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A series of novel 9-alkyl/aryl-2-aryl-6-carbamoylpurines were synthesized, and their activity against Mycobacterium tuberculosis strain H 37 Rv was assessed. The SAR analysis on the first set of derivatives, with an alkyl or aryl unit at N-9 and a phenolic unit at C-2, showed that the activity depends on the purine ring substituents at N-9 and C-2. A phenyl group at N-9 combined with a 3-hydroxyphenyl or 4-hydroxyphenyl at C-2 improve the activity. The most active compound of this set has a phenyl group at N-9 and a 4-hydroxyphenyl group at C-2, displaying an IC 90 = 1.2 μg/mL and a selectivity index higher than 25.5. This compound served as a Hit to design the second set of derivatives. A phenyl group at N-9 was maintained, and the group at C-2 was diversified. The SAR analysis showed that the aryl unit at C-2 must have an oxygen or nitrogen atom bonded in the para position. A proton, a small alkyl or a substituted aryl group may also be bonded to the oxygen. The compound with the 4-methoxyphenyl group at C-2, 1Bd, exhibits the highest activity with an IC 90 < 0.19 μg/mL. This compound is highly potent against M. tuberculosis strain H 37 Rv and non-toxic for VERO mammalian cells with an SI > 153.8. Compound 1Bd was also non-cytotoxic against primary macrophage cultures at IC 90 , 2xIC 90, and 10xIC 90 and significantly reduced the bacterial load in M. tuberculosis -infected macrophages at the same concentrations. Compound 1Bd showed a favorable pharmacokinetic profile when administered orally, with major lung and liver accumulation. In vivo antimycobacterial efficacy of 1Bd was tested at 25 mg/kg. At the tested regimen, a decrease in bacterial burden was observed in the liver. Optimization of the treatment regimen should be performed to fully potentiate the in vivo efficacy of our lead molecule, particularly in the lung, the main target organ of M. tuberculosis. [Display omitted] • Design, synthesis and in vitro activity of 6-carbamoylpurines against M. tb. • SAR study of 2,9-diaryl-6-carbamoylpurines against M. tb. • 2-(4-Methoxyphenyl)-9-phenyl-6-carbamoylpurine as Lead compound. • Lead compound in vivo antimicrobial efficacy in the liver. • 2,9-Diaryl-6-carbamoylpurines as a novel class of antituberculosis agents. [ABSTRACT FROM AUTHOR]

Growing global demand for new molecules to treat tuberculosis has created an urgent need to develop novel strategies to combat the menace. BM212 related compounds were found to be potent anti-TB agents and they inhibit mycolic acid transporter, MmpL3, a known potent drug target from Mycobacterium tuberculosis. In order to enhance their inhibitory potency, several silicon analogues of diarylpyrroles related to BM212 were designed, synthesized, and evaluated for anti-tubercular activities. In Alamar blue assay, most of the silicon-incorporated compounds were found to be more potent than the parent compound (BM212), against Mycobacterium tuberculosis (MIC = 1.7 μM, H37Rv). Docking results from the crystal structure of MmpL3 and silicon analogues as pharmacophore model also strongly correlate with the biological assays and suggest that the incorporation of silicon in the inhibitor scaffold could enhance their potency by stabilizing the hydrophobic residues at the binding pocket. The best docking hit, compound 12 showed an MIC of 0.1 μM against H37Rv with an acceptable in vitro ADME profile and excellent selectivity index. Overall, the present study indicates that, the designed silicon analogues, especially compound 12 could be a good inhibitor for an intrinsically flexible drug-binding pocket of MmpL3 and has potential for further development as anti-tubercular agents. [Display omitted] • Several analogues of BM212 with silicon incorporation were synthesized and tested for their anti-tubercular activity. • From SAR analysis, silicon substitution improved the potency of this series. • Docking studies suggests that silyl group enhances the potency by stabilizing hydrophobic residues at the binding pocket. • The best docking hit, compound 12 showed an MIC of 0.1 μM against H37Rv and displayed an acceptable in vitro ADME profile. [ABSTRACT FROM AUTHOR]

Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6 H -purin-6-one 10 as a potent antimycobacterial agent with MIC 99 of 4 μM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64 , respectively, were developed. These compounds showed strong in vitro antimycobacterial activity with MIC of 1 μM against Mtb H 37 Rv and against several clinically isolated drug-resistant strains, had limited toxicity to mammalian cell lines, medium clearance with respect to phase I metabolic deactivation (27 and 16.8 μL/min/mg), sufficient aqueous solubility (>90 μM) and high plasma stability. Interestingly, investigated purines, including compounds 56 and 64 , lacked activity against a panel of Gram-negative and Gram-positive bacterial strains, indicating a specific mycobacterial molecular target. To investigate the mechanism of action, Mtb mutants resistant to hit compound 10 were isolated and their genomes were sequenced. Mutations were found in dprE1 (Rv3790), which encodes decaprenylphosphoryl-β- d -ribose oxidase DprE1, enzyme essential for the biosynthesis of arabinose, a vital component of the mycobacterial cell wall. Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7 H -purines was proved using radiolabelling experiments in Mtb H 37 Rv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction. [Display omitted] • The phenotypic screening revealed antitubercular compounds in the purine family. • The initial hit 10 with MIC value of 4 μM (Mtb H 37 Rv) was optimized by SAR study. • Lead compounds showed antimycobacterial activity against drug-resistant strains. • Whole-genome sequencing and radiolabelling experiments confirmed DprE1 as a target. • The structure-binding relationship was elucidated by applying MM/MD simulations. [ABSTRACT FROM AUTHOR]

Tuberculosis remains a major public health problem and one of the top ten causes of death worldwide. The alarming increase in multidrug-resistant and extensively resistant variants (MDR, pre-XDR, and XDR) makes the disease more difficult to treat and control. New drugs that act against MDR/XDR strains are needed for programs to contain this major epidemic. The present study aimed to evaluate new compounds related to dihydro-sphingosine and ethambutol against sensitive and pre-XDR Mycobacterium strains, as well as to characterize the pharmacological activity through in vitro and in silico approaches in mmpL3 protein. Of the 48 compounds analyzed, 11 demonstrated good to moderate activity on sensitive and MDR Mycobacterium tuberculosis (Mtb), with a Minimum Inhibitory Concentration (MIC) ranging from 1.5 to 8 μM. They presented 2 to 14 times greater potency of activity when compared to ethambutol in pre-XDR strain, and demonstrated a selectivity index varying between 2.21 and 82.17. The substance 12b when combined with rifampicin, showed a synergistic effect (FICI = 0.5) on sensitive and MDR Mtb. It has also been shown to have a concentration-dependent intracellular bactericidal effect, and a time-dependent bactericidal effect in M. smegmatis and pre-XDR M. tuberculosis. The binding mode of the compounds in its cavity was identified through molecular docking and using a predicted structural model of mmpL3. Finally, we observed by transmission electron microscopy the induction of damage to the cell wall integrity of M. tuberculosis treated with the substance 12b. With these findings, we demonstrate the potential of a 2-aminoalkanol derivative to be a prototype substance and candidate for further optimization of molecular structure and anti-tubercular activity in preclinical studies. [Display omitted] • A series of dihydrosphingosine and ethambutol analogues demonstrated good activity against sensitive and MDR Mtb. • 12b when combined with rifampicin, showed a synergistic effect. • Induction of damage to cell wall integrity has been observed with 12b. • Binding these compounds with a protein essential to maintain the mycobacterial wall (mmpl3) has been modeled. • These 2-aminoalkanol derivatives represent promising new antitubercular agents. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis infections still pose a serious threat to human health. Combination therapies are effective medical solutions to the problem. Mycobacterium tuberculosis is an intracellular pathogen that mainly depends on a virulence factor (Mycobacterium tuberculosis protein tyrosine phosphatase B, MptpB) for its survival in the host. Therefore, MptpB inhibitors are potential components of tuberculosis combination treatments. Herein, a new series of MptpB inhibitors bearing a rhodanine group were developed using a structure-based strategy based on the virtual screening hit. The new MptpB inhibitors displayed potent MptpB inhibitory activities and great improvements in cell membrane permeability. The optimal compounds reduced the bacterial burden in a dose-dependent manner in a macrophage infection model, especially, a combination of compound 20 and rifampicin led to a bacterial burden reduction of more than 95%, greater than the reductions achieved with compound 20 or rifampicin alone. This research provides new insights into the rational design of new MptpB inhibitors and verifies that the MptpB inhibitor has a promising potential as a component of tuberculosis treatment. [Display omitted] • New MptpB inhibitors bearing rhodanine motif were identified by rational design. • Compounds exhibited great improvements in cell membrane permeability. • Compounds showed dose-dependent anti-TB activity in mouse macrophages. • Compound 20 can increase the efficacy of RFP in mouse macrophages. • The results verified MptpB inhibitor has potential as a component of TB treatment. [ABSTRACT FROM AUTHOR]

