Mycobacterium Tuberculosis H37Rv Strain Research Articles

Synthesis, crystal structure, electronic structure, and anti-tubercular properties of two new coumarin derivatives bearing theophylline moiety

In this work, synthesis, crystal and electronic structure of newly synthesized coumarin-theophylline hybrids exhibiting high anti-TB activity were investigated by experiments and quantum chemical calculations. The molecular structure determined by single crystal X-ray diffraction method revealed that the compound crystalize in the monoclinic system with the space group P21/c. The molecule is stabilized by strong and weak intra-/inter-molecular hydrogen bonds. The crystal structure compares well with the optimized geometry calculated at B3LYP/6–311++G(d,p) level by using density functional theory. The electronic structure of the compound has been explored by investigating frontier molecular orbitals, natural atomic charges, natural populations of the molecular orbitals, Hirshfeld and molecular electrostatic potential surfaces. It is realized that the compounds show substantial in vitro anti-tuberculosis activity with the MTBH37Rv strain and were identified as a hit candidate, exhibiting MIC of 0.39 & 0.78 µg/mL against Mycobacterium tuberculosis.

In-silico and in-vitro analysis of novel substituted benzimidazolyl derivatives for antimycobacterial potentials targeting enoyl acyl carrier protein reductase (InhA)

BackgroundThe emergence of mutated drug-resistant strains of Mycobacterium tuberculosis has reinvigorated the development of effective chemotherapy for MDR-TB (multidrug-resistant resistance tuberculosis). Enoyl acyl carrier protein reductase (InhA) involved in the mycobacterial fatty acid elongation system has been chosen as a potential target.ResultAll of the lead compounds had a definite Rf value and a sharp melting point, confirming that no tautomeric forms exist and that the keto (CO) group is apparent in the IR and 13C NMR spectrum data. Structure-based drug design revealed the presence of amino acid residues like TYR 158, ILE 194, and PHE 149 which are crucial for InhA inhibitory activity and were considered favorable interactions. Among all, compounds 4, 5a, and 5c showed better docking and binding free energy owing to favorable interactions. Interestingly, there was a strong correlation between the binding free energy and the antimycobacterial susceptibility assay, where compounds 4, 5a, and 5c had greater activity. All the lead compounds also had good oral absorption and gut permeability. The presence of a carboxylic linker (–COOH–) between benzimidazole and the rest of the structure of the lead compounds was found to be crucial for activity as the oxygen atom and hydroxyl group of the linker formed most of the favorable interactions. The presence of chlorophenyl showed a favorable effect on InhA inhibition which might be owing to its hydrophobic interaction with PHE 149.ConclusionThree of the seven lead compounds synthesized had an IC value of approximately 0.5 μg/ml in the in-vitro Alamar blue assay against the Mycobacterium tuberculosis H37Rv strain, which is roughly comparable to the standard marketed drug, Isoniazid (INH). This manifestation of promising activity that resulted from combining in-silico and wet lab experimentation could be a great starting point for developing potent antimycobacterial agents to combat multidrug-resistant tuberculosis.Graphical abstract

Identification of potential inhibitors of Mycobacterium tuberculosis shikimate kinase: molecular docking, in silico toxicity and in vitro experiments.

Tuberculosis (TB) is one of the main causes of death from a single pathological agent, Mycobacterium tuberculosis (Mtb). In addition, the emergence of drug-resistant TB strains has exacerbated even further the treatment outcome of TB patients. It is thus needed the search for new therapeutic strategies to improve the current treatment and to circumvent the resistance mechanisms of Mtb. The shikimate kinase (SK) is the fifth enzyme of the shikimate pathway, which is essential for the survival of Mtb. The shikimate pathway is absent in humans, thereby indicating SK as an attractive target for the development of anti-TB drugs. In this work, a combination of in silico and in vitro techniques was used to identify potential inhibitors for SK from Mtb (MtSK). All compounds of our in-house database (Centro de Pesquisas em Biologia Molecular e Funcional, CPBMF) were submitted to in silico toxicity analysis to evaluate the risk of hepatotoxicity. Docking experiments were performed to identify the potential inhibitors of MtSK according to the predicted binding energy. In vitro inhibitory activity of MtSK-catalyzed chemical reaction at a single compound concentration was assessed. Minimum inhibitory concentration values for in vitro growth of pan-sensitive Mtb H37Rv strain were also determined. The mixed approach implemented in this work was able to identify five compounds that inhibit both MtSK and the in vitro growth of Mtb.

