anti-TB Activity Research Articles

Repurposing an Antioxidant to Kill Mycobacterium tuberculosis by Targeting the 50S Subunit of the Ribosome.

Tuberculosis and drug-resistant TB remain serious threats to global public health. It is urgent to develop novel anti-TB drugs in order to control it. In addition to redesigning and developing new anti-TB drugs, drug repurposing is also an innovative way to develop antibacterial drugs. Based on this method, we discovered SKQ-1 in the FDA-approved drug library and evaluated its anti-TB activity. In vitro, we demonstrated that SKQ-1 engaged in bactericidal activity against drug-sensitive and -resistant Mtb and confirmed the synergistic effects of SKQ1 with RIF and INH. Moreover, SKQ-1 showed a significant Mtb-killing effect in macrophages. In vivo, both the SKQ-1 treatment alone and the treatment in combination with RIF were able to significantly reduce the bacterial load and improve the survival rate of G. mellonella infected with Mtb. We performed whole-genome sequencing on screened SKQ-1-resistant strains and found that the SNP sites were concentrated in the 50S ribosomal subunit of Mtb. Furthermore, we proved that SKQ-1 can inhibit protein translation. In summary, from the perspective of drug repurposing, we discovered and determined the anti-tuberculosis effect of SKQ-1, revealed its synergistic effects with RIF and INH, and demonstrated its mechanism of action through targeting ribosomes and disrupting protein synthesis, thus making it a potential treatment option for DR-TB.

A review of synthesis, biological activity, & docking studies of anti-tubercular agents

The World Health Organization suggests treating tuberculosis with a 6-month course of isoniazid (INH), rifampicin (RMP), ethambutol, and pyrazinamide. The anti-TB activity of a number of novel styryl-1,2,4-oxadiazoles against the MTB H37Ra strain was assessed. These compounds were motivated by the molecular structure of cinnamic acid. There is a substantial correlation between the antibacterial activity and the location of the pyridine substituent on the thiosemicarbazide skeleton. A total of thirty-three ligands were docked against the two proteins AftaA and EmbA during the primary protein-ligand docking process, which was carried out using iGemDock. The following study included eight anti-tuberculosis medications as a control group: rifampicin, isoniazid, bed aquiline, delamanid, ethionamide, ethambutol, Gemifloxacin, and thioacetazone.

Expanding structural diversity of 5'-aminouridine moiety of sansanmycin via mutational biosynthesis.

Sansanmycins represent a family of uridyl peptide antibiotics with antimicrobial activity specifically against Mycobacterium tuberculosis (including drug-resistant M. tuberculosis) and Pseudomonas aeruginosa. They target translocase I (MraY) to inhibit bacterial cell wall assembly. Given the unique mechanism of action, sansanmycin has emerged as a potential lead compound for developing new anti-tuberculosis drugs, while the 5'-aminouridine moiety plays a crucial role in the pharmacophore of sansanmycin. For expanding the structural diversity of the 5'-aminouridine moiety of sansanmycin through biosynthetic methods, we firstly demonstrated that SsaM and SsaK are responsible for the biosynthesis of the 5'-aminouridine moiety of sansanmycin in vivo. Using the ssaK deletion mutant (SS/KKO), we efficiently obtained a series of new analogues with modified 5'-aminouridine moieties through mutational biosynthesis. Based on molecular networking analysis of MS/MS, twenty-two new analogues (SS-KK-1 to -13 and SS-KK-A to -I) were identified. Among them, four new analogues (SS-KK-1 to -3 and SS-KK-C) were purified and bioassayed. SS-KK-2 showed better antibacterial activity against E. coli ΔtolC than the parent compound sansanmycin A. SS-KK-3 showed the same anti-TB activity as sansanmycin A against M. tuberculosis H37Rv as well as clinically isolated, drug-sensitive and multidrug-resistant M. tuberculosis strains. Furthermore, SS-KK-3 exhibited significantly improved structural stability compared to sansanmycin A. The results suggested that mutasynthesis is an effective and practical strategy for expanding the structural diversity of 5'-aminouridine moiety in sansanmycin.

