anti-TB Activity Research Articles

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

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

Antimycobacterial Activity of Solid Lipid Microparticles Loaded with Ursolic Acid and Oleanolic Acid: In Vitro, In Vivo, and Toxicity Assessments

Ursolic acid (UA) and oleanolic acid (OA) are hydrophobic triterpenoid isomers with demonstrated anti-mycobacterial (Mtb) and immune-regulatory properties, although their poor solubility limits clinical use. We report the development of solid lipid microparticles (SLMs) as delivery vehicles for UA and OA and evaluate their anti-Mtb efficacy in vitro and in vivo, as well as their acute toxicity. SLMs measured 0.7–0.89 µM in size, with complete in vitro release of OA and UA at 40 and 32 h, respectively. The minimum inhibitory concentration (MIC) of SLMs loaded with OA and UA was 40 µg/mL SLMs + 20 µg/mL OA + 20 µg/mL UA for drug-sensitive Mtb and 80 µg/mL SLMs + 40 µg/mL OA + 40 µg/mL UA for multidrug-resistant (MDR) Mtb. These SLMs showed an efficient reduction in Mtb burden in infected alveolar macrophages. In a murine model of late-stage progressive MDR-TB, aerosolized delivery of SLMs containing OA and UA via a metered-dose inhaler significantly reduced pulmonary bacterial loads and extended survival. In vivo, acute toxicity studies revealed no mortality or signs of toxicity. These findings demonstrate that SLMs are an optimal delivery system for terpenoids, providing potent in vitro and in vivo anti-TB activity with an excellent safety profile.

Ni(II)-selenosemicarbazones complexes as promising anticancer and anti-tubercular agents: Synthesis, characterization, molecular docking and binding studies with HSA and ct-DNA

Reaction of nickel(II) acetate with selenosemicarbazones (2-HOxsesc, 3-MeHOxsesc, 6-ClHOxsesc, 3-HIndsesc, 3-AcHIndsesc, 9-HAnsesc, 1-HNapsesc, 2-HNapsesc) in 1:2 (M:L) molar ratio yielded complexes of formula, [Ni(sesc)2] 1–8 (sesc = 2-Oxsesc 1, 3-MeOxsesc 2, 6-ClOxsesc 3, 3-Indsesc 4, 3-AcIndsesc 5, 9-Ansesc 6, 1-Napsesc 7, 2-Napsesc 8).Complexes are characterized using elemental analysis, FTIR, NMR (1H and 13C) spectroscopy and Mass spectrometry. The full optimized energy for 2-HOxsesc and its complex was found through Density Functional Theory calculation using B3LYP level and predicted geometry parameters are compared with literature. Selenosemicarbazones and their complexes were tested for their anti-tuberculosis activity against M. tuberculosis H37RV strain and anticancer activity against PA-1 and DU145cell lines. The anti-TB activity of 3-AcHIndsesc (MIC = 25 μg/mL) got exceptionally enhanced on complexation with Ni(II) (complex 5, MIC = 0.8 μg/mL). Anticancer activity of ligands have got enhanced on complexation with Ni(II) metal ion and best results were obtained in case of complex 5 (PA-1, IC50 =1.28; DU145, IC50 =3.83). The binding constant of 6.5 × 103M-1 and 3 × 104M−1 obtained from absorption spectroscopy (UV–Vis) indicates strong binding of complex 5 with HSA and ct-DNA. The molecular interaction of 3-AcHIndsesc and complex 5 with mycobacterium tuberculosis enoyl reductase and DNA (PDB ID: 1BNA) were checked with docking studies. The docking studies with mycobacterium tuberculosis enoyl reductase and DNA (PDB ID: 1BNA) gave minimum binding energy of -8.9 Kcal/mol and -7.5 Kcal/mol respectively for complex 5. The docking results are in well agreement with experimental data.

Synthesis, Structural, DFT studies, Biological Effectiveness, and Molecular Docking Aspects of Multitarget Novel N-(4-Phenylthiazol-2-yl)hydrazine carboxamide Hybrids as COX inhibitors, Anti-TB, and Anti-oxidant activity

