mediterraneum genotypes. The chemical composition of the essential oils was determined by gas chromatography (GC-FID/MS). Minimal inhibitory concentrations (MIC) were determined using the resazurin method. R. alba oil showed the highest inhibitory activity when tested on all strains of different phylogenetic origins with MIC in the range of 0.16–0.31 mg/mL, while R. gallica oil was the least active (MIC 0.62–1.25 mg/mL). The obtained results show heterogeneity of rose oil action on different mycobacterial strains and we hypothesize that the combined level of geraniol and nerol is a key factor that underlies the antimycobacterial action of the rose oils. Strain Beijing 396 was relatively more susceptible to the rose oils probably due to multiple and likely deleterious mutations in its efflux pump genes. Two clinical MDR strains have likely developed during their previous adaptation to anti-TB drugs certain drug tolerance mechanisms that also permitted them to demonstrate intrinsic tolerance to the essential oils. Further research should investigate a possible synergistic action of the new-generation anti-TB drugs and the most promising rose oil extracts on the large panel of different strains.

IL-27 attenuated macrophage injury and inflammation induced by Mycobacterium tuberculosis by activating autophagy.

Interleukin-27 (IL-27) is a cytokine that is reported to be highly expressed in the peripheral blood of patients with pulmonary tuberculosis (PTB). IL-27-mediated signaling pathways, which exhibit anti- Mycobacterium tuberculosis (Mtb) properties, have also been demonstrated in macrophages infected with Mtb. However, the exact mechanism remains unclear. This study aimed to clarify the potential molecular mechanisms through which IL-27 enhances macrophage resistance to Mtb infection.Both normal and PTB patients provided bronchoalveolar lavage fluid (BALF). Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and stimulated with 50ng/mL macrophage-colony stimulating factor (M-CSF) to obtain monocyte-derived macrophages (MDMs). Using 100ng/mL phorbol 12-myristate 13-acetate (PMA), THP-1 cells were induced to differentiate into THP-1-derived macrophage-like cells (TDMs). Both MDMs and TDMs were subsequently infected with the Mtb strain H37Rv and treated with 50ng/mL IL-27 prior to infection. The damage and inflammation of macrophages were examined using flow cytometry, enzyme-linked immunosorbent assay (ELISA), and Western blotting.Patients with PTB had elevated levels of IL-27 in their BALF. Preconditioning with IL-27 was shown to reduce H37Rv-induced MDMs and TDMs apoptosis while also decreasing the levels of Cleaved Caspase-3, Bax and the proinflammatory cytokines TNF-α, IL-1β, and IL-6, promoting the expression of Bcl-2 and the anti-inflammatory factors IL-10 and IL-4. Silencing of the IL-27 receptor IL-27Ra increased macrophage damage and inflammation triggered by H37Rv. Mechanistically, IL-27 activates autophagy by inhibiting TLR4/NF-κB signaling and activating the PI3K/AKT signaling pathway, thereby inhibiting H37Rv-induced macrophage apoptosis and the inflammatory response.Our study suggests that IL-27 alleviates H37Rv-induced macrophage injury and the inflammatory response by activating autophagy and that IL-27 may be a new target for the treatment of PTB.

Mathematical modeling suggests heterogeneous replication of Mycobacterium tuberculosis in rabbits.

How quickly Mycobacterium tuberculosis ( Mtb ) replicates and dies in lungs of infected individuals is likely to determine the outcome of the infection - either control/clearance of the bacteria by the host immune response or progression to active disease, tuberculosis ( TB ). And yet, only a few studies, primarily in mice, rigorously estimated the rates of Mtb replication and death during an in vivo infection. We infected rabbits with a novel clinical isolate of Mtb carrying an unstable, "replication clock" plasmid and followed the dynamics of bacteria over time. Interestingly, previous methods developed to estimate Mtb replication and death rates using similar data for Mtb infection of mice failed to describe our novel data on Mtb dynamics in rabbits; we showed that heterogeneous dynamics of Mtb in semi-independent subpopulations in lungs of Mtb-infected rabbits may be one explanation of this failure of the method. Our results highlight potential differences in Mtb dynamics in different mammalian hosts and suggest ways to evaluate heterogeneity of Mtb replication and death rates in vivo.