Oxazoline/amide derivatives against M. tuberculosis: experimental, biological and computational investigations

Tuberculosis (TB) is a treatable contagious disease that continuously kills approximately 2 million people yearly. Different oxazoline/amide derivatives were synthesized, and their anti-tuberculosis activity was performed against different strains of Mtb. This study designed the anti-Mtb compounds based on amide and oxazoline, two different structural moieties. The compounds were further synthesized and characterized by spectral techniques. Their anti-Tb activity was evaluated against strain (M. tuberculosis: H37Rv). Selectivity and binding affinity of all synthesized compounds (2a–2e, 3a–3e) against PanK in Mtb were investigated through molecular docking. Molecular dynamics simulation studies for the promising compounds 2d and 3e were performed for 100 ns. The stability of these complexes was assessed by calculating the root mean square deviation, solvent-accessible surface area, and gyration radius relative to their parent structures. Additionally, free energy of binding calculations were performed. Among all synthesized compounds, 2d and 3e had comparable antitubercular activity against standard drug, validated by their computational and biological study.

Synthesis and screening of clerodane diterpene analogues from 16 hydroxycleroda 3,13(14)-Z-diene 15,16-olide for potential anti-mycobacterial activity

In recent years, clerodane diterpenes, a class of bioactive compounds, have come into the spotlight due to their amazing bioactivities. Three novel clerodane diterpene analogues were obtained by synthesising 16-hydroxycleroda-3,13(14)-Z-diene-15,16-olide (Lactone) with primary amines. Anti-tubercular activity was determined using Microplate Alamar Blue Assay. Among all the synthesised compounds from methanolic extract of seeds, results clearly showed that compounds 3 and 5 have significant anti TB activity with an MIC of 1.56 µg/ml against the Mycobacterium tuberculosis MTB H37Rv bacilli strain than the gold standard drugs pyrazinamide (3.13 µg/ml), ciprofloxacin (3.13 µg/ml), streptomycin (6.25 µg/ml) and rifampicin (6.25 µg/ml). Compound 5 exhibited significant antibacterial activity with zone of inhibition of 10.8 mm with Gram + ve and 7.95 mm with Gram -ve bacteria at a conc of 50 µg/ml respectively. In the current investigation, three novel heterocycles (compounds 3-5) of the diterpenoid were prepared, in high yield, using one-pot, efficient approach.

Synthesis, Spectral Analysis, DFT Calculations, in Vitro Screening, and Molecular Docking of New Metal Complexes with Quinoline and Isoniazid Schiff Base as Antimicrobial and Antioxidant Agents

We herein report the synthesis, spectral analysis, DFT calculations, in vitro and in silico biological activities of novel N'-((2-thioxo-1,2-dihydroquinolin-3 yl)methylene)isonicotinohydr-azide with its Cu(II), Co(II), Ni(II), and Zn(II) complexes have been successfully prepared. The ligand and the complexes were characterized by analytical, FT-IR, 1H NMR, mass, UV–visible spectroscopy, molar conductivity, and magnetic susceptibility measurements. Density Functional Theory (DFT) estimations for the ligand at the DFT/B3LYP level via 6-31 G++ (d, p) replicate the structure and geometry. Furthermore, molecular docking and ADME calculations were also performed to correlate and interpret the experimental results. The antimicrobial activity study illustrated enhancement in the activity of the free ligand upon complex formation, and the Cu(II) complex (MIC 25 µg mL−1) may be considered a promising antibacterial agent, and Ni(II) and Zn(II) complexes (MIC 25 µg mL−1) as promising antifungal agent. Also, synthesized Ni(II) and Zn(II) metal complexes (MIC 3.125 µg mL−1) showed promising anti-TB activity against Mycobacterium tuberculosis. In the antioxidant activity, the Cu(II) complex showed excellent activity as compared to standard drugs and in silico docking studies were carried out against Cytochrome c Peroxidase (PDB ID: 2X08).

