Mycobacterium Tuberculosis H37Rv Research Articles

Pyrazole Amides Towards Trailblazing Antimicrobial Research: Bridging in Vivo Insights and Molecular Docking Studies

Antimicrobial resistance presents a significant threat to contemporary healthcare systems, making it increasingly difficult to treat infections that were once easily managed. This study aims to assess the efficacy of pyrazole benzamide derivatives (M5a–M5o), which were synthesized for their antimicrobial and antifungal activities. These compounds were tested against methicillin resistant staphylococcus aureus (MRSA), vancomycin resistant staphylococcus aureus (VRSA), mycobacterium tuberculosis H37Rv and other resistant species. The minimum inhibitory concentrations (MIC) were determined using standardized protocols to evaluate their potency and effectiveness. Molecular docking studies were also conducted to explore potential interactions and binding affinities at the molecular level, providing further insights into their antimicrobial and anti-tubercular mechanisms. Compounds M5i, M5k, and M5b emerged as the most potent, displaying MIC value of 3.12 μg/ml. These compounds show great potential as new agents in addressing the growing problem of antimicrobial resistance. Molecular docking studies against Enoyl-[acyl-carrier-protein] reductase (4DRE), revealed key interactions, with compound M5n showing a docking energy of -9.8 kcal/mol and compound M5g at -9.6 kcal/mol. These compounds formed important hydrogen bonds and π-interactions with residues like Lys165, Gly14, Ser94, and Ile21. Overall, the findings indicate that specific pyrazole-benzamide derivatives exhibit promising antimicrobial and antifungal activities, underscoring their potential as therapeutic agents. Additionally, the integration of molecular docking studies proves valuable in guiding the development and optimization of these compounds for future therapeutic applications.

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.

Comparison of Four Different DNA Isolation Methods from MGIT Culture for Long-Read Whole Genome Sequencing of Mycobacterium tuberculosis

Background: Tuberculosis (TB) remains a global health challenge, particularly due to drug resistance and limitations in rapid diagnosis. Next-generation sequencing (NGS), especially long-read whole genome sequencing (WGS), shows promise for rapidly detecting TB and drug resistance, but it requires high-quality DNA, which is difficult to extract from Mycobacterium tuberculosis due to its complex cell wall. Objectives: This study evaluated four DNA isolation methods for extracting pure DNA from M. tuberculosis, aiming to standardize protocols for long-read WGS. Methods: Mycobacterium tuberculosis H37RV colonies were grown in BACTEC MGIT liquid medium. Two pellets were prepared as the initial material for the DNA extraction protocol: Pellets from 1 mL McFarland 2 suspensions and all growing colonies from two MGIT liquid cultures. Four DNA extraction methods were used: The cetyltrimethylammonium bromide (CTAB) method, GeneJET Genomic DNA Purification Kit, Quick-DNA Fecal/Soil Microbe Kit, and Genematrix Tissue/Bacterial DNA Purification Kit, with some modifications. DNA quality was assessed based on concentration, purity, and integrity. Results: Among the tested methods, the Quick-DNA Fecal/Soil Kit yielded approximately 85 ng/mL of DNA and a purity of 1.9 at 260/280 nm from the colonial pellet of two MGIT tubes. However, lower intact DNA [DNA integrity number (DIN) ~ 6.8] was obtained with this kit. The CTAB method provided the highest intact DNA (DIN ~ 9.5), although the purity of the DNA was not sufficient. Conclusions: Based on three repetitions of McF-2 and colonial pellet extractions, the Quick-DNA Fecal/Soil Kit yielded the highest DNA quantity and purity but showed lower integrity compared to other methods, indicating the need for adjustments. A pellet from two MGIT cultures (~ 100 µL) is suitable for long-read WGS with this kit. However, a larger sample size is required to generalize these findings. For effective long-read sequencing of M. tuberculosis, DNA extraction protocols must be optimized to balance yield, fragment size, and purity for accurate sequencing and drug resistance analysis.

Th1 and Th2 cytokine response of peripheral blood macrophages-lymphocyte co-culture on challenge with Bacillus Calmette-Guérin and Mycobacterium tuberculosis H37RV in different categories of tuberculosis patients

Th1 and Th2 cytokine response of peripheral blood macrophages-lymphocyte co-culture on challenge with Bacillus Calmette-Guérin and Mycobacterium tuberculosis H37RV in different categories of tuberculosis patients

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.