Silver(I) and gold(III) complexes with miconazole: The influence of the metal ion on the antimicrobial activity of the coordinated azole

To develop a new antimicrobial agent, we used the clinically approved antifungal azole, miconazole (mcz), as a ligand for the synthesis of silver(I) and gold(III) complexes. The new complexes [Ag(NO3-O)(mcz-N)2] (1) and [AuCl3(mcz-N)] (2) were synthesized and characterized by 1H NMR, IR and UV–Vis spectroscopy and mass spectrometry, while the crystal structure of 1 was determined by single-crystal X-ray diffraction analysis. From the results obtained, it can be concluded that in both complexes, mcz is monodentately coordinated to the silver(I) and gold(III) ions through the imidazole nitrogen atom N3. In the solid state, complex 1 contains two mcz ligands and monodentately coordinated nitrate in the third position, while in the case of 2 gold(III) ion is coordinated by one mcz and three chlorido ligands, resulting in the expected square-planar arrangement around the metal center. DFT and TDDFT calculations were employed to elucidate the electronic structures and thermodynamic stability of the synthesized complexes in solution to complement the experimental findings. The coordination of mcz to silver(I) and gold(III) ions leads to an enhancement of its activity against Gram-negative Escherichia coli and Pseudomonas aeruginosa strains, while against the panel of Staphylococcus aureus and Candida species, only 2 shows improved activity compared to mcz. Both complexes 1 and 2 were tested in vitro for their antimycobacterial activity against the strain Mycobacterium tuberculosis H37Rv and showed good growth inhibition with minimum inhibitory concentration (MIC) values of 3.12 and 8.69 μM, respectively, with complex 1 being twice effective as mcz (MIC = 7.50 μM). Complex 2 significantly reduced the production of pyocyanin, a virulence factor in P. aeruginosa controlled by quorum sensing, while this effect was not observed for 1.

Benzyl/phenyl‐1,2,3‐Triazole Tethered 3‐Acetyl Coumarins as Potential Drug‐Resistant Antitubercular Agents: Synthesis, Biology, and in Silico Investigations as Mtb DNA Gyrase Inhibitors

AbstractOwing to the emergence of multi‐drug resistant tuberculosis, there is a need for the exploration of new antitubercular agents. In this context, new coumarin‐based 1,2,3‐triazole hybrids were developed and evaluated for their antimicrobial activity against ESKAPE pathogens and the Mtb H37Rv strain. Among them, compounds 9 c and 12 showed MICs of 1 and 2 μg/mL, respectively, against the Mtb strain. The lead compounds exhibited a good selectivity index against Vero cells and were equally effective against ETB‐resistant and RIF‐resistant Mtb strains. Time‐kill kinetic studies revealed the bacteriostatic properties of the lead compounds, while combination studies using FDA‐approved antibiotics showed no drug interactions. Based on the structural similarity, it was envisaged that they might inhibit the DNA gyrase, which was further proved by the DNA supercoiling inhibition assay. Additionally, in silico docking studies, binding energy calculations, and ADME/T studies for the synthesized conjugates showed favourable pharmacokinetic and physicochemical characteristics. Hence, these molecules could further pave the way for discovering new potent antitubercular agents to combat AMR.