Effect of teriparatide on drug treatment of tuberculous spondylitis: an experimental study

Tuberculous spondylitis often develops catastrophic bone destruction with uncontrolled inflammation. Because anti-tuberculous drugs do not have a role in bone formation, a combination drug therapy with a bone anabolic agent could help in fracture prevention and promote bone reconstruction. This study aimed to investigate the influence of teriparatide on the effect of anti-tuberculous drugs in tuberculous spondylitis treatment. We used the virulent Mycobacterium tuberculosis (Mtb) H37Rv strain. First, we investigated the interaction between teriparatide and anti-tuberculosis drugs (isoniazid and rifampin) by measuring the minimal inhibitory concentration (MIC) against H37Rv. Second, we evaluated the therapeutic effect of anti-tuberculosis drugs and teriparatide on our previously developed in vitro tuberculous spondylitis model of an Mtb-infected MG-63 osteoblastic cell line using acid-fast bacilli staining and colony-forming unit counts. Selected chemokines (interleukin [IL]-8, interferon γ-induced protein 10 kDa [IP-10], monocyte chemoattractant protein [MCP]-1, and regulated upon activation, normal T cell expressed and presumably secreted [RANTES]) and osteoblast proliferation (alkaline phosphatase [ALP] and alizarin red S [ARS] staining) were measured. Teriparatide did not affect the MIC of isoniazid and rifampin. In the Mtb-infected MG-63 spondylitis model, isoniazid and rifampin treatment significantly reduced Mtb growth, and cotreatment with teriparatide did not change the anti-tuberculosis effect of isoniazid (INH) and rifampin (RFP). IP-10 and RANTES levels were significantly increased by Mtb infection, whereas teriparatide did not affect all chemokine levels as inflammatory markers. ALP and ARS staining indicated that teriparatide promoted osteoblastic function even with Mtb infection. Cotreatment with teriparatide and the anti-tuberculosis drugs activated bone formation (ALP-positive area increased by 705%, P = 0.0031). Teriparatide was effective against Mtb-infected MG63 cells without the anti-tuberculosis drugs (ARS-positive area increased by 326%, P = 0.0037). Teriparatide had no effect on the efficacy of anti-tuberculosis drugs and no adverse effect on the activity of Mtb infection in osteoblasts. Furthermore, regulation of representative osteoblastic inflammatory chemokines was not changed by teriparatide treatment. In the in vitro Mtb-infected MG-63 cell model of tuberculous spondylitis, cotreatment with the anti-tuberculosis drugs and teriparatide increased osteoblastic function.

Bacillibactin class siderophores produced by the endophyte Bacillus subtilis NPROOT3 as antimycobacterial agents.

The bacterial endophytes isolated from the halophyte Salicornia brachiata were explored for the antimicrobial potential to discover novel microbial inhibitors that combat multidrug resistance. Upon investigation, ethyl acetate extract of the endophyte Bacillus subtilis NPROOT3 displayed significant potency against Mycobacterium smegmatis MTCC6 as well as Mycobacterium tuberculosis H37Rv strain. Further investigation of ethyl acetate crude extract by repeated chromatographic separations followed by characterization using UV, HR-ESI-MS, MALDI-MS, MALDI-MS/MS, CD, and NMR spectroscopy yielded a series of five known siderophores, namely, SVK21 (1), bacillibactin C (2), bacillibactin B (3), tribenglthin A (4), and bacillibactin (5). A total of two out of five compounds, 4 (MIC 38.66 μM) and 5 (MIC 22.15 μM) exhibited significant inhibition against the strain M. smegmatis MTCC6 comparable with positive control rifampicin (MIC 12.15 μM). None of these five bacillibactin molecules are previously reported to exhibit bioactivity against Mycobacterium sp. Herein for the first time, all the compounds were screened for their antibacterial activities against a panel of bacterial pathogens of humans. Furthermore, the probable mechanism of action of bacillibactin compounds for their antimycobacterial activity is also discussed. The findings of this study open up a new chemotype for inhibition of the Mycobacterium sp. and other multidrug-resistant pathogens.