We herein report, a series of N-(4-phenylthiazol-2-yl)hydrazinecarboxamide based multitarget compounds 3(a-i) were designed and synthesized. Ten compounds 2, and 3(a-i) were characterized by FTIR, NMR (1H and 13C), and mass analysis and subsequently, tested for their potential COX inhibitors, anti-TB, and anti-oxidant activities. The physicochemical and ADME studies for newly synthesized compounds were disclosed. The DFT calculations were taken for the selected molecules using CAM-B3LYP hybrid functional with a 6–31+g(d) all-electron basis set using the Gaussian 09 package. The compounds 3d, 3e, and 3f recognized outstanding COX-II inhibitions with IC50 values of 0.62, 0.78, and 0.72 μM compared to standard drugs. The compounds 3d, 3e, and 3f showed outstanding anti-TB activity with a MIC value of 0.78μg/mL. The compound 3d, and 3f attested outstanding antioxidant activity at 10 μg/mL with a rate of inhibition of 68.12%, and 68.85% respectively. Finally, the molecular docking studies carried out with cyclooxygenase-2 (PDB ID: 6COX), M. tuberculosis enoyl reductase (INHA) (PDB ID: 4TZK), and cytochrome c peroxidase (PDB ID: 2×08), for all the newly synthesized derivatives. Finally, selected compounds were taken for their molecular dynamic studies.

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

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

Synthesis and evaluation of the anti-TB activity of novel 7-(2-(4-substituted-phenyl)-4,5-diphenyl-1H-imidazol-1-yl)-4-methyl-2H-chromen-2-one derivatives and their DFT studies for NLO application

A series of novel 7-(2-(4-substituted-phenyl)-4,5-diphenyl-1H-imidazol-1-yl)-4-methyl-2H-chromen-2-one derivatives 5(a-g) have been synthesized and reported as anti-TB activity and non-linear optical applications. The activity results show that compounds 5b, 5c, 5d, 5f, and 5g exhibited excellent efficacy with a MIC value of 3.12 μg/mL, one-fold greater than the reference standard streptomycin (6.26 μg/mL). An in silico molecular docking study was performed against InhA protein and the results were consistent with the experimental results. Computational studies were performed using the DFT method and results reveal that the presence of greater electronegativity atoms increases the HOMO-LUMO energy gap. The NLO properties show that the presence of stronger electron-donating substituents increases the ICT, charge delocalization and β0 values. The NBO analysis shows significant interactions between LP (Lone pair), π* and σ* in compounds account for the high polarization and enhanced NLO activity.

Design, Synthesis, and Evaluation of the Antitubercular Activity of 5-Phenyl Substituted-5, 6-dihydropyrido[2, 3-d]pyrimidine-4, 7(3H, 8H)-dione Compounds.

Tuberculosis (TB) remains a major public health challenge, with research on new anti-TB drugs crucial for global TB elimination efforts. Here, we report a novel class of anti-TB agents. Especially, compounds 5b and 5j exhibited the highest activity [minimum inhibitory concentration (MIC) H37Rv: 0.16 and 0.12 μg/mL]. Chiral resolution was performed on compounds 5b and 5j; the isomers were evaluated for their activity and safety, confirming that the R-isomer 5bb and 5jb displayed significant anti-TB activity (MIC H37Rv: 0.03-0.06 μg/mL; MDR-Mtb: 0.125-0.06 μg/mL) and low hERG toxicity. Further evaluations on 5bb and 5jb demonstrated good metabolic stability, favorable kinetic parameters and oral bioavailability (F: 56.7 and 63.8%, respectively). The results of in vivo activity assessment indicate that 5bb and 5jb exhibit protective and therapeutic effects on zebrafish larvae and adult zebrafish infected with Mycobacterium marinum. Based on these results, compounds 5bb and 5jb are considered promising candidates for further in-depth studies.

Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H37Rv and MDR-MTB strains (MIC: <0.029–0.095 μM), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 μg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.

Investigation of biological activity of oxindole semicarbazones based copper (II) complexes: Synthesis, antimicrobial activities and molecular modelling

Copper (II) acetate reacted with 2-oxindole semicarbazone (2-Hoxsc, H1L), 3-methyl 2-oxindole semicarbazone (3-MeHoxsc, H2L) and 6-Chloro-2-oxindole semicarbazone (6-ClHoxsc, H3L) in 1:2 (M:L) molar ratio to form complexes of general formula, [Cu(L2)] (1L, 1; 2L 2; 3L 3. Stoichiometric ratio of complexes was established using UV–Vis spectroscopy. All the complexes were characterised by the CHN analysis, IR, ESR spectroscopy and Mass spectrometry. From the ESR spectrum, g values obtained (g‖ = 2.20; g⊥ = 2.05) for complex 2 confirms axial symmetry for this complex, whereas a broad isotropic signal in 1 and 3 (giso = 2.060, 1; 2.057, 3) indicates extensive exchange coupling. All the synthesized compounds (ligands and complexes) complexes were examined for their anti-tubercular activity against M. tuberculosis H37RV strain. Compounds were also tested for their anti-bacterial (B. subtilis, K. pneumonia) and antifungal (C. auris, C. albicans) activities. Biological investigations revealed that the antimicrobial activities (anti-TB, antibacterial and antifungal) of ligands get improved on complexation with Cu (II) due to formation of chelate ring, which can make the ligand a more powerful biological agent. Complex 3 has shown excellent anti-TB (MIC = 1.6 g/ml) and antibacterial (ZOI = 26 mm at 5 mg/mL) activities. Strong binding of complex 3 was observed (Kb = 24.22 × 105 M−1) with Human Serum Albumin (HSA) using fluorescence spectroscopy. Molecular modelling of complex 3 was also done with the active site of amino acid of M. tuberculosis enoyl reductase. The minimal binding energy of −10.1 kcal/mol indicated significant intermolecular interaction between M. tuberculosis enoyl reductase and complex 3 and is in well agreement with experimental data.