Synthesis and InhA Inhibition of Imidazo[1,2-a]pyridine Derivatives as Anti-Tuberculosis Agents

Abstract: Imidazopyridine holds significance as a crucial fused bicyclic heterocycle within the realm of medicinal chemistry, being acknowledged as a "privileged scaffold" owing to its extensive utility. Numerous methodologies for the synthesis of imidazo[1,2-a]pyridines have been documented, with a considerable focus on strategies aimed at functionalizing these compounds. This study aimed to explore the potential of novel imidazo[1,2- a] pyridine derivatives as agents against drug-resistant Mycobacterium tuberculosis, which poses significant challenges in tuberculosis (TB) treatment. The research involved the synthesis of substituted imidazo[1,2- a]pyridine derivatives using site identification and molecular docking techniques. Characterization of the synthesized compounds was carried out using FT-IR, LC-MS, 1H NMR, and 13C NMR analysis. Compounds 6a and 6k showed good anti-TB activity against the H37Rv strain of Mycobacterium tuberculosis, with MIC values of 0.6 μM and 0.9 μM, respectively, which were comparable with the standard drug isoniazid. These findings suggest that imidazo[1,2-a]pyridine derivatives, especially compounds 6a and 6k, have potential as agents against drug-resistant TB, providing valuable insights for ongoing efforts in developing effective TB treatments.

Microwave-Assisted Synthesis and Characterization of Novel 1,3,4-Oxadiazole Derivatives and Evaluation of In Vitro Antimycobacterial Activity.

Objective The study's goal was to come up with and make a new group of 1,3,4-oxadiazole derivatives (3a-3e) and test how well they could kill Mycobacterium tuberculosis (Mtb) H37Rv strain. Additionally, molecular docking and pharmacokinetic properties were analyzed using computational software to identify potential inhibitors, followed by in vitro antimycobacterial assays. Methods A group of 1,3,4-oxadiazoles was prepared by reacting acyl hydrazides with alanine, an N-protected α-amino acid, and a small amount of POCl3. This was carried out under microwave treatment. The structural characterization of the newly synthesized compounds was performed using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. The in vitro antimycobacterial activity of the 1,3,4-oxadiazole derivatives (3a-3e) was assessed using the microplate Alamar Blue assay against the Mtb H37Rv strain. The synthesized compounds were subjected to molecular docking investigations in order to gain insights into their interaction mechanisms with the mycobacterial enzyme InhA (enoyl-acyl carrier protein reductase). Computational analysis of pharmacokinetic properties was performed to predict the oral bioavailability and drug-likeness of the compounds. Results All synthesized compounds inhibited the growth of Mtbat concentrations of 50 and 100 μg/mL. At a concentration of 50 μg/mL, compounds 3c and 3d exhibited the most prominent antimycobacterial action. Molecular docking results revealed that compound 3d exhibited the highest binding energy interaction with the InhA enzyme (-9.1 kcal/mol). Pharmacokinetic predictions indicated that all compounds possess favorable drug-like properties suitable for oral administration. Conclusion This study successfully synthesized a novel series of oxadiazole derivatives (3a-3e) using a microwave-assisted method with high yields. The synthesized compounds demonstrated significant antimycobacterial activity, particularly compounds 3c and 3d. Molecular docking and pharmacokinetic analyses further confirmed the potential of these compounds as promising leads for the development of anti-tubercular agents.

Synthesis and structural elucidation of novel quaternary pyridinium salt and indolizine derivatives as an anti-tubercular agent: In Silico and In Vitro screening

The in vitro anti-mycobacterial activity of a novel series of diversely substituted quaternary pyridinium salts (3a-m) and indolizines (5a-h) were assessed against H37Rv strain of Mycobacterium tuberculosis (M.tb). The series of intermediate 1-(2-oxo-2-phenylethyl)-4-(piperidin-1-yl)pyridin-1-ium bromide, which contains a heterocyclic ring molecule, has been prepared by reacting with 4-(piperidin-1-yl)pyridine and phenacyl bromide at room temperature. The final ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues were prepared by using pyridin-1-ium bromide with electron-deficient acetylene, undergoing 1, 3-dipolar cycloaddition at the ambient temperature using anhydrous potassium carbonate and N, N-dimethylformamide as a solvent. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H and 13C NMR, and HRMS. All the synthesized intermediates and final compounds were evaluated for their anti-tubercular activities against H37Rv (ATCC 27294) strain. All the compounds exhibited anti-tubercular activities in the range of 12.5–50 µM. In vitro screening of all derivatives concluded that among all the screened candidates 3k emerged as an active hit with MIC 12.5 µM, 3l and 3m with MIC 25 µM.

