H37Rv Strain Research Articles

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.

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

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.

Synthesis of indole-functionalized isoniazid conjugates with potent antimycobacterial and antioxidant efficacy.

Aim: Developing potent medicinal alternates for tuberculosis (TB) is highly desirable due to the advent of drug-resistant lethal TB strains.Methods & results: Novel indole-isoniazid integrates have been synthesized with promising antimycobacterial action against the H37Rv strain, and the nitro analogs 4e and 4j show the highest efficacy with a minimum inhibitory concentration of 1.25μg/ml. The molecular docking studies against InhA support the experimental findings. Indole conjugates display remarkable radical quenching efficiency, and compounds 4e and 4j demonstrate maximum IC50 values of 50.19 and 52.45μg/ml, respectively. Pharmacokinetic analysis anticipated appreciable druggability for the title compounds.Conclusion: The notable bioaction of the indole-isoniazid templates projects them as potential lead in developing anti-TB medications with synergetic antioxidant action.

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.

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.

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.

In Silico Approach: Anti-Tuberculosis Activity of Caespitate in the H37Rv Strain.

Tuberculosis is a highly lethal bacterial disease worldwide caused by Mycobacterium tuberculosis (Mtb). Caespitate is a phytochemical isolated from Helichrysum caespititium, a plant used in African traditional medicine that shows anti-tubercular activity, but its mode of action remains unknown. It is suggested that there are four potential targets in Mtb, specifically in the H37Rv strain: InhA, MabA, and UGM, enzymes involved in the formation of Mtb's cell wall, and PanK, which plays a role in cell growth. Two caespitate conformational structures from DFT conformational analysis in the gas phase (GC) and in solution with DMSO (CS) were selected. Molecular docking calculations, MM/GBSA analysis, and ADME parameter evaluations were performed. The docking results suggest that CS is the preferred caespitate conformation when interacting with PanK and UGM. In both cases, the two intramolecular hydrogen bonds characteristic of caespitate's molecular structure were maintained to achieve the most stable complexes. The MM/GBSA study confirmed that PanK/caespitate and UGM/caespitate were the most stable complexes. Caespitate showed favorable pharmacokinetic characteristics, suggesting rapid absorption, permeability, and high bioavailability. Additionally, it is proposed that caespitate may exhibit antibacterial and antimonial activity. This research lays the foundation for the design of anti-tuberculosis drugs from natural sources, especially by identifying potential drug targets in Mtb.

The Nitrofuran-Warhead-Equipped Spirocyclic Azetidines Show Excellent Activity against Mycobacterium tuberculosis.

A series of 21 new 7'H-spiro[azetidine-3,5'-furo [3,4-d]pyrimidine]s substituted at the pyrimidine ring second position were synthesized. The compounds showed high antibacterial in vitro activity against M. tuberculosis. Two compounds had lower minimum inhibitory concentrations against Mtb (H37Rv strain) compared with isoniazid. The novel spirocyclic scaffold shows excellent properties for anti-tuberculosis drug development.

First Indonesian report of WGS-based MTBC L3 discovery

ObjectiveRecent spoligotyping results in the island nation of Indonesia had revealed the existence of Mycobacterium tuberculosis complex lineage 3 (MTBC L3) or Central Asian (CAS) strains. In this work, whole-genome sequencing (WGS) – based methods were used to search for the presence of MTBC L3.ResultsTwo unrelated Indonesian L3 strains discovered by WGS-based SNP phylogenomics are presented here for the first time. Assemblies of their genomes yielded 96.95% (MTBC strain Mtb_S6970) and 98.35% (Mtb_S19106) of the known reference strain H37Rv. Their respective constructed genome coverages are 45.38 ± 12.95x and 63.13 ± 21.10x. The two L3 genomes have 4062 and 4121 genes, respectively, which are well within the number of genes predicted in MTBC strains. Instead of having three rRNA genes usually, Mtb_S6970 possesses four. These L3 isolates exhibit cross-class antibiotic susceptibility. FadD26, fadE24, fbpA, lprO, and panC, which are thought to be important in the pathophysiology of MTBC, were discovered to have 3–7 times more loci in L3 than L2 or L4. The penetration of L3 in the nation, despite its antibiotic sensitivity, is a concerning indicator of borderless global spread that may eventually be overcome by the phenotypes of acquired drug resistance.

Unlocking the biological potential of transition metal complexes with Thiosemicarbazone ligands: Insights from computational studies

In the previous study, the synthesis and characterization of 4-(3-fluorophenyl)-3-thiosemicarbazide and benzaldehyde derivatives based thiosemicarbazone ligands and their Co(II), Ni(II), Cu(II), Zn(II) complexes were carried out to evaluate their malarial and oxidant and inflammatory inhibition abilities, demonstrating that these compounds have robust efficacy for these ailments. In the present research, to find out a combating agent against breast cancer, tuberculosis, bacterial and fungal ailments, the compounds were tested through MTT, microplate alamar blue and serial dilution protocols. ADMET and DFT investigation were analyzed against highly bioactive compounds (2, 7–10) to give a new insight about compound's reactivity, stability and drug likeness properties. Furthermore, activity results shows that the ligand (2) and its complexes demonstrate greater efficacy compared to ligand (1) and its complexes. The Cu(II) (9) and Zn(II) (10) complexes were observed as highly efficient for breast cancer (MCF-7 cell line), TB (H37Rv strain), bacterial and fungal ailments in comparison of standard drugs with 0.029 ± 0.001 μM IC50 value for (9) in anticancer activity and 0.0034 ± 0.0017 μmol/mL MIC value for (10) in anti-tuberculosis activity. In the molecular docking investigation, the various kind of binding interactions and lowest binding affinity of (9) (against 4RJ3 (−10.0 kcal/mol), 2VCJ (−7.9 kcal/mol)) and (10) (−7.8 and −8.3 kcal/mol for 5V3Y and 3PTY protein) support their bioactivity. This research highlights the pharmaceutical importance of transition metal complexes having thiosemicarbazones, presenting a significant approach for the discovery of potent anti-infectious agent.