Substituent-Oriented Synthesis of Substituted Pyridines/Pyrido[3,2-C]coumarins via Sequential Reactions of α-H and Me/Aryl Substituted Oxime Acetates and 3-Formylchromones.

A facile one pot sequential and highly chemoselective synthesis of substituted pyridines/pyrido[3,2-c]coumarins has been developed from oxime acetates and 3-formylchromones in the presence of FeCl2. This reaction was oriented by different substituents on the α-position (H, methyl/aryl) of oxime acetates. Mechanistic investigations suggested that substituted pyridines were formed via intramolecular aza-Michael addition followed by ring opening, while pyrido[3,2-c]coumarins were formed via intermolecular Michael addition. Besides, anti-TB activity was screened for some of the synthesized pyridines. Among the tested compounds, 3ga, 3ha, 3ja, 3ma, 3ac, 4pa, 4pb and 4sb were found to have good activity with an MIC of 12.5 μg/mL.

Cytotoxicity and activity of thiosemicarbazones and semicarbazones in Mycobacterium tuberculosis: a systematic review

Mycobacterium tuberculosis (M. tuberculosis), causing agent of tuberculosis (TB), is a slow growth with a lipid-rich-cell wall, that confers protection against the action of a significant number of drugs. Thiosemicarbazones (TSCs) and semicarbazones (SCs) have a broad spectrum of pharmacological properties, especially antimicrobial. To the best of our knowledge, there is no systematic review reporting evidence of the anti-M. tuberculosis activity of these substances. This research carried out a systematic review to assess the available literature on the activity of TSCs and SCs on M. tuberculosis, as well as the cytotoxicity in different cell types. Four electronic databases (PubMed, Embase, Web of Science and Scopus), were searched according to the PRISMA statement. The search resulted in 2,187 articles. Among the 32 selected, 27 addressed the activity and cytotoxicity of substances related to TSCs and/or SCs. For M. tuberculosis, MIC ranged from 0.031-1,403 µM. Among all substances analyzed, 63 were considered active in relation to standard drugs. The predominant cytotoxicity assay was MTT (69%) and almost half of the articles used VERO cells. Toxicity of most substances was promising. Many TSCs have anti-TB activity superior to many drugs already used in the basic regimens of TB treatment, with low toxicity, both in sensitive and resistant M. tuberculosis. New research should be carried out to obtain new chemical drug prototypes for treating TB.

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.

Investigating the molecular interactions of 11-substituted-1-(4-chlorophenyl)-8H-indolo[3,2-c][1,2,4]triazolo[3,4-a]isoquinolines for Antimicrobial Potential: Synthesis, Spectral, In vitro and In silico study interpretations

Indole molecules are one of the important scaffolds in the discovery and development of new drugs. We herein described a synthesis of new 11-substituted-1-(4-chlorophenyl)-8H-indolo[3,2-c][1,2,4]triazolo[3,4-a]isoquinoline 6 (a-h). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and mass. The DFT calculations were taken for the selected molecules using CAM-B3LYP hybrid functional with a 6–31+g(d) all-electron basis set using the Gaussian 09 package. The drug-likeness calculations were explained for the synthesized derivatives. The compounds 6b, 6c and 6 g exhibited excellent antibacterial, antifungal and anti-TB activities against tested pathogens at MIC 3.125 μg/ml. Furthermore, molecular docking studies of these compounds against S. aureus Gyrase (PDB ID:2XCT), Staphylococcus aureus tyrosyl-tRNA synthetase (PDB ID:1JIJ), and Mycobacterium tuberculosis enoyl reductase (INHA) (PDB ID:4TZK), revealed the potential binding mode of the ligands to the site of the appropriate targets. Finally, drug likeness and SAR studies were disclosed. Lastly, the protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through molecular dynamics simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified.

