Antituberculosis Activity Research Articles

Design, Synthesis, and Anti-tuberculosis Activity of Streptomycin Derivatives

Background: The treatment of tuberculosis has been a serious medical and health problem that needs to be solved urgently. Streptomycin has been one of the important anti-tuberculosis drugs for decades; however, no systematic structural modification of streptomycin has been done, which means that the anti-tuberculosis ability of streptomycin derivatives deserves further exploration. Objective: In this study, we investigated the effect of systematic structural modification of the aldehyde groups in streptomycin on its anti-tuberculosis activity. Methods: Streptomycin was selected as the lead compound, and its aldehyde group was modified to obtain hydrazone, amino hydrazide, and sulfonyl hydrazide derivatives, respectively. In addition, siderophore fragments were introduced into streptomycin. The anti-tuberculosis activities of the new compounds against H37Rv were evaluated. Results: A total of 21 novel streptomycin derivatives have been designed and synthesized. All compounds were characterized with 1H NMR, 13C NMR, and HRMS. The preliminary bioactivity test showed that most analogues bearing hydrazine, acylhydrazine, or sulfonyl hydrazine, such as 12a, 13a-d, and 15a-f, possessed potent anti-tuberculosis activity with MIC value of 2 μg/mL, which was comparable to streptomycin, while secondary amine or siderophore derivatives caused a dramatic reduction in activity. Conclusion: The structural modification and structure-activity relationship of the aldehyde group of streptomycin were systematically studied for the first time. The results showed that the aldehyde group was not necessary for exhibiting its activity. It was well tolerated when the aldehyde group was converted into hydrazine, acylhydrazine, or sulfonyl hydrazine. These novel analogues provide potential lead structures for further modification in the future.

Two new naturally dimers constituent from Indonesian Sesbania grandiflora plant and their bioactivity

Abstract A new dimer of natural isoflavonoid along with some known flavonoid compounds was successfully isolated from the roots of Indonesian Sesbania grandiflora plant using ethyl acetate extraction. The new compound specified as naturally bi-isoflavonoid with (4→6) inter-isoflavanyl linkage and four known flavonoids xenognosin B, liquiritigenin, 7,2′4′-trihydroxyisoflavone, demethylvestitol, and 1,1′-bi-2-naphthol was isolated and the antituberculosis activity of the compounds was studied. The structure of all compounds was elucidated with the aid of 1D and 2D NMR, UV spectroscopy, and HRESI mass spectrometry. The data obtained were also compared with the previous published data. Among compounds, 1,1′-bi-2-naphthol was found to exhibit the highest activity against Mycobacterium tuberculosis H37Rv with the MIC’s value of 10.9 µM while the biisoflavonoid with (4→6) inter-isoflavanyl linkage showed moderate activity with the MIC’s value of 92.2 nM, compared with isozianid as a positive control with the MIC’s value of 0.569 nM. It is worth to note that 1,1′-bi-2-naphthol and biisoflavonoid with (4→6) inter-isoflavanyl linkage were isolated for the first time from a natural source. Both compounds have been previously reported as synthetic compounds, which is synonymous with 3,4- trans-4-[(3S)-7,2′-dihydroxy-4′-methoxyisoflavan-6-yl]-7,2′-dihydroxy-4′-methoxyisoflavan and 1,1′-bi-2-naphthol, respectively. In this respect, the results of this study suggest that the roots of S. grandiflora is a potential source of new natural product compounds, with promising bioactivities.

