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Objectives: Rifampin (RIF), isoniazid (INH) and pyrazinamide (PZA) are essential components of the short-term first-line anti-tuberculosis (anti-TB) chemotherapy regimen and can cause hepatotoxicity. However, the mechanism of anti-TB drug-induced hepatotoxicity (ATDH) is currently unclear. We investigate the relevant contributions to liver injury and the pathway of the above-mentioned drugs administered alone or in combination., Methods: UPLC-Q-TOF/MS-based metabolomics, bile acids (BAs) analysis and FXR/SHP detection were used to evaluate the toxicity of these drugs and clarify the underlying metabolism-related pathway., Results: In C57BL/6 mice administered the corrected clinical doses, RIF, INH and PZA could induced hepatotoxicity; with less toxicity in the combination therapy than RIF. The pathological biochemistry, BAs concentration and metabolically regulated FXR/SHP gene expression analyzes in mice were consistent with the metabolomics results. FXR played a role in the hepatotoxicity of anti-tuberculosis drugs in the obeticholic acid treated and FXR -/- mice. Additionally, the purine and lipid metabolic pathways were involved in ATDH., Conclusion: ATDH was involved in bile acids and lipid and purine metabolism. The BAs metabolic pathway involvement in mice was validated in TB patients. The noninvasive metabolomics approach is more systemic than routine toxicity evaluation and can be used to assess compound toxicity and the underlying mechanism.

Tuberculosis remains a significant infectious lung disease that affects millions of patients worldwide. Despite numerous existing drug regimens for tuberculosis, drug-induced liver injury is a major challenge that limits the effectiveness of these therapeutics. Two drugs that form the backbone of the commonly administered quadruple antitubercular regimen, that is, pyrazinamide (PZA) and isoniazid (INH), are associated with such hepatotoxicity. Yet, we lack safe and effective alternatives to the antitubercular regimen. Consequently, current research largely focuses on exploiting the hepatoprotective effect of nutraceutical compounds as complementary therapy. Silibinin, a herbal product widely believed to protect against various liver diseases, potentially provides a useful solution given its hepatoprotective mechanisms. In our study, we identified silibinin's role in mitigating PZA- and INH-induced hepatotoxicity and elucidated a deeper mechanistic understanding of silibinin's hepatoprotective ability. Silibinin preserved the viability of human foetal hepatocyte line LO2 when co-administered with 80 mM INH and decreased apoptosis induced by a combination of 40 mM INH and 10 mM PZA by reducing oxidative damage to mitochondria, proteins, and lipids. Taken together, this proof-of-concept forms the rational basis for the further investigation of silibinin's hepatoprotective effect in subsequent preclinical studies and clinical trials.

Experimental studies of Perchlozone, an antituberculous drug with manifest inhibitory activity towards Mycobacterium tuberculosis and Mycobacterium bovis, were carried out. Genotoxicity of Perchlozone was evaluated by the DNA comet method on liver and lung tissues and blood cells after 14-day inhalation exposure of rats. The level of DNA aberrations in response to inhalations of the drug in a concentration of 102.6±13.7 mg/m 3 increased in lung tissue but not in the blood cells or liver. These results indicated genotoxic activity of antituberculous drug Perchlozone.

Tuberculous meningitis (TBM) is the most devastating form of TB, resulting in death or neurological disability in up to 50% of patients affected. Treatment is similar to that of pulmonary TB, despite poor cerebrospinal fluid (CSF) penetration of the cornerstone anti-TB drug rifampicin. Considering TBM pathology, it is critical that optimal drug concentrations are reached in the meninges, brain and/or the surrounding CSF. These type of data are difficult to collect in TBM patients. This review aims to identify and describe a preclinical model representative for human TBM which can provide the indispensable data needed for future pharmacological characterization and prioritization of new TBM regimens in the clinical setting. We reviewed existing literature on treatment of TBM in preclinical models: only eight articles, all animal studies, could be identified. None of the animal models completely recapitulated human disease and in most of the animal studies key pharmacokinetic data were missing, making the comparison with human exposure and CNS distribution, and the study of pharmacokinetic-pharmacodynamic relationships impossible. Another 18 articles were identified using other bacteria to induce meningitis with treatment including anti-TB drugs (predominantly rifampicin, moxifloxacin and levofloxacin). Of these articles the pharmacokinetics, i.e. plasma exposure and CSF:plasma ratios, of TB drugs in meningitis could be evaluated. Exposures (except for levofloxacin) agreed with human exposures and also most CSF:plasma ratios agreed with ratios in humans. Considering the lack of an ideal preclinical pharmacological TBM model, we suggest a combination of 1. basic physicochemical drug data combined with 2. in vitro pharmacokinetic and efficacy data, 3. an animal model with adequate pharmacokinetic sampling, microdialysis or imaging of drug distribution, all as a base for 4. physiologically based pharmacokinetic (PBPK) modelling to predict response to TB drugs in treatment of TBM., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Isoniazid and rifampicin are well-known anti-mycobacterial agents and are widely used to treat pulmonary tuberculosis (TB) as part of the combined therapy approach, recommended by the World Health Organization. The ingestion of these first-line TB drugs are, however, not free of side effects, and are toxic to the liver, kidney, and central nervous system. These side effects are associated with poor treatment compliance, resulting in TB treatment failure, relapse and drug resistant TB. This occurrence has subsequently led to the recent application of novel research technologies, towards a better understanding of the underlying toxicity mechanisms of TB drugs in humans, mostly focussing on the 2 most important TB drugs: isoniazid and rifampicin. In this review, we discuss the contribution that one such an approach, termed metabolomics has made toward this field, and also highlight the impact that this might have towards the development of improved TB treatment regimens., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The series of new 4-substituted picolinohydrazonamides were synthesized (6-25) and evaluated for tuberculostatic activity. Compounds having a hydrophilic cyclic amine such as morpholine and pyrrolidine at the end of the thiosemicarbazide chain, exhibited the highest antimycobacterial activity. The antimycobacterial activity of compounds 6, 11, and 15 (MIC 0.4-0.8 μg/mL) was higher than that of reference drugs. Moreover, derivative 15 exhibited lower activity against other tested microorganism such as bacteria gram-positive, gram-negative or fungi. Thus, this compound is characterized by the selectivity of antimicrobial activity. Antiproliferative study conducted against human dermal fibroblasts (HDF) and mouse melanoma cell line (B16-F10) revealed low cytotoxicity of compound 15. Conducted research allowed to identify compound 15 as leading for further research., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Combined antituberculosis substances induced a dose-dependent changes in activity of dehydrogenases and hydrolases in rat lymphocytes. The main toxic effect of the substances was related to inhibition of mitochondrial dehydrogenases (succinate dehydrogenase and α-glycerol phosphate dehydrogenase) usually followed by suppression of activity of hydrolytic enzymes (acid phosphatase and non-specific esterase). Opposite changes in lactate dehydrogenase activity reflected specific features of intoxication.