The impact of physiological state and environmental stress on bacterial load estimation methodologies for Mycobacterium tuberculosis

When processed in solid or liquid medium, tuberculosis patient samples yield different proportions of a heterogenous bacterial community over the duration of treatment. We aimed to derive a relationship between methodologies for bacterial load determination and assess the effect of the growth phase of the parent culture and its exposure to stress on the results. Mycobacterium tuberculosis H37Rv was grown with and without antibiotic (isoniazid or rifampicin) and sampled on day 0, 3, 11 and 21 of growth in broth culture. The bacterial load was estimated by colony counts and the BD BACTEC MGIT system. Linear and nonlinear mixed-effects models were used to describe the relationship between time-to-positivity (TTP) and time-to-growth (TTG) versus colony forming units (CFU), and growth units (GU) versus incubation time in MGIT. For samples with the same CFU, antibiotic-treated and stationary phase cells had a shorter TTP than antibiotic-free controls and early-logarithmic phase cells, respectively. Similarly, stationary phase samples reached higher GUs and had shorter TTG than early-log phase ones. This suggests that there is a population of bacterial cells that can be differentially recovered in liquid medium, giving us insight into the physiological states of the original culture, aiding the interpretation of clinical trial outputs.

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.

Microwave assisted synthesis, spectral characterization of novel [N-methyl-3t-alkyl-2r,6c-diarylpiperidin-4-ylidine]-5’,5’-dimethylthiazolidine-4-ones for antimicrobial and antimycobacterial activities: Docking investigation

A series of novel [N-methyl-3t-alkyl-2r,6c-diarylpiperidin-4-ylidine]-5’,5’-dimethylthiazolidine-4-ones (1-4) were synthesized using recyclable and environmentally friendly Amberlite IR-120H resin as a unique and highly efficient catalyst under microwave irradiation. The synthesized compounds were characterized by FT-IR and NMR spectral studies, which indicated that the piperidine ring adopts a chair conformation with equatorial orientations of the aryl groups and the methyl group at C-3. Notably, E and Z isomers were formed for all compounds. Antibacterial, antifungal, and antimycobacterial studies revealed that all compounds exhibited good activity against the tested bacterial and fungal strains. Among these, compound 1 was particularly effective against Staphylococcus aureus compared to the standard drug Streptomycin, and it also showed higher activity against Candida albicans and Aspergillus flavus than the standard drug Amphotericin B. Furthermore, compound 1 displayed significant anti-tubercular activity against Mycobacterium tuberculosis H37Rv. These antimicrobial activities are attributed to the presence of an electron-withdrawing group in the aryl moiety, highlighting the compounds' potential for developing new antimicrobial therapies. The use of recyclable Amberlite IR-120H resin as a catalyst with microwave irradiation in the synthesis of these novel thiazolidine derivatives highlights an environmentally friendly and efficient approach.

Novel dual-pathogen multi-epitope mRNA vaccine development for Brucella melitensis and Mycobacterium tuberculosis in silico approach.

Brucellosis and Tuberculosis, both of which are contagious diseases, have presented significant challenges to global public health security in recent years. Delayed treatment can exacerbate the conditions, jeopardizing patient lives. Currently, no vaccine has been approved to prevent these two diseases simultaneously. In contrast to traditional vaccines, mRNA vaccines offer advantages such as high efficacy, rapid development, and low cost, and their applications are gradually expanding. This study aims to develop multi-epitope mRNA vaccines argeting Brucella melitensis and Mycobacterium tuberculosis H37Rv (L4 strain) utilizing immunoinformatics approaches. The proteins Omp25, Omp31, MPT70, and MPT83 from the specified bacteria were selected to identify the predominant T- and B-cell epitopes for immunological analysis. Following a comprehensive evaluation, a vaccine was developed using helper T lymphocyte epitopes, cytotoxic T lymphocyte epitopes, linear B-cell epitopes, and conformational B-cell epitopes. It has been demonstrated that multi-epitope mRNA vaccines exhibit increased antigenicity, non-allergenicity, solubility, and high stability. The findings from molecular docking and molecular dynamics simulation revealed a robust and enduring binding affinity between multi-epitope peptides mRNA vaccines and TLR4. Ultimately, Subsequently, following the optimization of the nucleotide sequence, the codon adaptation index was calculated to be 1.0, along with an average GC content of 54.01%. This indicates that the multi-epitope mRNA vaccines exhibit potential for efficient expression within the Escherichia coli(E. coli) host. Analysis through immune modeling indicates that following administration of the vaccine, there may be variation in immunecell populations associated with both innate and adaptive immune reactions. These types encompass helper T lymphocytes (HTL), cytotoxic T lymphocytes (CTL), regulatory T lymphocytes, natural killer cells, dendritic cells and various immune cell subsets. In summary, the results suggest that the newly created multi-epitope mRNA vaccine exhibits favorable attributes, offering novel insights and a conceptual foundation for potential progress in vaccine development.