Coumarin Hydrazone Oxime Scaffolds as Potent Anti‐tubercular Agents: Synthesis, X‐ray crystal and Molecular Docking Studies

AbstractA series of new Coumarin hydrazone oxime scaffolds were synthesised as potential anti‐TB agents. The structures of the scaffolds were confirmed by spectroscopic and analytical techniques. X‐ray crystallography confirmed the structure of compound6‐methyl‐4‐((((Z)‐((E)‐3‐(2‐phenylhydrazono)butan‐2‐ylidene)amino)oxy)methyl)‐2H‐chromen‐2‐one(5a). The coumarin hydrazone oxime scaffolds were testedin‐vitroagainst theMycobacterium tuberculosisH37Rv strain, and Vero cells were used to assess cytotoxicity. Compound5bwas obtained as the hit candidate, exhibiting MIC 0.78 μg/mL, showing more potent anti‐TB activity than Rifamycin and comparable activity to Isoniazid. There was minimal cytotoxicity observed against Vero cells for the most active compounds, indicating a good safety‐profile.In addition, the most diligent compound5bdemonstrated substantial binding interactions at the PDB:4DQU enzyme's active site and also displayed greater C‐score value than that of 4DQU ligand which validates the observed results.

Aloe vera and its potency as antituberculosis against strains of Mycobacterium tuberculosis that is resistant to some tuberculosis drugs

Introduction: Aloe vera has anti-bacterial ability against Gram-positive and Gram-negative bacteria; however, anti-bacterial study, especially in multidrug resistant strain of Mycobacterium tuberculosis, has not been evaluated yet. This study aims to determine the potential of Aloe vera as an antituberculosis against drug-resistant strains of tuberculosis. Method: Stages of research include the production of ethanol extract of Aloe vera, then testing the phytochemicals (identification of alkaloids, steroids/triterpenoids, anthraquinone, flavonoids, saponins, tannins) and chemical content testing by thin layer chromatography (TLC). The anti-bacterial test for Mycobacterium tuberculosis was performed on the Lowenstein Jensen media. Results: Test results showed the qualitative identification, and TLC contains alkaloids, steroids/triterpenoids, anthraquinone, flavonoids, saponins, and tannins. Antioxidant activity against DPPH radical shows an IC50 value of 6927.133 ppm. Test of anti-bacterial activity to Mycobacterium Tuberculosis H37Rv and MDR TB strains HE (resistant to INH and Ethambutol), and SR (resistant to streptomycin and Rifampicin) showed inhibition ranging concentration of 50 mg/mL in all extracts as well as to test the sensitivity, a sensitive start to a concentration of 50 mg/mL in all extracts. Conclusions: Aloe vera contains alkaloids, steroids/triterpenoids, anthraquinone, flavonoids, saponins, and tannins that act as antioxidants and antituberculosis against strains of Mycobacterium tuberculosis that are not resistant and resistant to anti-tuberculosis drugs.

Ethionamide and Prothionamide Based Coumarinyl-Thiazole Derivatives: Synthesis, Antitubercular Activity, Toxicity Investigations and Molecular Docking Studies.