Design, synthesis, and in silico studies of pyrazine-based derivatives as potential antitubercular agents

Tuberculosis (TB) remains a major public health concern in spite of the existence of effective anti-TB medications. We present the design and synthesis of new compounds with pyrazine and pyridine/pyrimidine moieties. The Microplate Alamar Blue Assay (MABA) was used to test the activity of the synthesized compounds against the Mycobacterium tuberculosis (Mtb) H37Rv strain. Among the synthesized compounds, 8e and 8h showed considerable antitubercular activity. The most effective compounds were then effectively docked onto the active site of the Mtb enoyl reductase receptor. These compounds have demonstrated favorable binding interactions with amino acids present in the receptor. Furthermore, in silico prediction of physicochemical and pharmacokinetic properties revealed that the synthesized compounds can be used to generate novel anti-TB agents with increased activity and safety profiles.

A Robust In Vitro Anti‐tuberculosis, Antimicrobial, and Anti‐inflammatory Activities Based on Azomethine Chelates Incorporating Co(II), Ni (II), Cu(II), and Zn(II) Ions: Synthesis, Characterization, and Investigation of the Aspects of Docking Interaction

ABSTRACTIn recent times, there has been a growing exploration of transition metal complexes as potential solutions for significant health challenges, including tuberculosis, microbes infection, and inflammation. Therefore, in our ongoing effort to identify biologically effective agents, Co(II), Ni(II), Cu(II), and Zn(II) metal complexes of H2L1–H2L2 hydrazone ligands were synthesized. The structural features of synthesized compounds were recognized by employing several techniques such as FT‐IR, 1H NMR, 13C NMR, powder x‐ray diffraction (XRD), UV‐Vis, ESR, TG‐DTA, mass spectrometry, and molar conductance measurements. The bonding of ligands via Ophenolic, Oenolic, and Nazomethine donor atoms and the attachment of the three water molecules with metal ion to form the octahedral structure of complexes were corroborated by different spectroscopic techniques. The anti‐tuberculosis, antimicrobial, and anti‐inflammatory activities of the synthesized compounds were assessed using the microplate alamar blue assay, serial dilution, and bovine serum albumin (BSA) methods, respectively, and highlighted the more potency of the complexes than ligands. The synthesized Cu(II) (9) and Zn(II) (10) metal complexes exhibited excellent ability to inhibit the growth of H37Rv strain of Mycobacterium tuberculosis in comparison to standard drug streptomycin. The Cu(II) (6 and 9) and Zn(II) (10) complexes showed superb ability as antimicrobial agents, whereas Cu(II) (5) and Zn(II) (6) complexes exhibited significant anti‐inflammatory ability. The in vitro findings on the antituberculosis activity were reinforced by a significant molecular docking study, which has become a crucial component of computational research utilizing the enzyme Mtb Pks13 thioesterase domain of M. tuberculosis. Additionally, in this research work, the absorption–distribution–metabolism–excretion–toxicity (ADMET) study sparked the compounds' drug‐like behavior.

A click-chemistry based strategy for synthesizing coumarin piperazine analogues: Assessment of anti-tubercular, anti-cancer, anti-inflammatory and antioxidant potentials