Owing to its traditional applications, the current study focuses on Ajuga parviflora (A. parviflora) leaves extract for phytochemical and pharmacological analysis. The principle constituents were identified through gas chromatography (GC), and gas chromatography/mass spectroscopy (GC/MS), these includes phthalic acid, squalene, α-tocopherol, vitamin E, phytol, 2-methylenecholestan-3-ol, stigmasterol, cholest-22-ene-21-ol and 3,5-dehydro-6-methoxy. Hepatoprotective effect of A. parviflora was evaluated through isoniazid and rifampicin (INH and RFP) induced hepatotoxicity in rat. Animals in group A were treated with INH and RFP 50 mg/kg. Animals in group B, C, and D were pre-treated with A. parviflora extract at 100, 200 and 300 mg/kg dose prior drug administration. A. parviflora extract at 200 and 300 mg/kg in group C and D significantly reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and bilirubin (p<0.001) as compare to group B (100mg/kg). Total protein (TP) was also significantly (p<0.01) reduced in group C and D at dose of 200 and 300 mg/kg, respectively. The extract pre-treated animals with (A. parviflora, 200, and 300 mg/kg) showed that the epithelium of the central portal vein is intact with replete glucagon. The pre-treatment with A. parviflora protected the liver from INH and RFP induced hepatotoxicity. The results of pre-treated animals with A. parviflora 200, and 300 mg/kg dose prettily revert the severely disturb parameters like, cytolysis, lymphocytic infiltration, and lymphoid aggregate in portal vein and hydropic degeneration. The decrease peroxisome proliferator-receptor activator-δ (PPAR-δ) gene expression by INH, and RFP was significantly up regulated by A. parviflora extract in pre-treated animals at 200 and 300 mg/kg dose. These findings provide baseline pharmacological uses of A. parviflora in liver disorders. Further investigations are required for identification and isolation of biologically active components responsible for pharmacological activity.

Prepubertal Swiss albino mice of both sex were administered with first-line anti-tuberculosis drugs (ATDs) viz; rifampicin, isoniazid, pyrazinamide, streptomycin and ethambutol intraperitoneally, for 4 weeks. Two weeks after the completion of treatment, male mice were sacrificed to collect caudal spermatozoa and female mice were superovulated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) to collect metaphase II (MII) oocytes from oviduct. Administration of ATDs not only decreased the count, motility and, nuclear maturity and also, increased the head abnormalities, mitochondrial damage and DNA damage in epididymal spermatozoa. Reduction in number of ovulated oocytes, increased degeneration rate and altered distribution pattern of cytoplasmic organelles was observed in oocytes of female mice. Presence of ATDs in in vitro maturation (IVM) medium increased abnormalities in meiotic resulted in abnormal spindle organization (except ethambutol) without affecting nuclear maturation. In conclusion, the result of this study indicates that ATDs have considerable adverse effects on the functional competence of male and female gametes, however, with varied degree of toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, but produce undesirable side effects at clinically relevant doses. We have previously modified four novel phenothiazines and maintained their antimycobacterial activity. This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safet use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment with PTZ31 resulted in 20% mortality with no toxicity evident in biochemical or histological analysis, while exposure to PTZ32 resulted in a 45% survival with increased serum concentrations of uric acid and alkaline phosphatase. The combined non-neuroleptic and antimycobacterial effects of the novel phenothiazines PTZ3, PTZ4, PTZ31 and PTZ32 demonstrated favourable pharmacological and toxicity profiles in this study, highlight the potential of these compounds as suitable anti-tuberculosis drug candidates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recent disclosures about anti-bacterial and anti-tubercular potential of naphthalimide and quinoline core respectively propelled us to synthesize a library of 1,8-naphthalimide-7-chloroquinoline hybrids. Different modes of linkage between two pharmacophoric units viz. simple alkyl chains and induction of amide bond were used and the substituents on the naphthalimide core were varied in order to determine Structure-Activity-Relationship (SAR). Our findings demonstrated that simple alkyl chain linked conjugates showed better activity profiles without any cytotoxicity, while the inclusion of amide bond enhanced the cytotoxic tendency. An interesting behaviour of conjugates in terms of activity and cytotoxicity was observed via switching over the nature of linker between two pharmacophores., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of gatifloxacin-1,2,3-triazole-isatin hybrids 8a-l were designed, synthesized, and screened for their in vitro antimycobacterial activity as well as cytotoxicity toward Chinese Hamster Ovary (CHO) cells. The synthesized hybrids showed considerable activity against MTB H 37 Rv and two MDR-MTB strains with minimal inhibitory concentration (MIC) of 0.25-8 μg/ml, and the hybrid 8a (MIC MTB H37Rv : 0.25 μg/ml and MIC MDR-MTB : 0.5 and 1 μg/ml) was found to be most active against the tested strains, which was not inferior to the parent gatifloxacin (MIC: 0.5, 0.25, and 0.5 μg/ml) against all three tested strains, and was ≥128-fold more active than isoniazid (MIC: ≥64 μg/ml) and rifampicin (MIC: >128 μg/ml) against the two MDR-MTB strains. Moreover, hybrid 8a (CC 50 : 8.0 μg/ml) also displayed acceptable cytotoxicity toward CHO cells, and the selectivity index was 32. The structure-activity relationship and structure-cytotoxicity relationship were also enriched., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