Hedychium coronarium J.Koenig produced extracellular and intracellular anti-tuberculosis activity with morphological alteration of the tubercle bacillus

Hedychium coronarium J.Koenig (Zingiberaceae) is a medium-sized aromatic rhizomatous perennial monocotyledonous plant. The rhizome of H. coronarium is reported in traditional medicine for its use in the treatment of tonsillitis, bronchitis, cough, fever and other respiratory disorders. The present work was carried out to evaluate anti-mycobacterial activity of the ethanolic extract of rhizomes of H. coronarium against respiratory pathogen Mycobacterium tuberculosis (Mtb) with its safety assessment and action on morphology of the bacilli. Anti-mycobacterial activity was assessed using the in-vitro resazurin microtiter plate assay (REMA). The plant extract was further evaluated for its cytotoxicity against human THP-1 macrophages. Ex-vivo intracellular anti-TB activity was also determined using Mtb infected macrophage culture model. Scanning electron microscopy (SEM) was used to examine the morphological changes in Mtb in the presence of plant extract.H. coronarium exhibited promising antimycobacterial activity against drug sensitive Mtb H37Rv and multi drug resistant (MDR) clinical isolates of Mtb with minimum inhibitory concentration (MIC) values ranging from 15.62 to 31.25 µg mL−1. The IC50 (50% inhibitory concentration) of plant extract on THP-1 was found at higher concentration than MIC values against Mtb, indicating that the mammalian cells were not adversely affected at concentrations which are effective against Mtb. The plant extract displayed intracellular killing of bacilli inside the infected macrophages. H. coronarium also produced morphological alteration of the bacilli after 48 and 72 h of treatment. In this study, we conclude that H. coronarium has promising in-vitro and ex-vivo intracellular activity against Mtb and it also displayed activity against rifampicin and isoniazid resistant clinical isolates of Mtb without affecting eukaryotic cells.

Efficient ilamycins production utilizing Enteromorpha prolifera by metabolically engineered Streptomyces atratus

With the invasion of green tides and the increase of urban green areas worldwide, multimillion tons of Enteromorpha need to be reutilized. In this study, Enteromorpha prolifera powder is considered a promising biomass resource for the production of commercial chemical products production. Ilamycins, novel cyclic heptapeptides with significant anti-TB activities, are isolated from Streptomyces atratus SCSIO ZH16, a deep-sea-derived strain. Using EP powder as a nitrogen source, the production of ilamycins reached 709.97 mg/L through optimization of the nitrogen source using the engineered strain S. atratus SCSIO ZH16 ΔR. After mutant strain constructions and tests, strain S. atratus SCSIO ZH16 ΔR::bldD EP powder achieved a higher production titer of ilamycins. Furthermore, the production titer of ilamycins and ilamycin E reached 1561.77 mg/L and 745.44 mg/L, respectively, in a 5 L bioreactor. This study suggests that E. prolifera is a promising and eco-friendly nitrogen source for the production of ilamycins.

Some New 1,2,4-triazole Derivatives Bearing the Pyrimidine Moiety as Potential Antimycobacterial Agents: Synthesis and Docking Analysis