In this study, a novel series of coumarin piperazine analogues were synthesized using Click chemistry approach. Thus synthesized compounds (8a-j) were evaluated for their pharmacological potentialities. These compounds subjected for evaluation of their anti-tubercular, anti-cancer, anti-inflammatory, and antioxidant properties. Results revealed that analogues 8b, 8d, 8i and 8h are found to be the promising drug-like candidates against Mycobacterium tuberculosis H37Rv strain exhibiting more potent activity than isoniazid with MIC of 2.24, 1.04, 3.72, 5.35 µM respectively. Furthermore, the compound 8d displayed better anti-inflammatory and antioxidant activity with IC50 values of 66.43 µM and 69.14 µM respectively. Molecular docking studies insights into the binding affinities and interactions with a target protein. The in silico ADME profiles supported their pharmacokinetic viability. Predominantly, compound 8d exhibited anticancer activity with IC50 values of 12.42 µM and 26.16 µM with reference to HeLa and MCF-7respectively by inhibiting acetyl-CoA synthetase. These findings highlight more specifically the compound 8d as a potent anti-cancer agent.

5-Fluoroindole Reduces the Bacterial Burden in a Murine Model of Mycobacterium tuberculosis Infection.

Tuberculosis is a disease caused by a single pathogen that leads to a death toll estimated to be more than a million per year. Mycobacterium tuberculosis (Mtb), which affects mainly the lungs, spreads by airborne transmission when infectious respiratory particles from an infected human enter the respiratory tract of another person. Despite diagnosis and treatment being well established, the rise of cases of patients infected with Mtb strains with multidrug resistance to the antibiotics used in the regimen against the disease is alarming. Indole used as a core molecule has been described as a promising structure to treat several diseases. 5-Fluoroindole (5-FI) compound, evaluated in the free base and in the hydrochloride (5-FI.HCl) forms, inhibited the growth of pan-sensitive Mtb H37Rv strain in the same range (4.7-29.1 μM) of clinical isolates that have resistance to at least two first-line drugs. Although 5-FI showed no cytotoxicity in Vero and HepG2 cells, high permeability (2.4.10-6 cm/s) in the PAMPA assay, and high metabolic stability (Clint 9.0 mL/min/kg) in rat liver microsomes, limited solubility at plasmatic and intestinal pH values prompted formation and employment of its salt form (5-FI.HCl). Although the 5-FI.HCl compound showed increased solubility at pH values of 7.4 and 9.1 and increased stability in aqueous solutions, data for intrinsic clearance (Clint = 48 mL/min/kg) and a half-life (t 1/2 = 12 min) showed decreased metabolic stability. As 5-FI.HCl showed both good absorption and ability to reach the systemic circulation of animals without the need to use vehicles containing cosolvents or surfactants, it was chosen to evaluate its effectiveness in the model of tuberculosis in mice. The in vivo results showed the concentration of the compound in plasma increasing within 30 min in the systemic circulation and the capacity of reducing the Mtb burden in the lungs at the concentration of 200 μmol/kg after 21 days of infection, with no toxicity in mice.

Design, synthesis, and anti-mycobacterial evaluation of 1,8-naphthyridine-3-carbonitrile analogues.

Twenty-eight compounds, viz., 1,8-naphthyridine-3-carbonitrile (ANC and ANA) derivatives, were designed and synthesized through a molecular hybridization approach. The structures of these compounds were analyzed and confirmed using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated by in vitro testing for their effectiveness against tuberculosis using the MABA assay, targeting the Mycobacterium tuberculosis H37Rv strain. Their minimum inhibitory concentration (MIC) was determined, showing that the tested compounds' MIC values ranged from 6.25 to ≤50 μg mL-1. Among the derivatives studied, ANA-12 demonstrated prominent anti-tuberculosis activity with a MIC of 6.25 μg mL-1. Compounds ANC-2, ANA-1, ANA 6-8, and ANA-10 displayed moderate to good anti-tuberculosis activity with MIC values of 12.5 μg mL-1. Compounds with MIC ≤ 12.5 μg mL-1 were screened against human embryonic kidney cells to assess their potential cytotoxicity. Interestingly, these compounds showed less toxicity towards normal cells, with a selectivity index value ≥ 11. To further evaluate the binding pattern in the active site of enoyl-ACP reductase (InhA) from Mtb (PDB-4TZK), a molecular docking analysis of compound ANA-12 was performed using the glide module of Schrodinger software. The stability, confirmation, and intermolecular interactions of the cocrystal ligand and the highly active compound ANA-12 on the chosen target protein were investigated through molecular dynamics simulations lasting 100 ns. In silico predictions were utilized to assess the ADMET properties of the final compounds. A suitable single crystal was developed and analyzed for compound ANA-5 to gain a deeper understanding of the compounds' structures.