Curcumin is a plant diphenylheptanoid and has been investigated for its antibacterial activity. However, the therapeutic uses of this compound are limited due to its chemical instability. In this work, we evaluated the antimicrobial activity of diphenylheptanoids derived from curcumin against Gram-positive and Gram-negative bacteria, and also against Mycobacterium tuberculosis in terms of MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values. 3,3'-Dihydroxycurcumin (DHC) displayed activity against Enterococcus faecalis, Staphylococcus aureus and M. tuberculosis, demonstrating MIC values of 78 and 156 µg/mL. In addition, DHC was more stable than curcumin in acetate buffer (pH 5.0) and phosphate buffer (pH 7.4) for 24 h at 37 °C. We proposed that membrane and the cell division protein FtsZ could be the targets for DHC due to that fact that curcumin exhibits this mode of antibacterial action. Fluorescence microscopy of Bacillus subtilis stained with SYTO9 and propidium iodide fluorophores indicated that DHC has the ability to perturb the bacterial membrane. On the other hand, DHC showed a weak inhibition of the GTPase activity of B. subtilis FtsZ. Toxicity assay using human cells indicated that DHC has moderate capacity to reduce viability of liver cells (HepG2 line) and lung cells (MRC-5 and A549 lines) when compared with doxorubicin. Alkaline comet assay indicated that DHC was not able to induce DNA damage in A549 cell line. These results indicated that DHC is promising compound with antibacterial and antitubercular activities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tuberculostatic drugs are the most common drug groups with global hepatotoxicity. Awareness of potentially severe hepatotoxic reactions is vital, as hepatic impairment can be a devastating and often fatal condition. The treatment problems that may arise, within this class of medicines, are mainly of two types: adverse reactions (collateral, toxic or hypersensitive reactions) and the initial or acquired resistance of Mycobacterium tuberculosis to one or more antituberculosis drugs. Prevention of adverse reactions, increase treatment adherence and success rates, providing better control of tuberculosis (TB). In this regard, obtaining new drugs with low toxicity and high tuberculostatic potential is essential. Thus, in this work, we have designed or synthesized new derivatives of isoniazid (INH), such as new Isonicotinoylhydrazone (INH-a, INH-b and INH-c). These derivatives demonstrated good biocompatibility, antimicrobial property similar to that of parent isoniazid and last but not least, a significantly improved Pharmacotoxicological profile compared to that of isoniazid., (Copyright © 2019 Elsevier B.V. All rights reserved.)

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 μM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 μM). Compound 8b exhibited remarkable GI 50 values ranging from 0.57 to 12.4 μM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI 50  = 0.57 and 1.28 μM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 μM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L 2- , H 2 L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF 6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF 6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO 3 (3), [Fe(L)(amphen)]PF 6 (3a), [Fe(L)(Clphen)]PF 6 (4), [Fe(L)(epoxyphen)]PF 6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO 3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, 1 H and 13 C NMR and fluorescence spectroscopies. [Fe(phen)Cl 3 ] and [Fe(amphen)Cl 3 ] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies., (Copyright © 2019. Published by Elsevier Masson SAS.)

Isoniazid (INH) is a first-line anti-tuberculosis drug. INH has been detected in surface waters which may create a risk to aquatic organisms. In this study, the hepatotoxicity of INH was elucidated using zebrafish. The liver morphology, transaminase level, redox-related enzyme activity, reactive oxygen species (ROS) content and mRNA levels of liver injury-related genes were measured. The results showed that INH (4, 6 mM) significantly caused liver atrophy and increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in zebrafish. INH (6 mM) led to decreased catalase (CAT) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) content but increased ROS and malondialdehyde (MDA) levels. Moreover, INH (6 mM) decreased expression levels of miR-122 and pparα but increased mRNA levels of ap-1 and c-jun. Furthermore, mRNA levels of factors related to endoplasmic reticulum stress (ERS) (grp78, atf6, perk, ire1, xbp1s and chop), apoptosis (bax, cyt, caspase-3, caspase-8 and caspase-9) and the Nrf2 signalling pathway (nrf2, ho-1, nqo1, gclm and gclc) were significantly upregulated. INH may act on hepatotoxicity in zebrafish by increasing ROS content, which weakens the antioxidant capacity, leading to ERS, cell apoptosis and liver injury. In addition, the Nrf2 signalling pathway is activated as a stress compensation mechanism during INH-induced liver injury, but it is not sufficient to counteract INH-induced hepatotoxicity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Due to the emergence of multidrug-resistant and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis, new antituberculosis drugs are urgently required to improve the efficacy of current tuberculosis (TB) treatment. To achieve this goal, ca. 1000 chemical compounds were screened for potential antimycobacterial activity, among which methyl 5-(2-diethylaminoethoxy)-7,12-dioxo-7,12 dihydrodinaphtho[1,2-b;2',3'-d]furan-6-carboxylate (DNF-3) showed strong activity against all of the tested drug-susceptible and -resistant M. tuberculosis strains, with 50% minimum inhibitory concentrations (MIC 50 values) of 0.02-0.39 µg/mL both in culture broth and within murine RAW 264.7 macrophage cells. When DNF-3 was used in combination with rifampicin or streptomycin, it exhibited direct synergy against XDR-TB and an additive effect against M. tuberculosis H37Rv. DNF-3 displayed a long post-antibiotic effect (PAE) that was comparable with rifampicin but was superior to isoniazid, streptomycin and ethambutol. Importantly, DNF-3 showed no cytotoxicity to any cell line tested, with a selectivity index (SI) of >32. DNF-3 was also active against 27 nontuberculous mycobacteria (NTM) strains, Staphylococcus spp. and Streptococcus spp. Taken together, these results indicate that DNF-3 is a promising new candidate drug for treating TB. Further studies are warranted to establish the in vivo effect and therapeutic potential of DNF-3., (Copyright © 2019. Published by Elsevier B.V.)

Notwithstanding evidence that tuberculosis (TB) is declining, one of the greatest concerns to public health is the emergence and spread of multi-drug resistant strains of Mycobacterium tuberculosis (MDR-TB). MDR-TB are defined as strains which are resistant to at least isoniazid (INH) and rifampicin, the two most potent TB drugs, and their increasing incidence is a serious concern. Recently, notable efforts have been spent on research to pursue novel treatments against MDR-TB, especially on synergistic drug combinations as they have the potential to improve TB treatment. Our research group has previously reported promising synergistic antimicrobial effects between transition-metal compounds and antibiotics in Gram-negative and Gram-positive bacteria. In this work, we evaluated antimycobacterial activity of transition-metals/antibiotics combinatorial treatments against first-line drug resistant strains of Mycobacterium tuberculosis. Our data showed that INH/AgNO 3 combinatorial treatment had an additive effect (bactericidal activity) in an isoniazid-resistant clinical strain of Mycobacterium tuberculosis. Moreover, in vitro evaluation of cytotoxicity induced by both, the individual tratments of AgNO 3 and INH and the combinatorial treatment of INH/AgNO 3 in murine RAW 264.7 macrophages and human A549 lung cells; showed no toxic effects. Together, this data suggests that the INH/AgNO 3 combinatorial treatment could be used in the development of new strategies to treat resistant strains of Mycobacterium tuberculosis.