Inactivation of Phosphoserine/Threonine Phosphatase PstP in H37Rv Mycobacterium tuberculosis by In silico Drug Design Approach

Inactivation of Phosphoserine/Threonine Phosphatase PstP in H37Rv Mycobacterium tuberculosis by In silico Drug Design Approach

Levofloxacin activity at increasing doses in a murine model of fluoroquinolone-susceptible and -resistant tuberculosis.

High-dose levofloxacin was explored in a clinical trial against multidrug-resistant tuberculosis and failed to show increased efficacy. In this study, we used a murine model to explore the efficacy of a dose increase in levofloxacin monotherapy beyond the maximum dose evaluated in humans. A total of 120 4-week-old female BALB/c mice were intravenously infected with 106 CFU of Mycobacterium tuberculosis H37Rv wild-type (WT) or isogenic H37Rv mutants harboring GyrA A90V or D94G substitutions; the MICs were 0.25, 4, and 6 µg/mL, respectively. Levofloxacin 250 and 500 mg/kg were given every 12 h (q12h) orally for 4 weeks. Pharmacokinetic parameters were determined after five doses. These two regimens decreased lung bacillary load in mice infected with H37Rv WT but not in mice infected with the A90V and D94G mutants. Levofloxacin 250 mg/kg q12h in mice generated pharmacokinetic parameters equivalent to 1,000 mg/d in humans, whereas 500 mg/kg q12h generated a twofold greater exposure than the highest equivalent dose tested in humans (1,500 mg/d). In our dose-response model, the effective concentration at 50% (EC50) produced an AUC/MIC (AUC0-24h/MIC) ratio of 167.9 ± 27.5, and at EC80 it was 281.2 ± 97.3. Based on this model, high-dose levofloxacin regimens above 1,000 mg/d are not expected to cause a significant increase in bactericidal activity. This study suggests no benefit of high-dose levofloxacin above 1,000 mg/d in the treatment of fluoroquinolone-susceptible or -resistant tuberculosis.

Synergistic oral beta-lactam combinations for treating tuberculosis.

The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta-lactams in combination with a beta-lactamase inhibitor, which have been underutilised in TB treatment to date. Based on inhibitory concentration, oral bioavailability and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second-line TB drugs (moxifloxacin, levofloxacin and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit (CFU) enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index (DRI). The order of activity of beta-lactams was cefadroxil>tebipenem>cephradine>cephalexin>cefdinir>penicillin V>flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir/cephradine, cefadroxil/tebipenem, cefadroxil/penicillin V, cefadroxil/cefdinir, cephalexin/tebipenem, cephalexin/penicillin V, cephalexin/cefdinir, cephalexin/cephradine and cefadroxil/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin or linezolid resulted in antagonistic effects, except for the combinations of penicillin V/levofloxacin, penicillin V/moxifloxacin and cefdinir/moxifloxacin. Beta-lactam synergy may provide viable combination therapies for the treatment of TB.

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.

Microwave expedited Cu(I) catalyzed regioselective 1,2,3-triazoles as Mycobacterium Tuberculosis H37Rv inhibitors, in vitro α-amylase and α-glucosidase inhibition, in silico studies