ERK1/2-CEBPB Axis-Regulated hBD1 Enhances Anti-Tuberculosis Capacity in Alveolar Type II Epithelial Cells.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a global health crisis with substantial morbidity and mortality rates. Type II alveolar epithelial cells (AEC-II) play a critical role in the pulmonary immune response against Mtb infection by secreting effector molecules such as antimicrobial peptides (AMPs). Here, human β-defensin 1 (hBD1), an important AMP produced by AEC-II, has been demonstrated to exert potent anti-tuberculosis activity. HBD1 overexpression effectively inhibited Mtb proliferation in AEC-II, while mice lacking hBD1 exhibited susceptibility to Mtb and increased lung tissue inflammation. Mechanistically, in A549 cells infected with Mtb, STAT1 negatively regulated hBD1 transcription, while CEBPB was the primary transcription factor upregulating hBD1 expression. Furthermore, we revealed that the ERK1/2 signaling pathway activated by Mtb infection led to CEBPB phosphorylation and nuclear translocation, which subsequently promoted hBD1 expression. Our findings suggest that the ERK1/2-CEBPB-hBD1 regulatory axis can be a potential therapeutic target for anti-tuberculosis therapy aimed at enhancing the immune response of AEC-II cells.

Metal Catalyst-Free One-pot Synthesis of Carboxamide Derivatives via Ugi-4CC Reaction and Its Anti-tubercular Study

Background: A new series of ten composites with sulphur based carboxylic acid and benzylamine were synthesized by Ugi 4-components reaction (Ugi-4CR) and screened for antituberculosis activity against the Mycobacterium tuberculosis H37Rv strain. Objective: Target compounds were isolated, purified, identified, and characterized by MS, FT-IR, 1HNMR, APT, and 13C-NMR then the antituberculosis activity was examined by Microplate Alamar Blue Assay (MABA) method. Methods: This study was based on the articulation of carboxamide linkage bearing S-linkage in the core unit by reacting four different units, i.e., 2-(pyrimidin-2-ylthio)acetic acid, aromatic aldehyde, benzylamine and tertiary butyl isocyanide at RT in an atom economy route of synthesis. The desired product (5a- 5j) was synthesized via one-pot and Metal-free conditions. Results: Compounds (5a-5j) synthesized in good yields and compared to MIC values of Isoniazid 0.05 (μg/mL), Rifampicin 0.1 (μm/mL), and Ethambutol 1.56 (μg/mL) as a positive control. Conclusion: Synthesized compounds give excellent yield. Among the ten derivatives, compound 5f has comparable antituberculosis activity.

Synthesis of some chalcones derivatives series and their antituberculosis activity

Abstract Chalcone is an important biosynthetic precursor, due to the diverse pharmacological activities. The aim of this current study was to synthesize 14 new chalcone derivatives compounds by incorporating p-alkoxyacetophenones with substituted benzaldehydes. Two new series of chalcone derivatives have been synthesized using the alkylation and the base catalysed Claisen-Schmidt condensation. All the synthesized compounds were fully characterized by IR, 1D NMR (1H and 13C NMR) and 2D NMR (COSY, HMQC, HMBC) as well as mass spectrometry analysis. All the synthesized compounds were assayed in vitro for their antituberculosis activities against Mycobacterium tuberculosis strain. Among them, compounds (E)-1-[4-(heptoxy)phenyl]-3-(2-hydroxy-5-bromophenyl)prop-2-en-1-one (5a), (E)-1-[4-(octyloxy)phenyl]-3-(2-hydroxy-5-bromophenyl)prop-2-en-1-one (5b) and (E)-1-[4-(decyloxy)phenyl]-3-(2-hydroxy-5-bromophenyl)prop-2-en-1-one (5d) showed good activities with the lowest MIC value of 12.5 μg/mL.

Sudapyridine (WX-081) antibacterial activity against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo.

Due to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium chelonae during 2000-2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against M. avium, M. abscessus, and M. chelonae in vitro, in macrophages and mice, respectively.

An Overview of Diverse Biological Activities of Cinnoline Scaffold

Abstract: The cinnoline nucleus is a bicyclic ring and is an isosteric precursor to quinolone or isoquinoline. Cinnoline analogs are aromatic heterocyclic compounds having diverse therapeutic activities, such as antimicrobial, analgesic, anti-inflammatory, anti-tuberculosis, antimalarial, anticonvulsant, antioxidant, anticancer, antihypertensive, anti-anxiety, and other activities. This heterocyclic nucleus is attracting a lot of attention in medicinal chemistry and is used as a structural subunit in various compounds with attractive medicinal and chemical properties. In this review, we focus on the biological activities of cinnoline analogs with various substitutions.