Background: Pyrimidine and 1,2,4-triazole heterocycles have been linked to a variety of biological and pharmacological properties such as effective bactericides, fungicides, vermicides, insecticides, anticancer and antiviral agents. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents. Objective: A novel set of heterocyclic derivatives comprising 1,2,4-triazole, pyrimidine moieties was developed, synthesized, and assessed for their antimicrobial activity. Methods: In this study, we performed ligand-based pharmacophore modeling as a promising design strategy for the design of substituted triazolyl-pyrimidine derivatives as antitubercular agents. The designed compounds were synthesized and characterized by proton, carbon nuclear magnetic resonance spectroscopy, infrared, and mass spectroscopy. Synthesized compounds were screened for anti-TB activity using the agar micro dilution method against M. tuberculosis H37Rv strain. Results: Our results revealed that the target 1,2,4-triazoles 7d, 7e, 7c have potent potency against Gram- (+ve) bacteria S. epidermidis (MICs: 1.7, 3.7, 16.4 μg/mL), whereas final pyrimidines 7c, 7e, 7f, have the strongest antibacterial activity against Gram-(-ve) strain P. aeruginosa (MICs: 3.5, 6.4, 8.4 μg/mL). Among all tested compounds, 7a, 7e, and 7h revealed an outstanding antitubercular activity against M. tuberculosis H37RV strain with MICs of 3.24, 8.93, and 4.70 μg/mL, respectively. The most active ligand 7b reveals highest hydrophobic binding modes with ThrA:127 [2.194 A°], LysA:103 [3.103, 2.164 A°], GlyA:102 [1.713 A°], ArgA:238 [1.713 A°], ValA:101 [2.113 A°] (hydrogen bondings), AspA:129, GluA:201 [Pi-anion], AlaA:246, LeuA:180 [Pi-alkyl] and HisA:179 [3.104 A°] [Pi-Pi], respectively. Conclusion: In this communication, our aim has been verified by the synthesis of 3-methoxy-10,12- dimethyl-8-phenyl-6,7,8,12-tetrahydrobenzo[2,3]oxepino[4,5-d][1,2,4]triazolo[4,3-a] pyrimidine derivatives 7 in which 1,2,4-triazole and pyrimidine moieties with benzoxepine in a single molecular framework were found. After all the above findings, it can be concluded that these molecules become lead molecules for further synthetic and biological evaluation.

Microbial glycosylation of antitubercular agent chlorflavonin

Flavonoids have shown health-benefiting properties, such as antioxidative and anti-inflammatory activities, and are commonly used as nutraceuticals and pharmaceuticals. Although flavonoids are predominantly identified from plants, several filamentous fungal species have also been reported to produce bioactive flavonoids, including chlorflavonin from Aspergillus candidus, a novel halogenated flavonoid with potent antifungal and antitubercular (anti-TB) activities. Unfortunately, the low water-solubility of this molecule may hinder its bioavailability. Glycosylation is an effective method to enhance the polarity of natural products and alter their physicochemical properties. This work focuses on the development of novel water-soluble chlorflavonin derivatives to combat the threat of drug-resistant tuberculosis. In this study, we first increased the production titer of chlorflavonin in A.candidus NRRL 5214 by optimizing the fermentation and purification processes. Next, chlorflavonin-5-O-β-d-glucuronopyranoside (1) and chlorflavonin-7-O-4″-O-methyl-β-d-glucopyranoside (2) were produced from chlorflavonin using Streptomyces chromofuscus ATCC 49982 and Beauveria bassiana ATCC 7159, respectively. Compared to chlorflavonin (4.38 ± 0.54mg/L in water), the water solubility of the two new glycosides was determined to be 117.86 ± 4.81mg/L (1) and 124.34 ± 9.13mg/L (2), respectively. This study provides a promising method to create water-soluble glycosides of chlorflavonin for the development of novel anti-TB drugs.

In silico, in vitro and docking exploration for some novel coordination complexes derived from bioactive indole moiety

The reaction of 5-methyl-3-phenyl-1H-indole-2-carbohydrazide with 4-methoxybenzaldehyde gave the new ligand molecule; N'-(4-methoxybenzylidene)-5-methyl-3-phenyl-1H-indole-2-carbohydrazide. The novel Cu(II), Co(II) and Zn(II) coordination complexes have been successfully prepared. The newly prepared ligand and its coordination complexes were characterized by analytical, FT-IR, 1H NMR, mass, UV-visible, molar conductivity, and magnetic susceptibility measurements. The spectral data reveal the octahedral geometry for all the metal (II) complexes. DFT estimations for the ligand at the DFT/B3LYP level via 6-31G++ (d, p) replicate the structure and geometry. Furthermore, molecular docking and ADME calculations were also performed to correlate and interpret the experimental results. The biological activity study illustrated enhancement in the activity of the free ligand containing bioactive indole moiety upon complex formation. The newly prepared Cu(II) and Zn(II) coordination complexes may be considered a promising antibacterial and antifungal agent. The Cu(II) and Zn(II) complexes showed MIC 12.5 µg mL−1 against E. coli, S. aureus and C. oxysporum. Also, the Zn(II) complex showed promising anti-TB activity against M. tuberculosis (MIC 3.125 µg mL−1). Further, the study extended to evaluate their in vitro antioxidant activity, and in silico docking study against Cytochrome c Peroxidase (PDB ID: 2 × 08), the Cu(II) complex showed excellent activity as compared to standard drug.