Platinum (II) complexes derived from 4,6-dimethylpyrimidine-2-thiolate: Syntheses, structure and anti-tubercular studies

Current study discussed the reactivity of 4,6-dimethylpyrimidine-2-thiolate towards [PtCl2(P∩P)] [(P∩P) = dppm, dppe, dppp] and their efficacy against Mycobacterium tuberculosis. The finding showed that reaction of [PtCl2(P∩P)] [(P∩P) = dppm, dppe] with sodium salt of 4,6-dimethylpyrimidine-2-thiolate yielded cis configured product [Pt{2-SC4H(4,6-Me)2N2}2(P∩P)] [(P∩P) = dppm, dppe]. However, a similar reaction with [PtCl2(dppp)] resulted in an unexpected mononuclear chelated species [Pt{SC4H(4,6-Me)2N2}2: κ-S, κ-N] formed due to the removal of phosphine ‘dppp’. An elimination of chelated phosphine is quite surprising perhaps the steric hindrance presents in the geometry of [PtCl2(dppp)] and the degree of softness in its electronic structure may attributed to rapid reactivity. All the synthesized complexes were characterized by elemental analysis, NMR (1H, 13C{1H}, 31P{1H}). The molecular structure of complex [Pt{2-SC4H(4,6-Me)2N2}2(dppe)].CH3CN (2) and [Pt{SC4H(4,6-Me)2N2}2: κ-S, κ-N] (3) was confirmed by single crystal X-ray diffraction analyses. The ligand and complexes were studied to evaluate their potential against tuberculosis strain H37RV and discussed comparative prospects between palladium and platinum complexes.

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.

Confronting Tuberculosis: A Synthetic Quinoline-Isonicotinic Acid Hydrazide Hybrid Compound as a Potent Lead Molecule Against Mycobacterium tuberculosis.

The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR Mycobacterium tuberculosis (M.tb) strains were performed. It demonstrated an MIC50 value of 1.86 ± 0.21 μM for laboratory pathogenic M.tb strain H37Rv and 3.045 ± 0.813 μM for a clinical M.tb strain CDC1551. UH-NIP-16 also decreased the MIC50 values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR M.tb strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse M.tb proteins showed high binding affinities with multiple M.tb proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against M.tb, both alone and in combination with first-line drugs.

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.

Lysine acetylation of Hsp16.3: Effect on its structure, chaperone function and influence towards the growth of Mycobacterium tuberculosis

Hsp16.3 plays a vital role in the slow growth of Mycobacterium tuberculosis via its chaperone function. Many secretory proteins, including Hsp16.3 undergo acetylation in vivo. Seven lysine (K) residues (K64, K78, K85, K114, K119, K132 and K136) in Hsp16.3 are acetylated inside pathogen. However, how lysine acetylation affects its structure, chaperone function and pathogen's growth is still elusive. We examined these aspects by executing in vitro chemical acetylation (acetic anhydride modification) and by utilizing a lysine acetylation mimic mutant (Hsp16.3-K64Q/K78Q/K85Q/K114Q/K119Q/K132Q/K136Q). Far- and near-UV CD measurements revealed that the chemically acetylated proteins(s) and acetylation mimic mutant has altered secondary and tertiary structure than unacetylated/wild-type protein. The chemical modification and acetylation mimic mutation also disrupted the oligomeric assembly, increased surface hydrophobicity and reduced stability of Hsp16.3, as revealed by GF-HPLC, 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid binding and urea denaturation experiments, respectively. These structural changes collectively led to an enhancement in chaperone function (aggregation and thermal inactivation prevention ability) of Hsp16.3. Moreover, when the H37Rv strain expressed the acetylation mimic mutant protein, its growth was slower in comparison to the strain expressing the wild-type/unacetylated Hsp16.3. Altogether, these findings indicated that lysine acetylation improves the chaperone function of Hsp16.3 which may influence pathogen's growth in host environment.

Design, Synthesis and In Silico Molecular Docking Evaluation of New Series of 1,2,3‐Triazole Derivatives as Potent Antimicrobial Agents

AbstractChalcone and triazole scaffolds have demonstrated a crucial role in the advancement of science and technology. Due to their significance, research has proceeded on the design and development of novel benzooxepine connected to 1,2,3‐triazolyl chalcone structures. The new chalcone derivatives produced by benzooxepine triazole methyl ketone and different aromatic carbonyl compounds. Product structures were established by various spectral techniques such as IR, 1H NMR, 13C NMR, and mass specrometric analysis. Among the tested compounds, two compounds exhibited exceptional antibacterial susceptibilities with MIC (Minimum inhibitory concentration) range of 3.59–10.30 μM against the tested S. aureus strain. Few of the compounds displayed superior antifungal activity against F. oxysporum with MIC value range from 3.25‐4.89 μM, when compared to fluconazole (MIC=3.83 μM). In addition, few derivatives demonstrated equivalent antitubercular action against H37Rv strain with MIC range of 2.16–4.90 μM. The capacity of one of the ligand to form a stable compound on the active site of CYP51 from M. tuberculosis (1EA1) was confirmed by docking studies. Additionally, the chalcone‐1,2,3‐triazole hybrids ADME (absorption, distribution, metabolism, and excretion), molecular characteristics, estimation of toxicity, and bioactivity scores were assessed.