Synthesis, Antioxidant and Antituberculosis Evaluation of Eugenol Derivatives from Mannich Condensation

AbstractMannich bases are interesting class of molecules thanks to their various pharmacological properties. This paper presents the synthesis and characterization of eugenol derivatives following Mannich condensation. The in vitro antituberculosis activity of the synthesized derivatives was evaluated by the Resazurin microtiter assay (REMA). The 2,2′‐diphenyl‐1‐picrylhydrazyl (DPPH) free radical scavenging and ferrous cation (FeCl2) chelating tests were used to estimate the antioxidant capacity. All eugenol Mannich bases inhibited the Mycobacterium tuberculosis (Mtb) H37Rv growing. Those of 2‐dimethylaminomethyl‐6‐methoxy‐4‐propenylphenol (1) and 2‐methoxy‐4‐propenyl‐6‐pyrrolidinylmethylphenol (4) were the most active at 10 μg/mL. Additionally, significant antioxidant profile was exhibited by the synthesized derivatives, especially for 2‐dicyclohexylaminomethyl‐6‐methoxy‐4‐propenylphenol (5) that showed an antiradical activity of EC50=20 μg/mL, twice as strong as that of eugenol precursor, and for 2‐methoxy‐6‐methylpiperazinylmethyl‐4‐propenylphenol (3) and compound 4, which were promising iron chelators with EC50 of 0.016 and 0.018 mg/mL, respectively, better than EDTA standard. The molecular docking experiments on two different antituberculosis receptors showed excellent binding affinity of compounds 4 and 5 into the active site of pantothenate kinase (PanK, type I), suggesting PanK as potential molecular target. These encouraging findings showed the importance of Mannich reaction for the development of antitubercular candidates and the improvement of natural products bioactivity.

Cinnamate-amine hybrids: Antituberculosis activity and molecular docking

Antituberculosis activity and molecular docking experiments were performed on 14 cinnamate-amine hybrids. Cinnamamides 1a,b,c,d,i,j effectively inhibited the growth of Mycobacterium tuberculosis H37Rv, with cinnamamide 1c having the highest inhibition effects with a minimum inhibitory concentration value of 3.13 μg/ml. Based on the docking results, the molecule of cinnamamide 1c (binding energy of −4.13 kcal/mol) was found to be stretched from the edge of the active site to its sub-binding pocket, referred to as an extended conformation when binding to the InhA active site. Cinnamamide 1c turned out to be an inhibitor whose potency is unaffected by the conserved interaction network with the catalytic residue Tyr158. These findings suggest these cinnamate-amine hybrids as potential lead compounds in developing new antituberculosis drugs.

Synthesis, biological evaluation, and In silico molecular docking of N-(4-(4-substitutedphenyl)-6-(substituted aryl) pyrimidin-2-yl)-2-(2-isonicotinoyl hydrazinyl) acetamide.

Isonicotinohydrazide is the first-line medication in the prevention and treatment of tuberculosis. Antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial activity, anticancer, antineoplastic activity, and anti-HIV activity are all demonstrated by drugs with a pyrimidine ring. The current study focuses on the synthesis of N-(4-(substituted-phenyl)-6-(substituted-aryl) pyrimidin-2-yl)-2-(2-isonicotinoylhydrazinyl) acetamide from isonicotinohydrazide. Newly synthesized compounds were characterized by spectral studies (IR, 1 H-NMR, 13 C-NMR, and mass spectroscopy). They were screened for their antituberculosis, antimalarial, and antiprotozoal activities and compared with standard drugs. Molecular docking of isonicotinohydrazide-bearing pyrimidine motifs was also done for some of the active compounds.

Anti-tuberculosis activity of morusin: a promising flavonoid from white mulberry.

BACKGROUND: TB has remained a significant public health concern from historical times to the present day. Each year, growing drug resistance problems necessitate the discovery of new drugs and drug precursors for TB treatment. Morusin is an important flavone found in the bark of white mulberry (Morus alba L.) with anti-oxidant, antimicrobial, anti-tumour, anti-inflammatory and antiallergic activity.OBJECTIVE: To determine the anti-TB efficacy of morusin on Mycobacterium tuberculosis strains.DESIGN: Anti-TB efficacy of morusin was tested on H37Ra (American Type Culture Collection [ATCC] 25177), H37Rv (ATCC 27294), ATCC 35822 (isoniazid [INH] resistant), ATCC 35838 (rifampicin [RIF] resistant), and ATCC 35820 (streptomycin [SM] resistant) standard strains and its efficacy was determined using nitrate reductase assay (NRA).RESULTS: The minimum inhibitory concentration (MIC) of morusin was tested in the range of 53.83â-"0.21 μg/ml. The MIC for H37Ra (ATCC 25177), H37Rv (ATCC 27294) and ATCC 35838 (RIF-resistant) strains were found to be 6.72 μg/ml, and this was 13.45 μg/ml for the ATCC 35822 (INHresistant) and ATCC 35820 (SM-resistant) strains.CONCLUSION: To consider morusin as a viable alternative or precursor drug for TB treatment, it is imperative to conduct an exhaustive examination of its mechanism of action and conduct in vitro studies using clinical isolates.

Jolkinolide B ameliorates rheumatoid arthritis by regulating the JAK2/STAT3 signaling pathway

BackgroundJolkinolide B (JB), an ent‑abietane-type diterpenoid in Euphorbia plants, has various pharmacological activities, including anticancer, anti-inflammatory, and anti-tuberculosis activities. However, no previous studies have proven whether JB can be regarded as a targeted drug for the treatment of rheumatoid arthritis (RA). PurposeThis study aimed to evaluate the anti-RA effects of JB and explore the potential mechanisms. MethodsComponents and targets of JB and RA were identified in different databases, and potential targets and pathways were predicted by protein-protein interaction (PPI) network analysis and pathway enrichment analysis. Then, molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The anti-arthritic effects of JB were studied in vivo with collagen-induced arthritis (CIA) rat model and in vitro with lipopolysaccharide (LPS) and interleukin-6 (IL-6)-induced RAW264.7 macrophage. Potential mechanisms were further verified by in vivo and in vitro experiments. ResultsThe Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that Th17 cell differentiation, prolactin signaling pathway, and JAK/STAT signaling pathway might be associated with anti-RA effects of JB. Molecular docking and SPR results showed that JB bound effectively to JAK2. JB significantly decreased body weight loss, arthritis index, paw thickness, and synovial thickness in CIA rats. Histomorphological results suggested the protective effects of JB on CIA rats with ankle joint injury. Molecular biology analysis indicated that JB suppressed the mRNA expression of inflammatory factors in ankle joints for CIA rats and reduced the concentration of these factors in LPS- induced RAW264.7 macrophage. The protein expression level of the JAK2/STAT3 pathway was also significantly decreased by JB. ConclusionJB had a novel inhibitory effect on inflammation and bone destruction in CIA rats, and the mechanism might be related to the JAK2/STAT3 signaling pathway.

Synthesis and antituberculosis activity of new 5-alkynyl derivatives of 2-thiouridine: application of new scaffold

We herein describe new potent inhibitors of mycobacteria based on 5-substituted 2-thiouridine derivatives. A series of new 5-alkynyl-substituted 2-thiouridine derivatives were synthesized via palladium-catalysed Sonogashira cross-coupling reaction of 5-iodo-2-thiopyrimidine base with terminal acetylenes with good yields in DMF at room temperature. It was found that sulfur atom in C2 position of pyrimidine ring had no impact on yields of target compounds. All obtained compounds were evaluated for their antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis at concentrations of 0.1-100 µg/ml using MABA test. Synthesized nucleosides showed high antimycobacterial activity against Mycobacterium bovis and Mycobacteri um tuberculosis. The obtained MIC50 values of 2-thionucleosides 14, 15 and 16 (0.28-0.75 µg/ml) significantly exceed characteristics of reference drug rifampicin, D-cycloserine and isoniazid, which gives prerequisites for further more detailed studies.

Pyrazole Scaffolds Having Promising Pharmacological Potential: A Review.

Heterocyclic compounds have diverse structure, which makes them broad and economical therapeutic agents. Pyrazole is a five-membered aromatic ring that contains two nitrogen atom and is responsible for the diverse functions of heterocyclic compounds. This implies the need of reviewing the work that already has been done on the potential of pyrazole scaffolds in the field of medicinal chemistry for the synthesis of new compounds with more effective antimicrobial, antioxidant, anticancer, anti-tuberculosis, and anti-inflammatory activities.

Crystallization of isoniazid in choline-based ionic liquids: Physicochemical properties and anti-tuberculosis activity

Isoniazid is a drug commonly employed in the treatment of tuberculosis. One major barrier to its widespread use is that it can undergo hydrolysis when stored inadequately, resulting in the formation of hydrazine, a toxic and carcinogenic compound. Therefore, there is a clear need for further research aimed at improving the stability of isoniazid while still maintaining its therapeutic efficiency and solubility. To this end, five choline ionic liquids (ILs) were used for synthesizing improved forms of isoniazid: (2-hydroxyethyl)-trimethylammonium hydroxide [ChOH], (2-hydroxyethyl)-trimethylammonium hydrogen sulfate [ChBis], (2-hydroxyethyl)-trimethylammonium acetate [ChAc], (2-hydroxyethyl)-trimethylammonium citrate [ChCit], and (2-hydroxyethyl)-trimethylammonium benzoate [ChBenz]. The INH:[ChOH] and INH:[ChCit] forms were obtained in powder form, and presented low solubility and a minimum inhibitory concentration for Mycobacterium tuberculosis of 100 μg/mL and 12.5 μg/mL, respectively. The INH:[ChBenz], INH:[ChBis], and INH:[ChAc] forms showed a minimum inhibitory concentration value lower than 6.2 µg/mL. In the process using [ChBis], 2-(4-pyridiniumcarbonyl)-hydrazine sulfate with a water solubility of 155.9 mg/mL at 25 °C was produced, which showed to be more soluble than isoniazid (137.9 mg/mL). Therefore, the IL used had a direct influence on the solubility, conformational structure, and stability of isoniazid. This research is highly relevant and innovative for the use of new solvents in the crystallization of drugs, especially when aiming at the improvement of their properties.

New Complexes of Isoniazid Derivative with 3d Metals: Synthesis, Structure and Molecular Docking

This article reports the results of our study aimed at synthesizing and describing the structure and properties of new transition metal complexes with potential anti-tuberculosis and other related activities. For the first time, five bis-complexes of the ligand N’-(1-(6-methylpyridine-2-yl)ethylidene)isonicotinohydrazide (LH) with ions of five 3d metals (Cu(II), Mn(II), Co(II), Ni(II), and Zn(II)) were synthesized. The structures of all synthesized complexes in crystalline form were identified by X-ray diffraction (XRD) analysis. The resulting compounds were characterized by NMR, mass spectrometry, and electron spectroscopy. DFT/PCM calculations were performed on the structures of the five ML(OH) hydroxocomplexes formed during the hydrolysis of ML2 complexes in an aqueous medium within the physiological pH range. The binding energies of the ML(OH) complexes with the biotarget, the InhA protein of the Mycobacterium tuberculosis strain, were determined by molecular docking. The data obtained suggest that the studied complexes have high biological activity and warrant further biomedical research.