Clofazimine nanoclusters show high efficacy in experimental TB with amelioration in paradoxical lung inflammation

The rise of tuberculosis (TB) superbugs has impeded efforts to control this infectious ailment, and new treatment options are few. Paradoxical Inflammation (PI) is another major problem associated with current anti-TB therapy, which can complicate the treatment and leads to clinical worsening of disease despite a decrease in bacterial burden in the lungs. TB infection is generally accompanied by an intense local inflammatory response which may be critical to TB pathogenesis. Clofazimine (CLF), a second-line anti-TB drug, delineated potential anti-mycobacterial effects in-vitro and in-vivo and also demonstrated anti-inflammatory potential in in-vitro experiments. However, clinical implications may be restricted owing to poor solubility and low bioavailability rendering a suboptimal drug concentration in the target organ. To unravel these issues, nanocrystals of CLF (CLF-NC) were prepared using a microfluidizer® technology, which was further processed into micro-sized CLF nano-clusters (CLF-NCLs) by spray drying technique. This particle engineering offers combined advantages of micron- and nano-scale particles where micron-size (∼5 μm) promise optimum aerodynamic parameters for the finest lung deposition, and nano-scale dimensions (∼600 nm) improve the dissolution profile of apparently insoluble clofazimine. An inhalable formulation was evaluated against virulent mycobacterium tuberculosis in in-vitro studies and in mice infected with aerosol TB infection. CLF-NCLs resulted in the significant killing of virulent TB bacteria with a MIC value of ∼0.62 μg/mL, as demonstrated by Resazurin microtiter assay (REMA). In TB-infected mice, inhaled doses of CLF-NCLs equivalent to ∼300 μg and ∼ 600 μg of CLF administered on every alternate day over 30 days significantly reduced the number of bacteria in the lung. With an inhaled dose of ∼600 μg/mice, reduction of mycobacterial colony forming units (CFU) was achieved by ∼1.95 Log10CFU times compared to CLF administered via oral gavage (∼1.18 Log10CFU). Lung histology scoring showed improved pathogenesis and inflammation in infected animals after 30 days of inhalation dosing of CLF-NCLs. The levels of pro-inflammatory mediators, including cytokines, TNF-α & IL-6, and MMP-2 in bronchoalveolar lavage fluid (BAL-F) and lung tissue homogenates, were attenuated after inhalation treatment. These pre-clinical data suggest inhalable CLF-NCLs are well tolerated, show significant anti-TB activity and apparently able to tackle the challenge of paradoxical chronic lung inflammation in murine TB model.

Design, synthesis, biological evaluation and molecular dynamics of some novel 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based compounds as anti-tubercular agents

Decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1) is a druggable target which is being exploited for the development of new anti-TB agents. In the present work, we report developing a pharmacophore model and performing virtual screening of Asinex database using the developed pharmacophore model to get eight hits as potential DprE1 inhibitors. The hits were used as leads to design new 3-phenylpyrazolo[1,5-a]pyrimidine-2,7(1H,4H)-dione based potential anti-TB agents. On the basis of the identified lead molecules, a total of 18 compounds were synthesized and evaluated for their anti-TB activity by using MABA. ADMET predictions for all the compounds revealed that these compounds have drug-like and lead-like properties. One of the final compounds was found to exhibit potent anti-TB activity against Mycobacterium bovis. Communicated by Ramaswamy H. Sarma