The goal of this research work was to prepare and evaluate the antitubercular (anti-TB) activity of ethionamide (ETH) and prothionamide (PTH) based coumarinyl-thiazole derivatives. ETH and PTH were reacted with coumarin intermediates (3a-3e) to provide the target compounds (4a-4e and 4f-4j, respectively). Spectral studies confirmed the assigned structures of 4a-4j. The Microplate Alamar Blue Assay was utilized to evaluate the anti-TB activity of compounds 4a-4j against Mycobacterium tuberculosis H37Rv strain in comparison to ETH, PTH, isoniazid (INH), and pyrazinamide (PYZ) as standard drugs. The cytotoxicity studies were carried out versus HepG2 and Vero cell lines. In addition. molecular docking studies of 4a-4j concerning the DprE1 enzyme and the in-silico evaluation of physicochemical and pharmacokinetic parameters were performed. Compounds 4a, 4b, 4f, and 4g displayed equal minimum inhibitory concentration (MIC) values in comparison to INH (3.125 μg/ml) and PYZ (3.125 μg/ml), whereas 4c-4e and 4h-4j displayed better MIC values (1.562 μg/mL) than INH and PYZ. All compounds presented better anti-TB potential than ETH (6.25 μg/mL) and PTH (6.25 μg/mL). The studies of toxicity revealed that 4a-4j were safe up to 300 μg/mL concentration versus Vero and HepG2 cell lines. The molecular docking studies suggested that 4a-4j could possess anti-TB activity through the inhibition of the DprE1 enzyme. The in silico studies showed that 4a-4j followed Lipinski's rule (drug-likeliness) and exhibited better gastrointestinal absorption than BTZ043 and macozinone. In conclusion, the ETH and PTH-based coumarinyl-thiazole template can help developing selective DprE1 enzyme inhibitors as potent anti-TB agents.

The Use of Mesenchymal Stem Cells in the Complex Treatment of Kidney Tuberculosis (Experimental Study).

In recent years, the application of mesenchymal stem cells (MSCs) has been recognized as a promising method for treatment of different diseases associated with inflammation and sclerosis, which include nephrotuberculosis. The aim of our study is to investigate the effectiveness of MSCs in the complex therapy of experimental rabbit kidney tuberculosis and to evaluate the effect of cell therapy on the reparative processes. Methods: To simulate kidney tuberculosis, a suspension of the standard strain Mycobacterium tuberculosis H37Rv (106 CFU) was used, which was injected into the cortical layer of the lower pole parenchyma of the left kidney under ultrasound control in rabbits. Anti-tuberculosis therapy (aTBT) was started on the 18th day after infection. MSCs (5 × 107 cells) were transplanted intravenously after the start of aTBT. Results: 2.5 months after infection, all animals showed renal failure. Conducted aTBT significantly reduced the level of albumin, ceruloplasmin, elastase and the severity of disorders in the proteinase/inhibitor system and increased the productive nature of inflammation. A month after MSC transplantation, the level of inflammatory reaction activity proteins decreased, the area of specific and destructive inflammation in kidneys decreased and the formation of mature connective tissue was noted, which indicates the reparative reaction activation.

Immunoendocrine abnormalities in the female reproductive system, and lung steroidogenesis during experimental pulmonary tuberculosis

IntroductionTuberculosis (TB) caused by Mycobacterium tuberculosis mainly affects the lungs, but can spread to other organs. TB chronically activates the immune and endocrine systems producing remarkable functional changes.So far, it is unknown whether pulmonary non-disseminated TB cause changes in the female reproductive system and lung endocrinology. ObjectiveTo investigate whether pulmonary TB produces immunoendocrine alterations of the female mice reproductive organs, and lung estradiol synthesis. MethodsBALB/c mice were infected intratracheally with Mycobacterium tuberculosis (Mtb) strain H37Rv. Groups of six non-infected and infected animals were euthanized on different days. Bacillary loads were determined in the lungs, ovaries and uterus. Immunohistochemistry and morphometry studies were performed in histological sections. Serum estradiol wasassayed, and supernatantfrom cultured lung cells was analyzed by Thin Layer Chromatography (TLC). ResultsMtb only grew in lung tissue. Histopathology revealed abnormal folliculogenesis and decreased corpora lutea. Altered ovarian expression of IL-6, IL-1β was found. The infection increased serum estradiol. Estradiol synthesis by infected lung cells triplicate after 30 pi days.Aromatase immunostaining was found in the alveolar and bronchial epithelium, being stronger in the infected lungs, mainly in macrophages. ConclusionPulmonary TB affects the histophysiology of the female reproductive system in absence of its local infection, and disturbslung endocrinology.