Glucomannan is a promising isoniazid's enhancer that inducing macrophage phagocytosis.

Isoniazid (INH) is a frontline antituberculosis agent effective against Mycobacterium tuberculosis (Mtb), but the increasing challenge of avoiding multidrug-resistant tuberculosis, including INH resistance, necessitates innovative approaches. This study focused on enhancing macrophage phagocytosis to overcome INH resistance. Glucomannan, an immunomodulatory polysaccharide, emerged as a potential macrophage activator. Our objective was to characterize the glucomannan-INH mixture and assess its impact on INH efficacy and macrophage activity. Detailed examination of the glucomannan from Amorphophallus muelleri (0.05%-0.2%) was performed in several methods. INH sensitivity tests were carried out with the Mtb strain H37RV on Löwenstein-Jensen medium. Murine macrophage (RAW264.7) viability and activity were evaluated through MTT and latex bead phagocytosis assays. Ultraviolet-wavelength spectrophotometry was used to analyze chemical structure changes. Glucomannan (0.05%-0.2%) significantly enhanced murine macrophage viability and activity. When glucomannan was combined with INH, the IC50 value was greater compared to INH only. Phagocytosis assays revealed heightened macrophage activity in the presence of 0.05% and 0.1% glucomannan. Importantly, glucomannan did not compromise INH efficacy or alter its chemical structure. This study underscores the potential of glucomannan, particularly with a lower molecular weight, as a promising enhancer of INH, boosting macrophage phagocytosis against INH-resistant Mtb. These findings challenge the assumptions about the impact of glucomannan on drug absorption and prompt potential reevaluation. While specific receptors for glucomannan in macrophage phagocytosis require further exploration, the complement receptors are proposed to be potential mediators.

Preclinical tests for salicylhydrazones derivatives to explore their potential for new antituberculosis agents

PurposeThis study target the synthesis of 22 salicylhydrazones derivatives to apply in vitro screening to explore their potential in the search for new anti-TB prototypes drugs. MethodsThe minimum inhibitory concentration (MIC) were evaluated against Mycobacterium tuberculosis (Mtb) H37Rv and clinical isolates. Drug combination assay, cytotoxicity assay, ethidium bromide accumulation assay (EtBr) and in silico analysis regarding the absorption, distribution, metabolism, excretion and toxicity (ADMET) and pharmacological properties were also performed. ResultsThree most promising compounds were selected (10, 11 and 18) to proceed with screening tests. Compound 18 presented the lowest MIC value (0.49 μg/mL) against Mtb H37Rv strain, followed by compounds 11 (3.9 μg/mL) and 10 (7.8 μg/mL). All compounds showed activity against drug susceptible and resistant clinical isolates. Cytotoxicity results were promising for all salicylhydrazones, with SI values up to 4,205 for compound 18. The derivative 10 was the only one that demonstrated a non-promising cytotoxicity scenario for a single cell line. All derivatives showed an additive effect (FICI >0.5 to 4.0) in combination with isoniazid, ethambutol and rifampicin. ConclusionAll salicylhydrazones showed potential in the screening tests performed in this study and compound 18 stood out due to its activity against susceptible and resistant bacilli at low concentrations and low cytotoxicity.

A Green one-pot three component synthesis of thiazolidine-2,4-dione based bisspirooxindolo-pyrrolidines with [Bmim]BF4: their in vitro and in silico anti-TB studies.