Synthesis, Biological Evaluation, and Computational Studies of 6-Fluoro-3-(Piperidin-4-yl)-1,2-Benzisoxazole Sulfonamide Conjugates

Herein, the synthesis and biological evaluation of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole sulfonamide hybrids are discussed. All the synthesized molecules were assessed for anti-cancer and anti-TB activities using in vitro and in silico methods. The molecular docking study with CDK8 as a possible target for anti-cancer activity demonstrated that compounds 2, 3, 5, 7, 8, and 9 have a good binding affinity ranging from −8.7 to −10.3 kcal/mol against CDK8 (PDB 6T41) protein as compared with the standard drug 5-Fluorouracil (−5.0 kcal/mol). The in vitro anti-mycobacterial screening reveals that compounds 2 and 3 elicited moderate anti-TB activity with a MIC value of 25 µM. Compounds 2 and 3 exhibited moderate in vitro anti-proliferative potency against the cancer cell lines MCF-7 and HCT-116. Moreover, compound 3 exhibited a better anti-oxidant effect among all tested compounds. Some quantum chemical parameters and drug-likeness profiling of the molecules were modeled by density functional theory (DFT) and ADME studies. The obtained theoretical results are in good agreement with the experimental results.

Macrophage targeted polymeric curcumin nanoparticles limit intracellular survival of Mycobacterium tuberculosis through induction of autophagy and augment anti-TB activity of isoniazid in RAW 264.7 macrophages.

Rapid emergence of antibiotic resistance in tuberculosis has left us with limited resources to treat and manage multi drug resistant (MDR) cases of tuberculosis, prompting the development of novel therapeutics. Mycobacterium tuberculosis (MTB) perturbs the host protective pathways for its survival, therefore host directed therapeutic (HDT) interventions offer an attractive alternative strategy. Curcumin (CMN), the principle curcuminoid from Curcuma longa is known to have anti-TB activity against MDR strains of MTB in macrophages. We discovered that treatment of CMN induced autophagy in uninfected and MTB infected macrophages which was evident by conversion of LC3-I to LC3-II and degradation of p62. Inhibition of autophagy by a pharmacological inhibitor 3-MA resulted in significant inhibition of intracellular killing activity of CMN, suggesting the involvement of autophagy in intracellular clearance of MTB. Moreover, annexin v-FITC/PI staining data suggested induction of apoptosis in uninfected and MTB infected macrophages post CMN treatment. This finding was further corroborated by up-regulated expression of pro-apoptotic proteins, Bax, cleaved caspase-3 and PARP and diminished expression of anti-apoptotic protein Bcl-2 as evaluated by immunoblotting. Using GFP-MTB H37Rv and Lysotracker Red staining we demonstrated co-localization of GFP-MTB H37Rv containing phagosome to lysosome after CMN treatment, indicating enhanced phagosome lysosome fusion. Due to poor bioavailability of CMN, its clinical use is limited, therefore to overcome this issue, CMN was encapsulated in Poly(lactic-co-glycolic) acid (PLGA) shell, resulting in polymeric CMN nano particles (ISCurNP). Flow cytometric evaluation suggested >99% uptake of ISCurNP after 3h of treatment. In BALB/c mice, oral dose of ISCurNP resulted in 6.7-fold increase in the bioavailability compared to free CMN. Moreover, ISCurNP treatment resulted in significant decrease in the intracellular survival of MTB H37Rv through induction of autophagy. Adjunct action of ISCurNP and CMN in combination with isoniazid (INH) revealed >99% decrease in intracellular survival of MTB in macrophage as compared to ISCurNP, CMN or INH alone. In conclusion, our findings suggest the role of ISCurNP as novel host directed formulation to combat both sensitive and MDR strains of MTB by induction of autophagy.