In the present study, an efficient and convenient synthesis of novel 1,2,3-triazoles (8i-t) incorporated quinoline and coumarin cores has been reported. Microwave-assisted Huisgen 1,3-dipolar cycloaddition reaction of azide and alkyne resulted in high yields (88–94 %) of the title compounds. Regioselective single-product formation both under conventional and microwave methods is the foremost supremacy of this work. All the molecules were subjected to in vitro antibacterial assessment wherein the compounds 8i, 8k, 8l, 8n, and 8r demonstrated very good antibacterial activity against other bacterial strains tested. Compounds 8i, 8k, 8l, 8n, 8o, 8q, and 8r demonstrated excellent antitubercular activity with MICs in the range 1.60–6.25 µg/mL in comparison to the standard drugs (Isoniazid-1.60 µg/mL, Ciprofloxacin-3.25 µg/mL, Pyrazinamide-6.25 µg/mL). Compounds 8i, 8n, and 8r also exhibited inhibitory effects against α-amylase and α-glucosidase and thus, also showed anti-diabetic activity. The significantly active compounds were subjected to molecular docking and molecular dynamics simulation studies to study the putative binding pattern as well as the stability of the docked complexes, respectively. In silico ADME profiles of the titled compounds were also predicted to access the drug-likeness properties of the designed compounds. Titled compounds showed potential effectiveness as antibacterial and antidiabetic agents.

Design and Synthesis of Pyridyl and 2-Hydroxyphenyl Chalcones with Antitubercular Activity.

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC90 values ranging from 8.9-28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl-phenyl (26) B-rings showed an IC90 value of 28 µM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC50 values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor.

Trivalent transition metal ion mediated template synthesis: In silico molecular docking, DNA binding, antimicrobial evaluation and DFT studies

In order to reduce the chances of multiple drug resistance, there is an urgent requirement for the designing of new antimicrobial agents. In this current research, series of novel hexaazamacrocyclic trivalent transition metal complexes of ChromiumIII and IronIII have been prepared by adopting the pathway of metal ion mediated template condensation. The newly synthesized macrocyclic complexes were analyzed by Infra-Red Spectroscopy, Carbon-Hydrogen-Nitrogen analyzer, UltraViolet–visible, Powder X-Ray Diffraction, Electron Paramagnetic Resonance, Magnetic Susceptibilities, Molar conductance, Electron Spray Ionisation-Mass Spectrometry and Thermogravimetric analysis techniques. The electro-lytic behaviour of the complexes was suggested by conductance (molar) values. All the complexes (T7-T12) can be formulated or represented as [MLX] X2·yH2O, where M = FeIII, CrIII and L is the macrocyclic ring resulting from 1,8-diaminonaphthalene and succinimide and X = NO3−, Cl−, CH3COO− and y = 1 or 2. All the macrocyclic complexes have been anticipated to have a penta coordinated square pyramidal shape using several physico-analytical approaches. Monomeric nature of the complexes was confirmed by CHN analysis and mass spectral data. Powder X-Ray Diffraction studies were carried out for interpreting the crystallinity of the complexes. Density Functional Theory studies were performed for energy optimization and theoretical calculations of UV & IR. The DNA interaction studies showed intercalative mode of binding is present in the newly designed complexes with the DNA. In addition to these, all the metal complexes were screened for their antibacterial and antifungal activity against pathogenic strains of bacteria and fungi, Complex T7 has effective bactericidal action against B. cereus and E. coli. Molecular docking studies were also performed on SARS Cov-2 and Mycobacterium tuberculosis. The used proteins are NSP15 Endoribonuclease from SARS CoV-2 and DNA of Mycobacterium tuberculosis H37Rv. The results revealed that complex T10 is having good binding affinity against DNA of Mycobacterium tuberculosis H37Rv.

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.

Repurposing antiparasitic N,N'-aliphatic diamine derivatives as promising antimycobacterial agents.

In previous studies, we demonstrated the potent activity of a library of 25 N,N'-disubstituted diamines (NNDDA) toward Trypanosomatid and Apicomplexa parasites. Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment. We assayed this collection against Mycobacterium tuberculosis H37Rv and M. avium, obtaining several compounds with MIC values below 10 µM. The most active analogs were also evaluated against M. smegmatis, a non-pathogenic species, and the non-tuberculosis mycobacteria M. abscessus, M. kansasii, and M. fortuitum. 3c stands out as the lead mycobacterial compound of the collection, with potent activity against M. tuberculosis (minimal inhibitory concentration [MIC] = 3.4 µM) and moderate activity against M. smegmatis, M. kansasii, and M. fortuitum (all with MIC values of 26.8 µM). To unravel the mechanism of action, we employed the web-based platform Polypharmacology Browser 2 (PPB2), obtaining carbonic anhydrases as potential drug targets. Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog 3c, setting a stepping stone for further studies.

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 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.