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity.

Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1–SIH13). Following structural characterization by FTIR, 1H NMR, 13C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. Additionally, the cytotoxic effects of SIH1–SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1–SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1–SIH13 adhered to Lipinski’s rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb.

Untargeted metabolomics analysis reveals Mycobacterium tuberculosis strain H37Rv specifically induces tryptophan metabolism in human macrophages

BackgroundTuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) remains a global health issue. The characterized virulent M. tb H37Rv, avirulent M. tb H37Ra and BCG strains are widely used as reference strains to investigate the mechanism of TB pathogenicity. Here, we attempted to determine metabolomic signatures associated with the Mycobacterial virulence in human macrophages through comparison of metabolite profile in THP-1-derived macrophages following exposure to the M. tb H37Rv, M. tb H37Ra and BCG strains.ResultsOur findings revealed remarkably changed metabolites in infected macrophages compared to uninfected macrophages. H37Rv infection specifically induced 247 differentially changed metabolites compared to H37Ra or BCG infection. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed H37Rv specifically induces tryptophan metabolism. Moreover, quantitative PCR (qPCR) results showed that indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) which converts the tryptophan to a series of biologically second metabolites were up-regulated in H37Rv-infected macrophages compared to H37Ra- or BCG-infected macrophages, confirming the result of enhanced tryptophan metabolism induced by H37Rv infection. These findings indicated that targeting tryptophan (Trp) metabolism may be a potential therapeutic strategy for pulmonary TB.ConclusionsWe identified a number of differentially changed metabolites that specifically induced in H37Rv infected macrophages. These signatures may be associated with the Mycobacterial virulence in human macrophages. The present findings provide a better understanding of the host response associated with the virulence of the Mtb strain.

Discovery of oxazoline-triazole based hybrid molecules as DNA gyrase inhibitors: A new class of potential Anti-tubercular agents

A library of novel oxazoline-triazole hybrid analogues (6a-6 g and 7a-7 m)was designed using a molecular hybridization approach and synthesized from commercially available ethyl 2/3/4-hydroxybenzoate. The synthesized compounds were characterized by modern art instrumentation, including IR and NMR (1H, 13C). All the final compounds were evaluated for their in-vitro antibacterial (S. aureus, B. subtilis, E. coli and P. aeruginosa), antifungal (C. neoformans, C. albicans and A. niger) and anti-tubercular (Mycobacterium tuberculosis H37Rv, MDR and XDR strains) activities. Among the series, compound 7a-7i exhibited excellent activity (MIC = 1.6 µM) against H37Rv strain of M.tuberculosis. However, antibacterial screening data (in vitro) revealed a moderate inhibition for 6e-6 g and 7f-7 h against gram-positive bacteria (Bacillus subtilis) and 7a-7i against gram-negative bacteria with a MIC value of 25 µg/ml. While moderate activity was observed against fungal (C. neoformns and C. albicans) strains with MIC value of 25–200 µg/mL. Additionally, five compounds (7a, 7d-7f and 7 h) were further evaluated for their in vitro inhibitory activity against E-coli DNA gyrase. These compounds displayed significant inhibitory activity against the DNA gyrase enzyme with an IC50 value of 0.08 – 0.5 µM.

Design, Synthesis, and Biological Evaluation of quinoxaline bearing tetrahydropyridine derivatives as anticancer, antioxidant, and anti-tubercular agents.

Quinoxaline and Tetrahydropyridine derivatives showed various biological properties. The combination of these two scaffolds may contribute to good biological activity and may give novel and efficacious bioactive candidates. The present study aimed to identify bioactive agents with quinoxaline bearing tetrahydropyridine derivatives possessing anticancer, antioxidant, and anti-tubercular agents. A series of novel quinoxaline bearing tetrahydropyridine derivatives have been designed and synthesized in good yields. The synthetic protocol involves three-component Povarov reactions of 6-amino quinoxaline, propenyl guaethol, and substituted aldehydes using BF3•OEt2 as catalyst. The newly synthesized molecules were evaluated for their anticancer activity against four cell lines, i.e. A-549, MCF-7, PC-3, and HepG2. The results from in vitro assay indicated that compound 4a proved to be as potent as the standard drug adriamycin against all cell lines with GI50 values <10 μg/ml. Compounds 4b, 4f, and 4i exhibited good cytotoxicity against A-549 cell line. All synthesized molecules were evaluated for their antioxidant activity and the results revealed that the compounds 4a, 4b, and 4i showed promising antioxidant activities against DPPH and H2O2 scavenging. In addition, the anti-mycobacterial activity of the synthesized compounds against MTB H37Rv strain was determined using MABA method. The results indicate that the compounds 4a, 4b, 4g, and 4i showed better anti-mycobacterial activity than the standard drugs pyrazinamide, ciprofloxacin and streptomycin with MIC value 1.6 μg/ml. Furthermore, molecular docking studies and ADME properties showed good pharmacokinetic profile and drug-likeness properties. These studies showed that a series of novel quinoxaline bearing tetrahydropyridine derivatives exhibit anticancer, anti-mycobacterial, and antioxidant activities.

Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants.

We performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 was used for in vitro selection of spontaneous resistant mutants. The same mutations in six genes were detected in bacterial cultures grown under increased concentrations of 11 (2×, 4×, 8× MIC). The mutant positions were presented as mixed wild type and mutant alleles while increasing the concentration of the compound led to the semi-proportional and significant increase in mutant alleles. The identified genes belong to different categories and pathways. Some of them were previously reported as mediating drug resistance or drug tolerance, and counteracting oxidative and nitrosative stress, in particular: Rv0224c, fbiC, iniA, and Rv1592c. Gene-set interaction analysis revealed a certain weak interaction for gene pairs Rv1592–Rv1639c and Rv1592–Rv0224c. To conclude, this study experimentally demonstrated a multifaceted primary genetic response of M. tuberculosis to the action of nitrofurans. All three 11-treated subcultures independently presented the same six SNPs, which suggests their non-random occurrence and likely causative relationship between compound action and possible resistance mechanism.

Total Synthesis of the Antimycobacterial Natural Product Chlorflavonin and Analogs via a Late-Stage Ruthenium(II)-Catalyzed ortho-C(sp2)-H-Hydroxylation.

The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization’s (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed ortho-C(sp2)-H-hydroxylation of a substituted 3′-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against Mycobacterium tuberculosis (Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of Mtb (Minimal Inhibitory Concentrations (MIC90) = 0.78 μm). In addition, we determined the chemical and metabolic stability as well as the pKa values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure–activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives.

ON donor tethered copper (II) and vanadium (V) complexes as efficacious anti-TB and anti-fungal agents with spectroscopic approached HSA interactions

Antimicrobial drug resistance poses a significant threat worldwide, hence triggering an urgent situation for developing feasible drugs. 3D-transition metal coordination complexes being multifaceted, offer tremendous potency as drug candidates. However, there are fewer reports on non-toxic and safe transition metal complexes; therefore, we hereby attempted to develop novel copper and vanadium-based therapeutic agents. We have synthesised six metal complexes viz., [VVO2(Quibal-INH)] (1), [CuII(Quibal-INH)2] (2), [VVO(Quibal-INH) (cat)] (3), [CuII(Quibal-INH) (cat)] (4), [VVO(Quibal-INH) (bha)] (5) and [CuII(Quibal-INH) (bha)] (6). Quibal-INH (L) is an ON bidentate donor ligand synthesized from Schiff base reaction between 4-(2-(7-chloroquinolin-3-yl)vinyl)benzaldehyde (Quibal) and Isoniazid (INH). The synthesized compounds were characterized using analytical techniques involving ATR-IR, UV–Vis, EPR, 1H NMR, 13C NMR, and 51V NMR. Ligand (L) and compound 3 exhibited moderate growth inhibitory activity towards Candida albicans and Cryptococcus neoformans fungal species. Compound 6 has been identified as active against the above fungal species with no toxicity and hemolysis activity on the healthy cells. Compound 5 exhibited significant activity against the Mycobacterium tuberculosis H37Rv strain. Further, compounds 4, 5 and 6 exhibited excellent free radical scavenging activity. All the developed compounds were found to exhibit stability over a wide range of pH conditions. The complexes were additionally studied for their interaction with human serum albumin (HSA) with the UV–vis spectroscopic technique.

Design, Synthesis, Anti-microbial and Molecular Docking Studies of Novel 5-Pyrazyl-2-Sulfanyl-1, 3, 4-Oxadiazole Derivatives.

Chemical modification of Oxadiazole may lead to a potent therapeutic agent. A series of novel 5-pyrazyl-2-sulfanyl-1, 3, 4-oxadiazole derivatives (5ag) have been synthesised utilising pyrazinoic acid as a precursor. The new oxadiazole compounds were docked against potential targets and evaluated for antibacterial and antitubercular activity. The 5-pyrazyl-2-substituted sulfanyl-1, 3,4-oxadiazole derivatives (5a-g) were synthesized from the crucial intermediate 2-sulfanyl-5-pyrazyl-1, 3,4-oxadiazole (4), which was prepared by treating the 2-pyrazyl hydrazide with CS2 and pyridine. IR, 1HNMR, 13C, MS and elemental analyses were used to confirm the chemical structures. Antimicrobial activity was determined for each synthesized compound. Additionally, compounds were evaluated for antitubercular activity against the Mycobacterium Tuberculosis H37Rv strain. Compounds 5c, 5g, and 5a had a favourable antibacterial profile, while 5c and 5g (MIC = 25 g/ml) demonstrated potential antitubercular activity when compared to the other produced compounds. Molecular docking experiments using V-Life Science MDS 4.6 supplemented the biological data. Each compound has been tested for antibacterial and antitubercular action against a variety of microorganism strains and exhibits considerable activity. Additionally, molecular docking analysis confirmed the experimental results by describing improved interaction patterns.

Preparations Based on the Maleic Acid Copolymers Containing Silver Nanoparticles and Cations and Furan-2-Carboxylic Acid: Synthesis and Antituberculosis Activity

The complexes of silver ions with furan-2-carboxylic acid (Fur-COOH) and the conjugates of polymer-stabilized silver nanoparticles with silver cations and Fur-COOH are synthesized. The silver nanoparticles are studied by transmission electron microscopy (TEM), while the resulting conjugates—by UV–vis spectroscopy. All the objects obtained display prominent in vitro activity against the H37Rv strain of Mycobacterium tuberculosis. A synergistic effect of the silver components is revealed for the conjugates based on maleic acid-alt-N-vinylpyrrolidone containing nano- and cationic forms of silver, as well as Fur-COOH.

L-proline catalyzed ring transformation of 5-substituted tetrazole to 1,3,4-oxadiazoles as anti-tubercular agents

An innovative class of novel 2-aryl-5-(1-aryl-1H-pyrazol-3-yl)-1,3,4-oxadiazoles 5i–w have been synthesized from ring transformation using L-proline as an organocatalyst. This novel method using organocatalyst is a splendid example of the green reaction with improved yields. The molecular docking analysis of compounds 5i–w were investigated with enoyl-acyl carrier protein reductase (InhA) enzyme (PDB ID: 4TZK) as anti-tubercular target molecules. The docking study implied that the synthesized compounds exhibited favorable binding modes and affinity. Further, the anti-tubercular activity was investigated against Mycobacterium tuberculosis (MTB) H37Rv strain which demonstrated that the compounds 5i, 5j, 5k, and 5l exhibited excellent activity at the 6.25 µg/ml concentrations, whereas the compounds 5m, 5n, 5o, 5s, and 5w have shown the activity at 12.50 µg/ml concentration, respectively.