Spectroscopic, theoretical and computational investigations of novel benzo[b]thiophene based ligand and its M(II) complexes: As high portentous antimicrobial and antioxidant agents

The reaction of 3-chlorobenzo[b]thiophene-2-carbohydrazide with 4-(diethylamino) salicylaldehyde gave the new ligand; 3-chloro-N'-(4-(diethylamino)-2-hydroxybenzylidene)-benzo[b]thiophene-2-carbohydrazide. The Cu(II), Co(II), Ni(II), and Zn(II) complexes have been successfully prepared. The ligand and the complexes were characterized by analytical, FT-IR, 1H NMR, mass, UV–visible spectroscopy, molar conductivity, and magnetic susceptibility measurements. The FT-IR spectral data showed that the ligand adopted a tridentate fashion when binding with the metal ions via the nitrogen atoms of the imine (C = N), carboxyl (C = O), and phenolic oxygen (O–H) donor atoms. Density Functional Theory (DFT) estimations for the ligand at the DFT/B3LYP level via 6-31G++ (d, p) replicate the structure and geometry. Finally, HOMO and LUMO analyses were used for the charge transfer interface of the structure. Furthermore, molecular docking and ADME calculations were also performed to correlate and interpret the experimental results. The antimicrobial activity study illustrated enhancement in the activity of the free ligand upon complex formation, and the Cu(II) complex (MIC 25 µg mL−1) may be considered a promising antibacterial agent, and the Ni(II) and Zn(II) complexes (MIC 25 µg mL−1) as promising antifungal agents. Also, synthesized Cu(II) and Zn(II) metal complexes (MIC 3.125 µg mL−1) showed promising anti-TB activity against M. tuberculosis. Further, benzo[b]thiophene-based ligand and its metal complexes were evaluated for in vitro antioxidant activity, and in silico docking studies were carried out against Cytochrome c Peroxidase (PDB ID: 2X08).

Chemical analysis and antitubercular activity evaluation of the dried mycelial powders of the basidiomycete Ganoderma australe TBRC-BCC 22314

The isolation of lanostane triterpenoids possessing significant anti-tuberculosis (anti-TB) activity from mycelial cultures of the basidiomycete Ganoderma australe strain TBRC-BCC 22314 was previously reported. To demonstrate the potential of the dried mycelial powder for utilization in anti-TB medicinal products, its authentic chemical analysis was performed. Considering the possibility of the changes in the lanostane compositions and anti-TB activity by sterilization, both autoclave treated and non-autoclaved mycelial powder materials were chemically investigated. The study led to the identification of the lanostanes responsible for the activity of the mycelial extract against Mycobacterium tuberculosis H37Ra. The anti-TB activity of the extracts from autoclaved and non-autoclaved mycelial powders were the same (MIC 3.13 μg/mL). However, the analytical results revealed several unique chemical conversions of the lanostanes under the sterilization conditions. The most potent major lanostane, ganodermic acid S (1), was shown to be significantly active also against the extensively drug-resistant (XDR) strains of M. tuberculosis.

Pd(II)dipyrrinato complexes: Synthesis, crystal structure and their antibacterial applications

The synthesis and biological studies of a series of Pd(II)dipyrrinato complexes are reported. The thiogalactosyl and/or oligoethyleneglycol moieties were linked with themeso-aryl rings of the Pd(II)dipyrrinato complexes. The Pd(II)dipyrrinato complexes were characterized by MASS, IR, UV-Vis, and NMR spectroscopic techniques. Single crystal X-ray structure of the homoleptic Pd(II)dipyrrinato complex (Pd1) revealed typical square planar geometry around the metal center. The anti-bacterial studies of Pd(II) dipyrrinato complexes were performed on theM. Tuberculosis H37Rv and M. Bovis BCG strains and complex Pd4 showed excellent anti-TB activity with MIC values of 25 [Formula: see text]M and 12.5 [Formula: see text]M, respectively. The ease of synthesis and good MIC values of Pd(II)dipyrrinato complexes make them promising candidates for anti-TB activity.