A simple and effective three-component one-pot green methodology was employed for the synthesis of a new thiazolidine-2,4-dione based bisspirooxindolo-pyrrolidine derivatives using [Bmim]BF4 ionic liquid via [3 + 2] cycloaddition reaction. It is an environmentally benign, column chromatography-free, shorter reaction time, good yield and easy product isolation method. The synthesized compounds 10a-x, were thoroughly characterized by using various spectroscopic methods like FT-IR, 1H NMR, 13C NMR, Mass spectrometry and finally by single crystal X-ray diffraction method. In vitro anti-tubercular (anti-TB) activity studies were carried out on these synthesized compounds, and they showed good to moderate anti-TB activity against Mycobacterium tuberculosis H37Rv strain. The compound 10a exhibited good anti-TB activity, with an MIC (Minimum Inhibitory Concentration) value of 12.5µg/mL, and the compounds 10m, 10o and 10r showed moderate activity with an MIC value of 25.0µg/mL. Remaining compounds exhibited poor activity against Mycobacterium tuberculosis. Ethambutol, rifampicin and isoniazid were used as standard drugs. Furthermore, in silico molecular docking experiments on the TB protein (PDB ID: 1DF7) were carried out to understand the binding interactions, and they showed least binding energy values ranging from -8.9 to -7.2kcal/mol.

Design, synthesis and molecular docking study of novel triazole–quinazolinone hybrids as antimalarial and antitubercular agents

In a quest to discover new antimalarial and antitubercular drugs, we have designed and synthesized a series of novel triazole–quinazolinone hybrids. The in vitro screening of the triazole–quinazolinone hybrid entities against the plasmodium species P. falciparum offered potent antimalarial molecules 6c, 6d, 6f, 6g, 6j &6k owing comparable activity to the reference drugs. Furthermore, the target compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv strain. Among the screened compounds, 6c, 6d and 6l were found to be the most active molecules with a MIC values of 19.57–40.68 μM. The cytotoxicity of the most active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed. The computational study including drug likeness and ADMET profiling, DFT, and molecular docking study was done to explore the features of target molecules. The compounds 6a, 6g, and 6k exhibited highest binding affinity of −10.3 kcal/mol with docked molecular targets from M. tuberculosis. Molecular docking study indicates that all the molecules are binding to the falcipain 2 protease (PDB: 6SSZ) of the P. falciparum. Our findings indicated that these new triazole–quinazolinone hybrids may be considered hit molecules for further optimization studies.

2,3,5‐Trisubstituted Thiazolidinone Derivatives as Potential Antimicrobial and Antitubercular Agents and In Silico Studies

AbstractA series of novel 2,3,5‐trisubstituted thiazolidinone derivatives was designed and synthesized. Compounds were tested for their antimicrobial and antitubercular activities. Compounds 3‐(2,4‐difluorobenzyl)‐5‐[(5‐methylfuran‐2‐yl)methylidene]‐2‐(phenylimino)‐1,3‐thiazolidin‐4‐one (5 c) and 3‐(2,4‐difluorobenzyl)‐2‐((3‐fluorophenyl)imino)‐5‐((Z)‐4‐hydroxybenzylidene) thiazolidin‐4‐one (6 f) exhibited remarkable antimicrobial activity against Klebsiella pneumoniae and Escherichia coli respectively. All compounds except 3‐(2,4‐difluorobenzyl)‐5‐((3‐(4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl)methylene)‐2‐(phenylimino)thiazolidin‐4‐one (5 a) and (6 f) exposed excellent antitubercular activity in comparison with the standard drugs against H37RV strain of Mycobacterium tuberculosis (ATCC No‐ 27294). In addition, molecular docking and dynamic simulations studies were performed with E. coli Mur B (EMB) (PDB ID: 2Q85), Aspergillus fumigatus sterol 14‐alpha demethylase (ASD) (PDB ID: 4UYM) and Mycobacterium tuberculosis pantothenate synthetase (MPS) (PDB ID: 3IVX) proteins against all compounds and the most potent compound (5 c) displayed higher binding proficiency. These compounds may serve as lead compounds for further optimization to achieve promising therapeutic properties.