The four possible conformers of a new tetrakisguanidino calix[4]arene thought to interact deleteriously with bacterial membranes have been synthesized, characterized, and evaluated for their in vitro cytotoxicity and antibacterial activity against various reference Gram-negative and Gram-positive bacteria, as well as Mycobacterium tuberculosis. It appears that reversal of at least one phenolic unit results in clear increases in their activities. This can be attributed to the evolution towards bolaform structures, which are able to interact more deeply with the bacterial membrane. Indeed, the 1,3-alternate conformer 16 exhibits the best antibacterial activity (MIC<1.0 μg mL -1 on Staphylococcus aureus). Moreover, 16 displays very good antibacterial activities against an isoniazid-resistant strain of M. tuberculosis (MIC=1.2 μg mL -1 ), associated with the lowest cytotoxicity, thus making it the most potent compound of the series; this could open new ways of research in the field of anti-infective drug development to meet the huge current demand., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this article, we report a series of benzaldehyde thiosemicarbazone derivatives possessing high activity toward actively replicating Mycobacterium tuberculosis strain with minimum inhibitory concentration (MIC) values in the range from 0.14 to 2.2 μM. Among them, two compounds-2-(4-phenethoxybenzylidene)hydrazine-1-carbothioamide (13) and 2-(3-isopropoxybenzylidene)hydrazine-1-carbothioamide (20) also demonstrate submicromolar antimycobacterial activity against M. tuberculosis under hypoxia with MIC values of 0.68 and 0.74 μM, respectively. The activity of compounds 13 and 20 toward five investigated isoniazid-, rifampicin-, and fluoroquinolone-resistant M. tuberculosis isolates is similar to commercially available antituberculosis drugs. The compounds 13 and 20 possess good ADME properties and have low cytotoxicity toward human liver cells (HepG2). Therefore, 2-(4-phenethoxybenzylidene)hydrazine-1-carbothioamide (13) and 2-(3-isopropoxybenzylidene)hydrazine-1-carbothioamide (20) are valuable candidates for further preclinical studies.

Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl-β-d-ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A selectively antimycobacterial compound belonging to the nitrofuran class of antimicrobials has been developed via conjugation of the nitrofuran moiety to a series of spirocyclic piperidines through an amide linkage. It proved to have comparable activity against drug-sensitive (H37Rv) strain as well as multidrug-resistant, patient-derived strains of Mycobacterium tuberculosis. The compound is druglike, showed no appreciable cytotoxicity toward human retinal pigment epithelial cell line ARPE-19 in concentrations up to 100 μM and displayed low toxicity when evaluated in mice., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objectives: This work aims at getting more insights into the distinct behavior of S-oxide derivatives of thiocarbonyl-containing antitubercular drugs, in order to better understand their mechanism of action and toxicity., Methods: Computational calculation of relative free energy (ΔΔG) of S-oxide tautomers (sulfine R-C [SO]NH2), sulfenic acid (R-C [S-OH]NH) and sulfoxide (R-C [SHO]NH) derived from thioamide and thiourea antitubercular drugs and an update of the literature data with a new point of view about how the structural features of oxidized primary metabolites (S-oxide) can influence the outcome of the reactions and be determinant for the mechanisms of action and of toxicity of these drugs., Results: The calculated free energy of S-oxide tautomers, derived from thioamide and thiourea-type antitubercular drugs, supported by some experimental results, revealed that S-oxide derivatives could be found under sulfine and sulfenic acid forms depending on their chemical structures. Thiocarbonyl compounds belonging to the thioamide series are firstly oxidized, in the presence of H 2 O 2 , into the corresponding S-oxide derivatives that are more stable under the sulfine tautomeric form. Otherwise, S-oxides of thiourea-type (acyclic and cyclic) compounds tend to adopt the sulfenic acid tautomeric form preferentially. While the intermediate ethionamide-SO under sulfine form can be isolated and in the presence of H 2 O 2 can undergo further oxidation by a mechanism yielding radical species that are toxic for Mycobacterium tuberculosis and human, thioacetazone-SO, found mainly into sulfenic acid form, is unstable and sufficiently reactive in biological conditions to intercept different biochemical pathways and manifests thus its toxicity., Conclusion: Based on experimental and theoretical data, we propose that S-oxide derivatives of thioamide and thiourea-type antitubercular drugs have preference for distinct tautomeric forms. S-oxide of ethioamide is preferentially under sulfine form whereas S-oxide of thiourea compound as thioacetazone is mainly found under sulfenic acid form. These structural features lead to individual chemical reactivities that might explain the distinct mechanism of action and toxicity observed for the thioamide and thiourea antitubercular drugs., (Copyright © 2018 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