Substituted 2,5 thiophene dicarboxaldehyde bisthiosemicarbazones and their copper(II) complexes: Synthesis, structure elucidation, HSA binding, biological activities and docking studies

Reaction of copper (II) acetate with 2,5 thiophenedicarboxaldehyde bisthiosemicarbazone (2,5 H2bttsc, 1H2L), 2,5 thiophenedicarboxaldehyde-N1-methyl bisthiosemicarbazone (2,5 H2bttsc-N1-Me, 2H2L) and 2,5 thiophenedicarboxaldehyde -N1-phenyl bisthiosemicarbazone (2,5 H2bttsc-N1-Ph, 3H2L) in 1:1 (M:L) molar ratio yielded complexes of stoichiometry, [Cu(L)] 1-3 (1L, 1; 2L 2; 3L 3). All the complexes are characterized using elemental analysis FTIR, Mass and ESR spectroscopy. The two distinct g values, g‖ = 2.40 (1), 2.15 (2), 2.20 (3) and g⊥ = 2.08 (1), 2.07 (2), 2.12 (3) indicate axial symmetry for the complexes. The greater g‖ value than g⊥, confirms the presence of free electrons in dx2-y2 ground term in square planar geometry. The ligands (1H2L - 3H2L) and their complexes (1–3) were tested for DPPH radical scavenging, ABTS radical scavenging, FRAP ferric reducing, and CUPRAC cupric reducing antioxidant capacity assays. In general, all the ligands and their metal complexes exhibited moderate antioxidant potential, however 3H2L has shown best Cu2+ reducing activity (7.34 μg TE/ml) and ABTS radicals scavenging activity (IC50, 16.95) amongst all. Ligands (1H2L - 3H2L) and their complexes (1–3) were also evaluated for anti-tuberculosis activity against M. tuberculosis H37RV strain. It has been observed that with the increase of hydrophobicity of ligand due to substituent present at N1 atom, anti-TB activity increased (H, MIC = 6.25 µg/ml < Me, MIC = 3.12 µg/ml < Ph, MIC = 1.6 µg/ml). Molecular modeling studies have shown considerable intermolecular interaction of these compounds with minimum binding energy −5.8 (1H2L), −5.8 (2H2L), −9.6 (3H2L), −6.9 (1), −6.6 (2) and −9.6 (3) Kcal/ mol, which also supports the experimental data. Pharmacokinetics (effective transport of molecule to their target sites) was studied using drug-protein binding study of molecules with human serum albumin (HSA) was performed using UV–vis and fluorescence spectroscopy. The ligand 2H2L and complex 2 showed strong binding interactions with HSA having binding constant values of 4.24 × 105 M−1 and 4.92 × 105 M−1 respectively.

Naphtho[2,1-b]furan derived triazole-pyrimidines as highly potential InhA and Cytochrome c peroxidase inhibitors: Synthesis, DFT calculations, drug-likeness profile, molecular docking and dynamic studies

Napthofuran and its fused heterocyclic derivatives evaluated with varied biological activity functional groups comprise an important class of compounds for new chemical entities. We here in reporting synthesis of new 3-(4-substituted phenyl)naphtho[1′,2′:4,5]furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidines 6(a-f). 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 B3LYP hybrid functional with a 6–31+G (d, p) all-electron basis set using the Gaussian 09 package. The bioactivity predictions were evaluated for the synthesized compounds. The In vitro biological activities were reported for the all compounds 6(a-f). The compound 6a showed high activity of anti-TB and antioxidant activity with at MIC 1.6 μg/ml and at percentage of inhibition (72.54±0.21) at 10μg/ml respectively. The compound 6f (73.21±0.11) showed antioxidant activity better than standard drug BHA (71.32±0.13) at 10 μg/ml. Furthermore, the docking studies for the newly synthesized molecules were carried out by Auto dock software with proteins InhA (4TZK),Cytochrome c peroxidase (2 × 08) and protease (Mpro) of SARS-CoV-2 Omicron (PDB ID: 7TOB). All the compounds showed a strong binding affinity for the docked proteins. The outcome of docking results showed that compound 6ahad excellent binding energies -10.8, -9.4, and -9.0 kcal/mol with 4TZK, 2 × 08, and 7TOB respectively. Lastly, the protein stability, fluctuations of APO-Protein, protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified.