In vitro and ex vivo antitubercular activity of diarylheptanoids from the rhizomes of Alpinia officinarum Hance

Phytochemical investigation of methanol extract of the rhizomes of Alpinia officinarum Hance afforded four known diarylheptanoids 1,7-diphenylhept-4-en-3-one (1), 5-hydroxy-1,7-diphenyl-3-heptanone (2), 5-hydroxy-7-(4″-hydroxy-3″-methoxyphenyl)-1-phenyl-3-heptanone (3), and 7-(4″-hydroxy-3″-methoxyphenyl)-1-phenyl heptan-3-one (4).The acetate derivative of (4), 7-(4″-actetate-3″-methoxy phenyl)-1-phenyl heptan-3-one (5), was prepared. These diarylheptanoids exhibited promising in vitro and ex vivo antitubercular activity for the first time against dormant Mycobacterium tuberculosis H37Ra with the IC₅₀ values between 0.34–47.69 and 0.13–22.91 μM, respectively. All compounds showed comparable activity against Mycobacterium bovis BCG (dormant phage) and did not show any activity against two gram + ve and two gram –ve bacterial strains. These compounds were also weakly cytotoxic up to 300 μM against three human cancer cell lines THP-1, Panc-1 and A549.     

Antimicrobial Polyketide Metabolites from Penicillium bissettii and P. glabrum

Screening of several fungi from the New Zealand International Collection of Microorganisms from Plants identified two strains of Penicillium, P. bissettii and P. glabrum, which exhibited antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Further investigation into the natural products of the fungi, through extraction and fractionation, led to the isolation of five known polyketide metabolites, penicillic acid (1), citromycetin (2), penialdin A (3), penialdin F (4), and myxotrichin B (5). Semi-synthetic derivatization of 1 led to the discovery of a novel dihydro (1a) derivative that provided evidence for the existence of the much-speculated open-chained form of 1. Upon investigation of the antimicrobial activities of the natural products and derivatives, both penicillic acid (1) and penialdin F (4) were found to inhibit the growth of Methicillin-resistant S. aureus. Penialdin F (4) was also found to have some inhibitory activity against Mycobacterium abscessus and M. marinum along with citromycetin (2).     

Resonance raman spectra of poly‐(p‐phenylenebenzobisoxazole), poly‐(p‐phenylenebenzobisthiazole), and poly(pyridobisimidazole)

Resonance Raman spectra of poly(p‐phenylenebenzobisoxazole) (PBO), poly(p‐phenylenebenzobisthazole) (PBZT), and poly(pyridobisimidazole) (PIPD) were measured. In the case of PBO, no large dependence on wavelength of excited laser can be observed, whereas in the cases of PBZT and PIPD, the spectra depends on wavelength of excited laser. This difference may be attributed to the colors of the samples: PBO is gold, and PBZT and PIPD are metallic blue, which show the different conjugated states. The spectra of PBO are rather simpler than those of PBZT and PIPD. This is considered to be reflected by the fact that only a chain passes through the unit cell of PBO, while two chains pass through the unit cell of PBZT and PIPD. © 2001 John Wiley & Sons, Inc. J Polym Sci Part B: Polym Phys 39: 1791–1793, 2001     

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

Fidaxomicin ( 1 , lipiarmycin A3, clostomicin B1, tiacumicin B) constitutes a glycosylated 18-membered macrolactone and is a natural product isolated from various soil bacteria. Since 2011, fidaxomicin is a marketed antibiotic for the treatment of intestine infections caused by C. difficile in the clinic. Its promising in vitro antibacterial properties against resistant S. aureus and M. tuberculosis continue to attract interest. This review article describes the early history of the antibiotic fidaxomicin and highlights recent advances in the field, such as the elucidation of its mode of action and biosynthesis, as well as known derivatives. Furthermore, different synthetic strategies towards the total synthesis of fidaxomicin are summarized.     

An extensive review of studies on mycobacterium cell wall polysaccharide-related oligosaccharides – part II: Synthetic studies on complex arabinofuranosyl oligosaccharides carrying other functional motifs and related derivatives and analogs

Abstract

Lipoarabinomannan (LAM), mannosyl LAM (ManLAM), and mycolyl-arabinogalactan (mAG) are unique and ubiquitous cell wall constituents of Mycobacterium tuberculosis (M. tb), the bacterium causing tuberculosis (TB). It has been well documented that LAM, ManLAM, and mAG play an important role in mycobacterial infections and in the elicitation of specific immune responses against M. tb in the host. Therefore, LAM, ManLAM, mAG, and related molecules are attractive targets for the development of novel TB diagnostic and therapeutic strategies. Accordingly, numerous research groups have spent great effort on the chemical synthesis and biological studies of mycobacterium-related arabinofuranosyl oligosaccharides and their mimetics and conjugates. This article provides an extensive review about the progresses in this area. Due to the page limit of this journal, the review is published in three parts separately. This part (Part II) is focused on the synthesis of various ManLAM and mAG analogs containing mannose, galactose or galactosamine units and other natural structural motifs, as well as arabinofuranosyl oligosaccharide C-analogs and other derivatives.     

Synthesis and antimycobacterial screening of new 4-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-3-yl)quinoline derivatives

A new series of 4-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-3-yl)quinoline ( 6a-t ) have been synthesized by a click reaction of 4-(4-ethynyl-1-phenyl-1H-pyrazol-3-yl)quinoline ( 4a-d ) with a substituted benzyl azide ( 5a-e ). The starting alkyne derivatives 4a-d are obtained from Bestmann-Ohira reaction of 1-phenyl-3-(quinolin-4-yl)-1H-pyrazole-4-carbaldehyde and dimethyl(1-diazo-2-oxopropyl)phosphonate. The newly synthesized compounds are screened against M. tuberculosis H37Ra dormant and active, Escherichia coli, Pseudomonas fluorescence, Staphylococcus aureus and Bacillus subtilis strains at 30 μg/mL concentration. Most of the screened compounds showed good to moderate antibacterial activity against S. aureus, B. subtilis, and Mycobacterium tuberculosis H37Ra strains. The synthesized derivatives of quinolinyl-pyrazole-4-carbaldehyde and quinolinyl-pyrazole-4-ethyne reportd good to moderate activity against both strains of M. tuberculosis H37Ra. Ten derivatives of quinolinyl-pyrazole presented good activity against B. subtilis. These results suggested that further optimization and development of quinolinyl-pyrazolyl-1,2,3-triazole moeity could serve as lead compounds for antimycobacterial activity.     

Design,synthesis and biological evaluation of some 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives as selective DprE1 inhibitors

Abstract

Tuberculosis (TB) is an infectious disease and caused by various strains of mycobacteria. In the present study, pharmacophore model was developed using single ligand by ligand-based drug discovery approach. The key features responsible for DprE1 inhibitory activity were taken into consideration for developing pharmacophore. After the virtual screening, top 1000 hits were further subjected to docking study using GLIDE module, Schrödinger. Docking studies have shown promising interaction with amino residues with better glide score. Ligand-based drug design approach yielded a series of 15, 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives. All synthesized derivatives were characterized using NMR, mass, CHN analysis. The synthesized compounds were screened for In vitro antitubercular activity against Mycobacterium tuberculosis (H₃₇Rv). Four compounds, 5g (MIC-1.01?μM); 5i (MIC-0.91?μM); 5k (MIC-0.82?μM); and 5o (MIC-1.04?μM) has shown promising activity compared to MIC of standard isoniazid (INH) and DprE1 enzyme inhibition was compared to BTZ043. Two halogen-substituted compounds have exhibited drastic enzyme inhibition.     

“In vitro” activity of Melaleuca cajuputi against mycobacterial species

Abstract

The increasing incidence of resistance in tuberculosis and in atypical mycobacterial infections has prompted the search for alternative agents. We explored the antimycobacterial activity of Melaleuca cajuputi essential oil against tubercular and non tubercular mycobacterials isolates. The good activity observed towards M. cajuputi indicated that this essential oil might represent a promising antimicrobial agents, particularly in the management of microbial resistance.     

Ciprofloxacin–Isatin Hybrids and Their Antimycobacterial Activities

A series of diethylene glycol tethered ciprofloxacin–isatin hybrids 5a–j were designed, synthesized, and evaluated for their in vitro antimycobacterial activity against both drug‐sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains in this paper. The preliminary results revealed that all hybrids with greater lipophilicity than the parent ciprofloxacin displayed considerable activity against the tested strains with minimum inhibitory concentration (MIC) in a range of 1.56–64 μg/mL. In particular, hybrid 5f (MIC: 1.56 and 2 μg/mL) with low cytotoxicity in VERO cell line was comparable with the parent ciprofloxacin (MIC: 0.78 and 2 μg/mL) against M. tuberculosis H₃₇Rv and MDR tuberculosis strains and ≥16‐fold more potent than isoniazid and rifampicin (MIC: >128 and 32 μg/mL, respectively) against MDR tuberculosis, suggesting that it may serve as a new and promising candidate for further study.     

An extensive review of studies on mycobacterium cell wall polysaccharide-related oligosaccharides – part I: Synthetic studies on arabinofuranosyl oligosaccharides

Abstract

Lipoarabinomannan (LAM), mannosyl LAM (ManLAM), and mycolyl-arabinogalactan (mAG) are unique and ubiquitous cell wall constituents of Mycobacterium tuberculosis (M. tb), the bacterium causing tuberculosis (TB), one of the deadliest diseases worldwide. It has been well documented that LAM, ManLAM, and mAG play an important role in mycobacterial infections and in the elicitation of specific immune responses against M. tb in the host. Therefore, LAM, ManLAM, mAG, and related molecules are attractive targets for the development of novel diagnostic and therapeutic strategies for TB. Accordingly, great research efforts have been spent on the chemical synthesis and biological studies of mycobacterium-related arabinofuranosyl oligosaccharides and their mimetics and conjugates. This article provides an extensive review about the progresses in this area. Due to the page limit of the journal, this review is published separately in three parts. Part I is focused on various glycosylation methods or strategies and protection tactics for stereoselective and stereospecific construction of α- and β-arabinofuranosyl linkages, as well as their applications to the synthesis of simple to highly complex mycobacterium-related arabinofuranosyl oligosaccharides containing only α-linked or both α- and β-linked arabinofuranosyl residues.     

In vitro cytotoxicity evaluation of thiourea derivatives bearing Salix sp. constituent against HK-1 cell lines

Abstract

In searching for drugs from natural product scaffolds has gained interest among researchers. In this study, a series of twelve halogenated thiourea (ATX 1-12) via chemical modification of aspirin (a natural product derivative) and evaluated for cytotoxic activity against nasopharyngeal carcinoma (NPC) cell lines, HK-1 via MTS-based colorimetric assay. The cytotoxicity studies demonstrated that halogens at meta position of ATX showed promising activity against HK-1 cells (IC₅₀ value ≤15?µM) in comparison to cisplatin, a positive cytotoxic drug (IC₅₀ value =8.9?±?1.9?µM). ATX 11, bearing iodine at meta position, showed robust cytotoxicity against HK-1 cells with an IC₅₀ value of 4.7?±?0.7?µM. Molecular docking interactions between ATX 11 and cyclooxygenase-2 demonstrated a robust binding affinity value of ?8.1?kcal/mol as compared to aspirin’s binding affinity value of ?6.4?kcal/mol. The findings represent a promising lead molecule from natural product with excellent cytotoxic activity against NPC cell lines.     

Design and Synthesis of Imidazole and Triazole Pyrazoles as Mycobacterium Tuberculosis CYP121A1 Inhibitors

The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (K_D). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl ( 10 f ) and tert-butyl ( 10 g ) compounds displaying optimal activity (MIC 1.562 μg/mL, K_D 0.22 μM ( 10 f ) and 4.81 μM ( 10 g )). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5–6, molecular volume >340 ų, topological polar surface area <40 Ų.     

1H‐1,2,3‐Triazole‐tethered Isatin–coumarin Hybrids: Design,Synthesis and In Vitro Anti‐mycobacterial Evaluation

A series of novel 1H‐1,2,3‐triazole‐tethered isatin–coumarin hybrids 7a – l integrate three anti‐tuberculosis bioactive substances/pharmacophoric units including coumarin, isatin, and I ‐ A09 were designed, synthesized, and tested for their in vitro anti‐mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis H37Rv as well as cytotoxicity in VERO cell line. The results showed that all hybrids exhibited weak to moderate activity against the tested two strains with minimum inhibitory concentration ranging from 50 to 200 μg/mL.     

Additional synthesis on thiophene-containing trisubstituted methanes (TRSMs) as inhibitors of M. tuberculosis and 3D-QSAR studies

Abstract

We earlier reported thiophene-containing trisubstituted methanes (TRSMs) as novel cores carrying anti-tubercular activity, and identified S006-830 as the phenotypic lead with potent bactericidal activity against single- and multi-drug resistant clinical isolates of Mycobacterium tuberculosis (M. tb). In this work, we carried out additional synthesis of several TRSMs. The reaction scheme essentially followed the Grignard reaction and Friedel–Crafts alkylation, followed by insertion of a dialkylaminoethyl chain. We also performed microbiological evaluations including in vitro screening against the virulent strain M. tb H37Rv, cytotoxicity assessment in the Vero C-1008 cell line, and 3D-QSAR studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). CoMFA and CoMSIA models yielded good statistical results in terms of q² and r² values, suggesting the validity of the models. It was concluded that a para-substituted benzene ring with bulkier electron-donating groups and aminoalkyl chains are required for higher inhibitory capacity against M. tuberculosis. We believe that these insights will rationally guide the design of newer, optimal, TRSMs.     

Design,Synthesis, and Evaluation of Tetraethylene Glycol Tethered Ciprofloxacin–Isatin Hybrids as Novel Antitubercular Agents

A new set of tetraethylene glycol tethered ciprofloxacin–isatin hybrids 5a–l with greater lipophilicity than the parent ciprofloxacin was designed, synthesized, and screened for their in vitro antimycobacterial activity against drug‐sensitive Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant MTB strains as well as toxicity in a mammalian VERO cell line. The preliminary results revealed that all hybrids exhibited considerable activity against MTB H₃₇Rv with minimum inhibitory concentration in a range of 0.205–14.186 μg/mL. Especially, hybrid 5a with low cytotoxicity displayed highest activity against both drug‐sensitive MTB H₃₇Rv and two clinically isolates multidrug‐resistant MTB strains, suggesting that it may serve as a new and promising candidate for further study.     

MiR-144-3p is associated with pathological inflammation in patients infected with Mycobacteroides abscessus

Infection with rapidly growing nontuberculous mycobacteria is emerging as a global health issue; however, key host factors remain elusive. Here, we investigated the characteristic immune profiles of peripheral blood mononuclear cells (PBMCs) from patients infected with Mycobacteroides abscessus subsp. abscessus (Mabc) and M. abscessus subsp. massiliense (Mmass). Using an integrated analysis of global mRNA and microRNA expression profiles, we found that several inflammatory cytokines/chemokines [interleukin (IL)-1β, IL-6, C-X-C motif chemokine ligand 2, and C-C motif chemokine ligand 2] and miR-144-3p were significantly upregulated in PBMCs from patients compared with those from healthy controls (HCs). Notably, there was a strong correlation between the expression levels of miR-144-3p and proinflammatory cytokines/chemokines. Similarly, upregulated expression of miR-144-3p and proinflammatory cytokines/chemokines was found in macrophages and lungs from mice after infection with Mabc and Mmass. We showed that the expression of negative regulators of inflammation (SARM1 and TNIP3) was significantly downregulated in PBMCs from the patients, although they were not putative targets of miR-144-3p. Furthermore, overexpression of miR-144-3p led to a marked increase in proinflammatory cytokines/chemokines and promoted bacterial growth in macrophages. Together, our results highlight the importance of miR-144-3p linking to pathological inflammation during M. abscessus infection.Subject terms: Bacterial infection, Bacterial infection, Chemokines, Mechanisms of disease     

Rational design of InhA inhibitors in the class of diphenyl ether derivatives as potential anti-tubercular agents using molecular dynamics simulations

A series of diphenyl ether derivatives were developed and showed promising potency for inhibiting InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, leading to the lysis of Mycobacterium tuberculosis. To understand the structural basis of diphenyl ether derivatives for designing more potent inhibitors, molecular dynamics (MD) simulations were performed. Based on the obtained results, the dynamic behaviour in terms of flexibility, binding free energy, binding energy decomposition, conformation, and the inhibitor–enzyme interaction of diphenyl ether inhibitors were elucidated. Phe149, Tyr158, Met161, Met199, Val203 and NAD+ are the key residues for binding of diphenyl ether inhibitors in the InhA binding pocket. Our results could provide the structural concept to design new diphenyl ether inhibitors with better enzyme inhibitory activity against M. tuberculosis InhA. The present work facilitates the design of new and potentially more effective anti-tuberculosis agents.     

Synthesis and Biological Evaluation of Iodinated Fidaxomicin Antibiotics

Fidaxomicin ( 1 , tiacumicin B, lipiarmycin A3) is a marketed antibiotic that is used in the treatment of Clostridium difficile infections. Based on the analysis of a cryo-EM structure of fidaxomicin binding to its target enzyme (RNA-polymerase), a cation-π interaction of the aromatic moiety with an arginine residue was identified. Therefore, the variation of the substituents and concurrently changing the electronic properties of the aryl moiety represents an interesting strategy in the search for new fidaxomicin analogs. Herein, we report the first semisynthetic access to new fidaxomicin analogs with varying halogen substituents through a Pd-catalyzed hydrodechlorination reaction. Subsequent iodination gave access to the first iodo-fidaxomicin derivatives, which matched or improved antibacterial properties compared to fidaxomicin against Mycobacterium tuberculosis and Staphylococcus aureus ATCC 29213.     

Synthesis and Preliminary Screening of O-β-D-Galactopyranosides as Potential Mimic of UDP-Galp against Mycobacterium tuberculosis

O-Galactopyranosides were synthesized as potential mimics of uridine 5c-diphosphate galactopyranose (UDP-Galp), which is the substrate of the mutase enzyme involved in the mycobacterial cell wall biosynthesis by converting UDP-Galp to UDP-Galf. In vitro assay against the Mycobacterium tuberculosis H₃₇Rv strain gave promising results with minimum inhibitory concentration (MIC) values in the range of 3.13 to 25 μg/mL.     

Design,synthesis and biological evaluation of substituted 2-amino-1,3-thiazine derivatives as antituberculosis and anti-cancer agents

A series of substituted 2-amino-1,3-thiazines were synthesized as amides (9a–9i), carbamates (9j–9m), sulfonamides (9n–9o) and urea derivatives (9p–9q) by treating the compound 7 with acid chlorides (8a–8i), chloroformates (8j–8m), sulfonyl chlorides (8n–8o) and isocyanates (8p–8q) respectively. The synthesized compounds (9a–9q) were screened for antituberculosis activity against Mycobacterium tuberculosis H₃₇Rv ATCC 27294 and the results show that some of these derivatives possess good activity against Mycobacterium tuberculosis H₃₇Rv ATCC 27294. A few also display promising cytotoxic activity against human breast cancer MCF-7 and human esophageal cancer EC-9706 cell lines. Regarding both biological profiles 9b, 9m and 9h are the most active for anti-cancer, anti-TB activity.