Benzothiozinone derivatives with anti-tubercular Activity−Further side chain investigation

A series of novel benzothiozinone (BTZ) derivatives were designed, prepared and evaluated for antituberculosis activity. Specifically, the BTZ pharmacophore is retained and the previous heterocyclic ring linker is replaced by alkynyl or vinyl linker, the resulting compounds displayed about 5−fold improved antimycobacterial activity. We further revealed that the linker attached tail group affects the compound metabolic stability, potency and other drug like properties. This work led to the discovery of two compounds (A1 and A11) with acceptable low MICs and improved metabolic stability. The representative compound A11 demonstrated bactericidal efficacy in an acute TB infection mouse model.

Synthesis, characterization and biological activities of novel Schiff base ligand and its Co(II) and Mn(II) complexes

Azomethine, as an active biological component, has a broad scope of pharmacokinetics actions. Metal ions play a vital character in the human anatomy. In the area of biomedical engineering, the significance of metal complexes of Azomethine has been recognized. Herein, (Z)-2-(2-methyl-1-phenylpropylidene)hydrazine-1-carbothioamide ligand and its Co(II) and Mn(II) complexes have been synthesized. The synthesized complexes were characterized by physical and spectral characterization techniques such as Nuclear Magnetic Resonance, Fourier Transform Infrared, Mass, X-ray Diffraction. The Schiff ligand and its metal compounds have been evaluated for antimicrobial, antituberculosis, and anticancer activities. Although the azomethine ligand exhibit antimicrobial potency, the metal complexes were proved better antibacterial agents than the ligand, particularly Mn(II) complexes against Staphylococcus aureus (S. aureus). All the synthesized metal compounds revealed fairly good antifungal potency towards Aspergillus fumigatus (A. fumigatus) than Candida albicans (C. albicans). CoCl2 and MnCl2 showed good antituberculosis activity against MtbC-1565, and the complex synthesized by CoCl2 showed good antitumor activity against cervix HeLa cell lines.

GaMF1.39's antibiotic efficacy and its enhanced antitubercular activity in combination with clofazimine, Telacebec, ND-011992, or TBAJ-876.

New drugs are needed to combat multidrug-resistant tuberculosis. The electron transport chain (ETC) maintains the electrochemical potential across the cytoplasmic membrane and allows the production of ATP, the energy currency of any living cell. The mycobacterial engine F-ATP synthase catalyzes the formation of ATP and has come into focus as an attractive and rich drug target. Recent deep insights into these mycobacterial F1FO-ATP synthase elements opened the door for a renaissance of structure-based target identification and inhibitor design. In this study, we present the GaMF1.39 antimycobacterial compound, targeting the rotary subunit γ of the biological engine. The compound is bactericidal, inhibits infection ex vivo, and displays enhanced anti-tuberculosis activity in combination with ETC inhibitors, which promises new strategies to shorten tuberculosis chemotherapy.

A review on plants possesses anti tubercular activity

Tuberculosis is an infectious disease condition that mainly affects the lungs, and the responsible bacteria is . Over 4,000 people each day die from this disease, which also claims 1.2–1.5 million lives annually and has infected 1.7–2 billion individuals globally. The literature review was conducted by studying the research papers and review articles concentrating on the traditional plants having “Antituberculosis activity or anti-mycobacterial activity”, in electronic databases like PubMed, Science Direct, Scopus, and Google Scholar. The available synthetic therapy for tuberculosis treatment includes first-line treatment of five drugs namely “Isoniazid, Rifampicin, Ethambutol, Pyrazinamide, and Streptomycin. The synthetic drugs used in the treatment of tuberculosis result in hepatotoxicity and also cause resistance against bacteria, resulting in MDR TB and XDR TB. Plant-derived drugs have potent activity against tuberculosis bacteria also they give hepatoprotective activity, unlike the synthetic drugs with no resistance against the bacteria. Medicinal plant products are good alternatives to allopathic medicine with fewer side effects and with less chances of resistance. Because polyherbal formulation act by different mechanisms to inhibit the growth of bacteria. More research is required to explore the plant-based treatment of TB.