Unraveling the potential of graphene quantum dots against Mycobacterium tuberculosis infection.

The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains has underscored the urgent need for novel therapeutic approaches. Carbon-based nanomaterials, such as graphene oxide (GO), have shown potential in anti-TB activities but suffer from significant toxicity issues. This study explores the anti-TB potential of differently functionalized graphene quantum dots (GQDs) - non-functionalized, L-GQDs, aminated (NH2-GQDs), and carboxylated (COOH-GQDs) - alone and in combination with standard TB drugs (isoniazid, amikacin, and linezolid). Their effects were assessed in both axenic cultures and in vitro infection models. GQDs alone did not demonstrate direct mycobactericidal effects nor trapping activity. However, the combination of NH2-GQDs with amikacin significantly reduced CFUs in in vitro models. NH2-GQDs and COOH-GQDs also enhanced the antimicrobial activity of amikacin in infected macrophages, although L-GQDs and COOH-GQDs alone showed no significant activity. The results suggest that specific types of GQDs, particularly NH2-GQDs, can enhance the efficacy of existing anti-TB drugs. These nanoparticles might serve as effective adjuvants in anti-TB therapy by boosting drug performance and reducing bacterial counts in host cells, highlighting their potential as part of advanced drug delivery systems in tuberculosis treatment. Further investigations are needed to better understand their mechanisms and optimize their use in clinical settings.

A Comprehensive Examination of Heterocyclic Scaffold Chemistry for Antitubercular Activity.

Tuberculosis is a communicable disease which affects humans particularly the lungs and is transmitted mainly through air. Despite two decades of intensive research aimed at understanding and combating tuberculosis, persistent biological uncertainties continue to hinder progress. Nowadays, heterocyclic compounds have proven themselves in effective treatment of tuberculosis because of their wide range of biological and pharmacological activities. Antituberculosis or antimycobacterial agents encompass a broad array of compounds utilized singly or in conjunction to combat Mycobacterium infections, spanning from tuberculosis to leprosy. Here, we summarize the synthesis of various heterocyclic compounds which includes the greener synthetic route as well as use of nano compounds as catalyst along with their anti TB activities.

Synthesis, biological evaluation, and docking studies of pyrazole-linked benzothiazole hybrids as promising anti-TB agents

Tuberculosis (TB) is a global pandemic killing millions of people every year. Yet, resistant strains make curing TB quite challenging. Herein, a series of new pyrazole-linked benzothiazole hybrids was synthesized and evaluated for their anti-TB activity against three Mycobacterium tuberculosis strains (drug sensitive (DS), multidrug-resistant (MDR) and extensively drug-resistant (XDR)). The substituted 2,5-dimethylphenoxy -, 2,6-dichlorophenoxy -, 2,6-dimethoxyphenoxy -, 4-methylpiperazin-1-yl-,and pyrrolidin-1-ylpyrazole-benzothiazole conjugates (compounds 10j, 10k,10l, 11cand 12 respectively) displayed promising anti-TB activity in comparison to the reference compound isoniazid against the DS strain with (MIC: 1.74–3.68 μM/mL)To further study the mode of action of these anti-TB compounds, their inhibition of the Mycobacterium tuberculosisenoyl-acyl carrier protein reductase enzyme (InhA) was tested. The 3-acetamidophenoxy-, 2,6-dichlorophenoxy -,andpyrrolidin-1-ylpyrazole-benzothiazole conjugates(Compounds 10i, 10j and 12 respectively) showed strong inhibition of InhA in comparison to the reference compound, triclosan, with IC50 values of 6.4–7.9 μM. Moreover, a molecular docking study was carried out to investigate the predicted binding interactions of the synthesized inhA inhibitors in the binding pocket of the inhA enzyme. The calculated docking energies of the developed novel pyrazole-linked benzothiazole hybrids were consistent with their tested anti-tubercular activity.

Synthesis, Molecular Docking, Molecular Dynamic Simulation Studies, and Antitubercular Activity Evaluation of Substituted Benzimidazole Derivatives.

Tuberculosis, also known as TB, is a widespread bacterial infection that remains a significant global health issue. This study focuses on conducting a thorough investigation into the synthesis, evaluation of anti-Tb activity, molecular docking, and molecular dynamic simulation of substituted benzimidazole derivatives. A series of twelve substituted benzimidazole derivatives (1-12) were successfully synthesized, employing a scaffold consisting of electron-withdrawing and electron-donating groups. The newly synthesized compounds were defined by their FTIR, 1H NMR, and mass spectra. The microplate Alamar blue assay (MABA) was used to evaluate the antimycobacterial activity of the synthesized compound against Mycobacterium tuberculosis (Mtb). Compounds 7 (MIC = 0.8 g/mL) and 8 (MIC = 0.8 g/mL) demonstrated exceptional potential to inhibit M. tuberculosis compared to the standard drug (isoniazid). In addition, the synthesized compounds were docked with the Mtb KasA protein (PDB ID: 6P9K), and the results of molecular docking and molecular dynamic simulation confirmed the experimental results, as compounds 7 and 8 exhibited the highest binding energy of -7.36 and -7.17 kcal/mol, respectively. The simulation results such as the RMSD value, RMSF value, radius of gyration, and hydrogen bond analysis illustrated the optimum potential of compounds 7 and 8 to inhibit the M. tuberculosis strain. Hydrogen bond analysis suggested that compound 7 has greater stability and affinity towards the KasA protein compared to compound 8. Moreover, both compounds (7 and 8) were safe for acute inhalation and cutaneous sensitization. These two compounds have the potential to be potent M. tuberculosis inhibitors.

Unravelling the potential of Triflusal as an anti-TB repurposed drug by targeting replication protein DciA

The increasing prevalence of drug-resistant Tuberculosis (TB) is imposing extreme difficulties in controlling the TB infection rate globally, making treatment critically challenging. To combat the prevailing situation, it is crucial to explore new anti-TB drugs with a novel mechanism of action and high efficacy. The Mycobacterium tuberculosis (M.tb)DciA is an essential protein involved in bacterial replication and regulates its growth. DciA interacts with DNA and provides critical help in binding other replication machinery proteins to the DNA. Moreover, the lack of any structural homology of M.tb DciA with human proteins makes it an appropriate target for drug development. In this study, FDA-approved drugs were virtually screened against M.tb DciA to identify potential inhibitors. Four drugs namely Lanreotide, Risedronate, Triflusal, and Zoledronic acid showed higher molecular docking scores. Further, molecular dynamics simulations analysis of DciA-drugs complexes reported stable interaction, more compactness, and reduced atomic motion. The anti-TB activity of drugs was further evaluated under in vitro and ex vivo conditions where Triflusal was observed to have the best possible activity with the MIC of 25 μg/ml. Our findings present novel DciA inhibitors and anti-TB activity of Triflusal. Further investigations on the use of Triflusal may lead to the discovery of a new anti-TB drug.

Docking Studies, Synthesis, SAR and Anti-TB Activity of Glycinamido Analogues

Mycolic acid is a crucial component of the Mycobacterium tuberculosis cell wall and mycolic acid methyltransferases (MAMTs) are essential for mycolic acids to mature. In the present study, an inhouse library of 330 ligands was designed taking glycinamido moiety as scaffold. Virtual screening was carried out with this library of compounds against MmaA1 as the target protein. About 55 hits were identified through docking, ADMET studies and these molecules were synthesized by the Schotten-Baumann reaction followed by a nucleophilic substitution reaction. All the compounds were subjected to in vitro anti-Tb screening by microplate alamar blue assay (MABA). The Mdb1, Mdb4 &amp; Meb1 exhibited excellent activity against M. tuberculosis H37Rv bacilli strain with an MIC of 1.56 µg/mL. The SAR studies shows that the aryl ring attached directly to the nitrogen atom as present in 2(-N-substituted glycinamido) derivatives is essential for the compound to exhibit potent anti-TB activity.

Spectroscopic Studies on Structurally Modified Anthraquinone Azo Hydrazone Tautomer: Theoretical and Experimental Approach.

A series of unique four mono-azo substituted anthraquinone analogue were synthesized by using the anthraquinone components in the diazo-coupling technique. The FT-IR, 1H NMR, and HRMS, data were used to confirm the structure of the molecules, and spectroscopic techniques like UV-Vis, and photoluminescence spectroscopy were employed to estimate the photophysical properties of the molecules. The molecular optimized geometry and frontier molecular orbitals were estimated using density functional theory. Further, global chemical reactivity descriptors parameter was theoretically estimated using the value of the highest occupied molecular orbit and lowest unoccupied molecular orbits. The anti-tubercular action of the synthesised dyes were also examined. The results of this biological activity showed that N-isopropyl aniline combined with anthraquinone N-isopropyl aniline had superior anti-tubercular activity when compared to Rifampicin as the standard. As per molecular docking studies, the synthesized compound Q1 showed excellent binding energy (-10.0kcal/mol) among all compounds against the 3ZXR Protein. These results agreed with our in-vitro anti-TB activity results.