We report herein the design and synthesis of a series of less lipophilic Q203 derivatives containing an alkaline fused ring moiety. Most of them show considerable potency against MTB H37Rv strain (MIC < 0.25 μM). Nine compounds (13, 15, 19, 21, 23, 25, 29, 35, 36) have the same excellent activity against both drug-sensitive and -resistant strains (MIC < 0.035 μM) as Q203 and PBTZ169. Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the diagnostic value of macular ganglion cell-inner plexiform layer (mGCIPL) thickness versus peripapillary retinal nerve fibre layer (pRNFL) thickness for the early detection of ethambutol-induced optic neuropathy (EON)., Methods: Twenty-eight eyes of 15 patients in the EON group and 100 eyes of 53 healthy subjects in the control group were included. All patients with EON demonstrated the onset of visual symptoms within 3 weeks. Diagnostic power for pRNFL and mGCIPL thicknesses measured by Cirrus spectral-domain optical coherence tomography was assessed by area under the receiver operating characteristic (AUROC) curves and sensitivity., Results: All of the mGCIPL thickness measurements were thinner in the EON group than in the control group in early EON (p<0.001). All of pRNFL thicknesses except inferior RNFL showed AUROC curves above 0.5, and all of the mGCIPL thicknesses showed AUROC curves above 0.5. The AUROC of the average mGCIPL (0.812) thickness was significantly greater than that of the average pRNFL (0.507) thickness (p<0.001). Of all the mGCIPL-related parameters considered, the minimum thickness showed the greatest AUROC value (0.863). The average mGCIPL thickness showed a weak correlation with visual field pattern standard deviations (r 2 =0.158, p<0.001)., Conclusions: In challenging cases of EON, the mGCIPL thickness has better diagnostic performance in detecting early-onset EON as compared with using pRNFL thickness. Among the early detection ability of mGCIPL thickness, minimum GCIPL thickness has high diagnostic ability., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The present study attempts to identify the novel inhibitors of shikimate dehydrogenase (SD), the enzyme that catalyzes the fourth reaction in the shikimate pathway, through virtual screening and toxicity studies. Crystal structure of SD was obtained from Protein Data Bank (PDB ID 4P4G, 1.7 Å) and subjected to energy minimization and structure optimization. A total of 13,803 compounds retrieved from two public databases and used for the virtual screening based on physicochemical properties (Lipinski rule of five) and molecular docking analyses. A total of 26 compounds with good AutoDock binding energies values ranging between - 12.03 and - 8.33 kcal/mol was selected and further filtered for absorption distribution metabolism excretion and toxicity analyses (ADMET). In this, eight compounds were selected, which satisfied all the ADME and toxicity analysis properties. Three compounds with better AutoDock binding energies values (ZINC12135132, - 12.03 kcal/mol; ZINC08951370, - 10.04 kcal/mol; and ZINC14733847, 9.82 kcal/mol) were considered for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses revealed that the two ligands (ZINC12135132 and ZINC08951370) had better inhibitory activities within their complexes, after the 50-ns MD simulation, which suggested that the complexes formed stable conformation. It is noteworthy that compounds identified by docking, MD simulation, and MM-GBSA methods could be a drug for tuberculosis which required further experimental validation.

Fosmidomycin is a natural antibiotic with promising IspC (DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in Plasmodium falciparum and Mycobacterium tuberculosis. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report the application of two amino acid based prodrug approaches on a fosmidomycin surrogate. Conversion of the phosphonate moiety into tyrosine-derived esters increases the in vitro activity against asexual blood stages of P. falciparum, while phosphonodiamidate prodrugs display promising antitubercular activities. Selected prodrugs were tested in vivo in a P. berghei malaria mouse model. These results indicate good in vivo antiplasmodial potential., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Herein we report the design and synthesis of twenty-two novel benzofuran-isatin-imine hybrids 7a-v tethered through propylene, butylene, pentylene and hexylene, and for the evaluation of their in vitro anti-tubercular and anti-bacterial activities as well as cytotoxicity. All benzofuran-isatin-imine hybrids exhibited considerable in vitro anti-TB (MIC: <0.016-0.218 μg/mL and 0.062-14.15 μg/mL against drug-sensitive and MDR MTB, respectively) and anti-bacterial (MIC: 0.25-64 μg/mL and 0.06-16 μg/mL against Gram-positive and Gram-negative strains, respectively) activities. All of them also showed acceptable cytotoxicity towards VERO (CC 50 : 8-128 μg/mL). The most active hybrid 7j (MIC: <0.016, 0.062 and 0.16 μg/mL, respectively) was >4.8 and ≥ 48 folds more potent than the first line anti-TB agents RIF and INH against both drug-sensitive MTB H 37 Rv and MDR-TB isolates, respectively. Moreover, hybrid 7j also demonstrated promising anti-bacterial activities with MIC values of ≤1 μg/mL against the majority of the tested Gram-negative and Gram-positive pathogens, which was comparable to vancomycin (MIC: 0.5-4 μg/mL) and CPFX (MIC: 0.125-8 μg/mL) against Gram-positive bacteria, but slightly less potent than CPFX (MIC: ≤0.03-0.5 μg/mL) against Gram-negative bacteria. The results indicated that benzofuran-isatin-imine hybrids could act as candidates for the development of anti-TB and anti-bacterial agents., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Tuberculosis (TB) is the leading cause of death worldwide due to bacterial infection. The scarcity of effective drugs to treat the disease and the compounded problems due to the development of resistance to the available therapeutics and TB-HIV synergism drive medicinal chemists to search for new anti-Mtb chemotypes. Towards this endeavor, the α-sulfonamidophosphonate moiety has been identified as new anti-Mtb chemotype through the scaffold hopping as the design strategy, development of an effective synthetic methodology using green chemistry tools, and evaluation of anti-TB activity of the synthesized compounds against Mtb (Mycobacterium tuberculosis) H37Rv. Out of the sixteen compounds, five have been found to have MIC values of 1.56 μg/mL and one 3.125 μg/mL. The five most active compounds are non-cytotoxic to RAW 264.7 (mouse leukemic monocyte macrophage) cell lines. The compounds are found to possess acceptable values of the various parameters for drug likeness in accordance with the Lipinski rule with the topological surface area (tPSA) of >70 that suggest eligibility of these new molecular entities for further consideration as potential drug candidates., (Copyright © 2018. Published by Elsevier Inc.)

Auricularia polytricha is a popular mushroom found all over the world. This article describes a study of the antiepileptic effect of A. polytricha, a mushroom that is used traditionally for treating asthma, rheumatism, tumors, cough, fever, and epilepsy, and for its antimicrobial effect. We carried out toxicity studies to identify a standard dose of A. polytricha aqueous extract; maximal electroshock (MES)- and isoniazid (INH)-induced seizures in albino mice were used to screen for the extract's antiepileptic activity. Per Organisation for Economic Co-operation and Development Guideline 423, up to 2000 mg/kg body weight of extract was toxic. Animals were treated with aqueous extract at doses of 200, 400, and 600 mg/kg body weight. Phenytoin was used as the reference anticonvulsant drug for comparison. The investigation found a significant interruption in INH-induced clonic seizure. During MES, we found a reduction in the period of hind leg extensor phase; mice exhibited a significant decrease in the duration of hind limb extension after being treated with 400 and 600 mg/kg doses of A. polytricha. Comparable results were obtained in the INH group, as the extract seemed to delay the onset of a clonic seizure. The aqueous extract of A. polytricha showed antiepileptic action against MES- and INH-induced epilepsy in the mice. This extract, however, requires additional study in order to completely explain its active ingredients and their mechanisms of action.

Background: We screened a large library of differently decorated imidazo-pyrazole and pyrazole derivatives as possible new antitubercular agents and this preliminary screening showed that many compounds are able to totally inhibit Mycobacterium growth (>90 %). Among the most active compounds, we selected some new possible hits based on their similarities and, at the same time, on their novelty with respect to the pipeline drugs., Methods: In order to increase the potency and obtain more information about structure-activity relationship (SAR), we designed and synthesized three new series of compounds (2a-e, 3a-e, and 4a-l)., Conclusion: Performed tests confirmed that both new pyrazoles and imidazo-pyrazoles could represent a new starting point to obtain more potent compounds and further work is now underway to identify the protein targets of this new class of anti-TB agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Based on the advantages of azole molecules and fluoroquinolone drugs, we designed and synthesized 34 clinafloxacin-azole conjugates using fragment-based drug design and drug combination principles. The in vitro activities of the synthesized conjugates against Mycobacterium tuberculosis (H37Rv), Hela cell as well as Gram-positive and Gram-negative bacteria were assayed. The bioassay results revealed that most of the target molecules had anti-tuberculosis (anti-TB) activity, of which 14 compounds had very strong anti-TB activity [minimum inhibitory concentration (MIC) < 2 μM]. In addition, the compounds with strong activity towards H37Rv had weak activity towards Gram-negative and Gram-positive bacteria, showing obvious selectivity towards H37Rv. Predicted toxicity data indicated that 27 molecules were less toxic or equivalent to that of the original drug (clinafloxacin). Especially, it is demonstrated that compound TM2l exhibited the strongest anti-TB activity (MIC = 0.29 μM), low antibacterial activity, negligible toxicity, and good drug-likeness values, which can be considered as an ideal lead molecule for future optimization., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

First-line antituberculosis drugs, namely, isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA), contribute to diverse pathological complications. Testicular toxicity is one such complication. Berberis aristata DC is an herb with potentially curative characteristics. The aim of this study was to test whether extract of Berberis aristata DC (Berberidaceae) has curing potential against testicular toxicity. Characterization of extract was done using ultra-performance liquid chromatography along with acute toxicity testing. Antioxidant activity of extract was checked by DPPH inhibition assay and H 2 O 2 scavenging assay. Rats were dosed once daily for 28 days in groups: control group (saline), toxicant group (30.85 mg/kg body weight INH + 61.7 mg/kg body weight RIF + 132.65 mg/kg body weight PZA), treatment groups (TB drugs + 150/300 mg/kg body weight extract) and standard group (TB drugs +100 mg/kg body weight silymarin). Spectrophotometric evaluations of lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), glutathione-S-transferase (GST), and catalase (CAT) content in testes were done using standard protocols. DNA fragmentation and histopathological studies were performed to check the damage at the cellular level. Acute toxicity studies revealed LD 50 > 5 g/Kg body weight of B. aristata extract. IC 50 for DPPH free-radical scavenging activity and H 2 O 2 scavenging assay were 44.78 µg/mL and 85.28 µg/mL, respectively. Results revealed significant increase in thiobarbituric acid reactive substances, decrease in glutathione and different antioxidants levels, DNA fragmentation pattern, and changes in histology in toxicant group. All the changes were absent in high-dose (300 mg/kg body weight) extract treatment group. This work proved that B. aristata extract has protective efficacy against testicular damage caused by anti-TB drugs.

Background Development of drug-induced hepatic damage (DIHD) during chemotherapy is the most common reason for interruption in chemotherapy. This study evaluated the hepatoprotective activity of the ethanolic extract of Tamarindus indica stem bark (EETI) against the induced DIHD in Sprague Dawley rats. Methods The rats were divided into five groups (n=5). Group I, group III, group IV, and group V rats received 1 mL 1% carboxymethyl cellulose, EETI 100 mg/kg body weight (b.wt), EETI 200 mg/kg b.wt, and silymarin 100 mg/kg b.wt, respectively, orally once every day for 28 days. After 1 h-group II, group III, group IV, and group V rats were administered with isoniazid (INH) and rifampicin (RIF) 50 mg/kg b.wt each orally once every day for 28 days. Then, 24 h after the last dosing, blood was withdrawn from the rats and analyzed for liver specific enzymes and biochemical markers. They were examined for histopathology. Results Co-administration of INH and RIF in group II significantly increased alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase, serum bilirubin, and cholesterol levels while reduced the total protein and albumin levels compared to that of group I. EETI in group III and group IV rats significantly restored the liver specific enzymes and biochemical markers altered due to co-administration of INH and RIF to normal in a dose-dependent manner. EETI 200 mg/kg b.wt showed better protection to liver than EETI 100 mg/kg b.wt and was comparable to silymarin 100 mg/kg b.wt. It was well supported with histopathology of liver tissues. Conclusions EETI possesses hepatoprotective activity against DIHD in rats. It may have a substantial impact on developing clinical strategies to treat patients with hepatic damage.

Background: Treatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes., Methods: We searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies., Results: We included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56-1.00; p = 0.047, I 2  = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38-48.68, I 2  = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19-3.21, I 2  = 0%)., Conclusions: Generally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants' ethnicity was sparsely reported in the included studies., Systematic Review Registration: PROSPERO registration number: CRD42017068448.

Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1 H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There is growing evidence for the role of mitochondrial dysfunction in the toxic optic neuropathies. Due to the structural similarities between antibiotic targets and mitochondrial machinery, several antibiotics known to cause optic neuropathy have deleterious effects on mitochondrial function. We review the literature on the prevalence, clinical manifestations, and management of antibiotic induced toxic optic neuropathies. The effect of these antibiotics on mitochondrial function in regard to the optic nerve is discussed.

Ethnopharmacological Relevance: Bidens odorata Cavanilles is a medicinal and edible plant known as "mozote blanco, aceitilla, acahual, mozoquelite" which is traditionally used in Mexico as a diuretic, hypoglycaemic, anti-inflammatory, antipyretic, antitussive, to treat gastrointestinal disorders, kidney pain, and lung or respiratory diseases., Aim of the Study: This research study was aimed at phytochemical analysis of aerial extracts of B. odorata for antimycobacterial and lipid-lowering activities., Materials and Methods: Compounds 1 (((2R, 3R, 4S, 5S, 6R)-3,4,5-Tryhidroxy-6-(((E)-3-(4-hydroxyphenyl) acryloyl) oxy) tetrahydro-2H-pyran-2-yl) methyl-4-hydroxybenzoate) and 2 (3,5-Dihydroxybenzoic acid) were isolated from B. odorata aerial shoots and their structural elucidation was carried out using 1 and 2D NMR, infrared spectroscopy (IR) and mass spectrometry (ESI-MS). The antimycobacterial activity of various extracts and compounds 1 and 2 was determined using the Microplate Alamar Blue Assay (MABA). The evaluation of the hypolipidemic effect of the ethanolic extract and the glycosylated compound 1 was tested in a murine model of hypercholesterolemia induced by diet and by Triton WR-1339. On the other hand, the LD 50 of the ethanolic extract was evaluated in ICR mice by the OECD protocol TG 423., Results: Antimycobacterial assay of hexane, CH 2 Cl 2 , EtOAc, ethanolic and aqueous extracts, as well as the new glycosidic compound 1 and benzoic acid derivative 2 isolated from B. odorata showed minimal inhibitory concentrations (MIC) of 100, 12.5, 12.5, 12.5, ≥200, 3.125 and 50 μg/mL, respectively, against Mycobacterium tuberculosis H37Rv. Only hexane and CH 2 Cl 2 extracts were observed to be active against Mycobacterium smegmatis mc 2 155 at a concentration of 50 and 100 μg/mL, respectively. The ethanolic extract showed lipid-lowering activity at doses of 100 and 1000 mg/kg, while glycosidic compound 1 was active at doses of 50 and 100 mg/kg. In addition, the LD 50 of the ethanolic extract was >2000 mg/kg, meaning that this extract does not cause lethality or adverse effects, and no signs of organs alterations or tissue damage were observed., Conclusion: The hexane, CH 2 Cl 2 , EtOAc, and ethanolic extracts of B. odorata, as well as their components 1 and 2, displayed antimycobacterial activity against M. tuberculosis. Moreover, the ethanolic extract and glycosidic compound 1 showed an important lipid-lowering effect, without lethality or secondary effect. The results of this study support the documented traditional use for B. odorata., (Copyright © 2018 Elsevier B.V. All rights reserved.)

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure-activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.

The infectious disease tuberculosis remains a serious global health issue and is responsible for nearly 1.8 million deaths every year. In our previous study, DFC-2 was confirmed to show anti-tubercular activity against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. To support the safety-in-use of DFC-2 as an anti-tubercular drug, DFC-2 was tested via single- and 28-day repeated-dose oral toxicity study and mutagenicity assays. In the oral toxicity study, a single oral dose of DFC-2 at 2000 mg/kg did not produce deaths or abnormal lesions in the internal organs of rats. The results of a 28-day orally repeated dose of DFC-2 did not show treatment-related deaths or obvious toxicity symptoms in the animals treated with a dose of 300 mg/kg/day during the experimental period. Therefore, the no-observed-adverse-effect level (NOAEL) of DFC-2 was determined as 300 mg/kg/day for both male and female rats. In addition, DFC-2 showed no genetic toxicity in in vitro bacterial reverse mutation test, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus formation test. These results indicate that DFC-2 is a promising anti-tubercular drug candidate with a favorable safety profile., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The success in exploring anti-tubercular potency of nitroimidazole and quinoline, the core moieties of recently approved anti-tubercular drugs instigated us to synthesize a series of alkylated/aminated 2-methyl-5-nitroimidazoles and nitroimidazole-7-chloroquinoline conjugates and to evaluate them for their activities against Mycobacterium tuberculosis as well as for their cytotoxicity towards the J774 murine macrophage cell line. Although the synthesized compounds did not surpass the activity of the standard drug Isoniazid, they have appreciable activities with minimal cytotoxicity. The synthesized nitroimidazole-7-chloroquinoline conjugate, 11c, having butyl chain as linker, proved to be the most potent among the series with an MIC 50 value of 2.2 μg/mL., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aims: Long-term treatment of Isoniazid (INH) in tuberculosis (TB) patients can lead to anti-tuberculosis drug-induced hepatotoxicity. To understand the mechanism of hepatotoxicity, an attempt has been made to elucidate the role of Nrf2, a transcription factor induced by oxidative stress, in INH induced apoptosis liver cancer cell lines., Materials and Methods: Cytotoxicity was evaluated by MTT assay. Apoptosis and reactive oxygen species (ROS) generation was performed by flow cytometry. mRNA and protein expression of various genes involves in INH induced toxicity was evaluated via Real-time PCR and western blot analysis respectively. Differential protein expression was performed by two-dimensional gel electrophoresis followed by identification using MALDI TOF/TOF., Key Findings: INH induced ROS and apoptosis in HepG2 as well as THLE-2 cells. Nuclear damage was also observed by INH treatment in HepG2 cells. Expression of apoptotic (Cytochrome C and Caspase 9) and antioxidative (Keap1 and Nrf2) genes were observed to increase. INH induced PKCδ phosphorylation and released Nrf2 from its inhibitor Keap1 in the cytoplasm of HepG2 cells. However, over-expression of Nrf2 did not affect nuclear Nrf2 protein level as well as its downstream target NQO1. Nrf2 importer, Karyopherin β1 level was observed to decrease in HepG2 as well as THLE-2 cells following INH treatment., Significance: These findings suggest that INH prevented Nrf2 translocation into the nucleus by inhibiting its importer Karyopherin β1. Therefore Nrf2 might not able to bind ARE sequences from inducing antioxidative response for protecting the cells undergoing apoptosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pyrazinamide (PYZ)-an essential component of primary drug regimen used for the treatment and management of multidrug resistant or latent tuberculosis-is well known for its hepatoxicity. However, the mechanism of PYZ-induced hepatotoxicity is still unknown to researchers. Studies have shown that the drug is metabolized in the liver to pyrazinoic acid (PA) and 5-hydroxy pyrazinoic acid (5-OHPA) which individually may cause different degrees of hepatotoxicity. To evaluate this hypothesis, PYZ, PA, and 5-OHPA were administered to albino Wistar rats orally (respectively, at 250, 125, and 125 mg kg -1 for 28 days). Compared to normal rats, PYZ and its metabolic products decreased the weights of dosed rats and induced liver injury and a status of oxidative stress as assessed by combined histopathological and biochemical analysis. Compared to normal controls, the biochemical and morphological changes were more aberrant in PA- and 5-OHPA-dosed rats with respect to those dosed with PYZ. Finally, the serum metabolic profiles of rats dosed with PYZ, PA, and 5-OHPA were measured and compared with those of normal control rats. With respect to normal control rats, the rats dosed with PYZ and 5-OHPA showed most aberrant metabolic perturbations in their sera as compared to those dosed with PA. Altogether, the study suggests that PYZ-induced hepatotoxicity might be associated with its metabolized products, where 5-OHPA contributes to a higher degree in its overall toxicity than PA.

A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases.

Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 μM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) assay model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal candidate for further development of oral anti-TB agent., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The administration of the "Phosphogliv®" hepatoprotector in the comprehensive treatment of patients with pulmonary tuberculosis will allow determining its effect on the lipid composition of membranes of mononuclear cells under conditions of etiotropic chemotherapy according to 1 standard regimen. The determination of the ratios of the most important classes of phospholipids in membranes of peripheral blood mononuclear cells will give an idea of the structural-functional state violation of the most important representatives of the cellular immunity in patients with tuberculosis prior to treatment, against the backdrop of the intensive phase of the main course of chemotherapy as well as the change in these indices when the "Phosphogliv®" drug is administered in the comprehensive treatment therapy. The study included 356 patients with pulmonary tuberculosis of young and middle age, out of which 308 patients received etiotropic chemotherapy without the administration of phosphogliv, and 48 patients receiving comprehensive treatment used a combined scheme of oral-parenteral administration of phosphogliv. The administration of the "Phosphogliv®" hepatoprotector in the comprehensive treatment of tuberculosis patients made it possible to reduce the severity of the toxic effect of anti-tuberculosis drugs on peripheral blood mononuclear cells, to reduce the degree of disorganization of their membranes and to bring the phospholipid spectrum closer to the corresponding values of the control group. Direct positive clinical and radiological dynamics in 81.5% of patients in the second group and 87.5% in the third group was noted during the analysis of laboratory data and the X-ray pattern. After 2 months of the intensive phase of anti-tuberculosis chemotherapy, abacilation was achieved in 61% of patients having no phosphogliv administered, and in 81% of patients receiving complex therapy with the administration of "Phosphogliv®" hapatoprotector. More apparent positive X-ray dynamics (infiltration zone and dissemination foci decrease) was observed in patients receiving Phosphogliv®., Competing Interests: The authors declare no conflict of interest.

Tuberculosis - a disease caused by Mycobacterium tuberculosis (Mtb), is one of the most devastating disease. The discovery of Ser/Thr protein kinases (STPKs) in Mtb opened a new avenue for developing anti-tubercular inhibitors. The in-vivo inhibitory effects of many metal ions have been demonstrated in literature. But, one of the limitations of metal ions as inhibitors is their inability to traverse the hydrophobic membrane due to polar nature and their propensity for non-specific interactions. To overcome this, we attached a metal ion to 2-A9P - an analog derived from a cell permeable scaffold, 2-Aminopurine (2-AP) which is a known kinase inhibitor. We investigated the inhibitory potential of 2-AP and its analog 2-A9P against protein kinase B (PknB) and showed that both of these can inhibit Mtb STPKs. Next, we evaluated the latent inhibitory activity of metal ions and for the first time showed that they can inhibit the phosphotransfer reaction in PknB, PknG and PknL. Subsequently, 6 different metal complexes (MC) of 2-A9P were used for inhibitory studies and their estimated IC 50 values show that most MCs inhibited PknB with low micromolar potency. Further, MIC values determined for the six MCs against Mtb showed that MC-4 and MC-6 exhibit whole cell inhibitory activity. Cytotoxicity studies show that MC-4 and MC-6 do not affect cell viability of A549 cell lines, suggesting that these inhibitors can be further developed as anti-tubercular agents., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Adverse drug reactions are inevitable risk factors associated with use of modern medicines. First-line anti-tuberculosis drugs contribute to diverse pathological complications, and hepatotoxicity is one of them. This study investigated the effects of anti-TB drugs in combination (rifampicin [RIF] + isoniazid [INH] + pyrazinamide [PZA]) on Wistar rats. Rats were grouped as control group (saline), toxicant group that was given (30.85 mg/kg b.wt., INH + 61.7 mg/kg b.wt., RIF + 132.65 mg/kg b.wt. PZA in dosage extrapolated from dose that is used in human). Different anti-oxidant enzymes were measured in the liver along with histopathology, hematology, genotoxic effect on bone marrow chromosomes, and DNA fragmentation. In addition, gene and protein expression of CYP2E1, NR1I2, NAT, and CYP7A1 was measured by qPCR and western blot. After administration of anti-TB drugs to Wistar rats for 28 days, there was an increase in thiobarbituric acid reactive substances and a decrease in anti-oxidant enzymes. Marked changes in histopathology, hematology, DNA fragmentation, chromosomes, and in gene expression were observed. Results of the study proved increased hepatotoxicity due to combinational treatment of anti-TB drugs and also that CYP2E1, NR1I2, NAT, and CYP7A1 genes play a vital role in anti-TB drug-induced hepatotoxicity.

The World Health Organization acknowledges tuberculosis as a global threat. Tuberculosis infection is one of the top 10 causes of death worldwide. Nanotechnology and microbiology researchers are looking for new and safe nano drugs for eliminating Mycobacterium tuberculosis, the causative agent of tuberculosis. In this study, AgZnO nano-crystals (AgZnONCs) is synthesized via the decomposition of the precursor of oxalate method. Characterization of AgZnONCs were evaluated. Next, various concentrations of AgZnONCs, as well AgZnONCs+Rifampicin, were prepared. The MTT assay was employed to study the viability of human macrophage cell lines (THP-1) exposed to AgZnONCs. The bactericidal effects of AgZnONCs and AgZnONCs+Rifampicin were studied by Minimum Bactericidal Concentration (MBC) test. Subsequently, THP-1 were infected by H 37 Rv strain of M. tuberculosis (H 37 RvMtb). Also, bactericidal effects of AgZnONCs and AgZnONCs+Rifampicin were compared with ex-vivo conditions. The MBC of AgZnONCs and AgZnONCs+Rifampicin were ratios of 1:4 and 1:32 respectively (p-value <0.05). Also, more than 50% and 80% of THP-1 were alive in ratios of 1:4 and 1:32 in the presence of AgZnONCs, respectively. All phagocytic H 37 RvMtb were killed in the presence of AgZnONCs+Rifampicin (p-value <0.05), while AgZnONCs were not able to kill all the H 37 RvMtb (p-value >0.05). This study showed that, AgZnONCs+Rifampicin has the most anti-tubercular behavior with respect to the macrophages., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)