Tuberculosis remains one of the world's leading infectious disease killers, causing more than 1.5 million of deaths each year. It is therefore a priority to discover and develop new classes of anti-tuberculosis drugs to design new treatments in order to fight the increasing burden of resistant-tuberculosis. Fragment-based drug discovery (FBDD) relies on the identification of small molecule hits, further improved to high-affinity ligands through three main approaches: fragment growing, merging and linking. The aim of this review is to highlight the recent progresses made in fragment-based approaches for the discovery and development of Mycobacterium tuberculosis inhibitors in a wide range of pathways. Hit discovery, hit-to-lead optimization, SAR and binding mode when available are discussed. • Review of recent Fragment-based approaches against Mycobacterium tuberculosis. • Hit discovery, hit optimisation and binding modes. • Cell wall synthesis inhibitors. • Metabolites synthesis inhibitors. • Host-pathogen interactions. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains a major global health problem and new therapeutic antitubercular agents are urgent needed. Among the novel antituberculosis drugs in the pipeline, Benzothiazinones (BTZs) are among the most potent antituberculosis agents against both drug-susceptible and multidrug-resistant (MDR) tuberculosis. Our group has focused on structural modifications of the side chain at C-2 position of the BTZ core and WAP-2101/2102 with excellent in vitro activity were discovered in our lab. However, the severe in vivo toxicity was observed during subsequent acute toxicity evaluation. Herein, a series of novel N -(amino)piperazinyl benzothiazinone derivatives were designed and synthesized as new anti-TB agents to reduce the in vivo toxicity. Our results show that majority of them exhibit the same potent or comparable activity against both MTB H 37 Rv and MDR-MTB strains (MIC: 4.00 - <1 ng/mL) as PBTZ169. Especially, compound 2c with low cardiac toxicity, low cell cytotoxicity and acceptable oral pharmacokinetic (PK) profiles have low acute toxicity in mice (LD 50 > 500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery. [Display omitted] • 26 N -(amino)piperazine BTZs were synthesized to study the SAR of cyclohexane ring. • The cyclohexane moiety might be closely related to the in vivo toxicity. • 2c showed acceptable PK profile and good in vitro and in vivo safety. [ABSTRACT FROM AUTHOR]

Abstract A series of reduced lipophilic N-benzylic imidazo[1,2-a]pyridine carboxamides (IPAs) with various side chains were designed and synthesized as new anti-TB agents in this work. Five derivatives A2 , A3 , A4 , B1 and B9 exhibit excellent in vitro activity (MIC: < 0.035 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains, and acceptable PK properties. Compound B1 bearing a cyclohexylmethyl piperazine moiety, the same side chain of PBTZ169, was found to have obviously greater AUC 0-∞ and C max than Q203 and PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery. Graphical abstract Image 1 Highlights • Novel reduced lipophilic imidazo[1,2-a]pyridine-3-carboxamide derivatives were synthesized. • SARs were summarized for further antitubercular agents discovery. • Anti-MDR-TB activity, cytotoxicity and PK properties were investigated. • Compound B1 may serve as a new and promising candidate for further study. [ABSTRACT FROM AUTHOR]

Abstract In this study, three novel series of benzoxazinone, benzothiopyranone and benzopyranone derivatives were designed through scaffold morphing from benzothiazinones to target DprE1. All compounds were evaluated for their in vitro activities against Mycobacterium tuberculosis and cytotoxicity against Vero cell line. Among these three series, the benzothiopyranone series displayed excellent antimycobacterial activity and low cytotoxicity. In particular, compound 6b exhibited potent in vitro activity against both drug-susceptible and drug-resistant tuberculosis clinical strains with MICs <0.016 μg/mL. In addition, compound 6b demonstrated excellent ADME/T and PK properties and potent in vivo efficacy with bactericidal activity in an acute mouse model of tuberculosis. The antituberculosis effect of compound 6b is most likely attributed to its excellent anti-DprE1 activity. As such, compound 6b is under evaluation as a potential clinical candidate for treatment of tuberculosis. The current study provided new insight into the structural and pharmacological requirements for DprE1 inhibitors as potent antitubercular agents. Graphical abstract Image 1 Highlights • The benzothiopyranones displayed excellent anti-TB activity and low cytotoxicity. • Compound 6b exhibited good inhibitory activity against DprE1. • Compound 6b exhibited potent in vitro activity against both DS-TB and DR-TB. • Compound 6b displayed superior ADME/T and PK properties. • Compound 6b demonstrated potent in vivo efficacy in an acute mouse model of TB. [ABSTRACT FROM AUTHOR]

Abstract Mycobacterium tuberculosis (MTB) , the causative agent of tuberculosis is known to secrete low molecular mass compounds called siderophores especially under low iron conditions to chelate iron from host environment. Iron is essential for growth and other essential processes to sustain life of the bacterium in the host. Hence targeting siderophore is considered to be an alternative approach to prevent further virulence of bacterium into the host. This review article presents classification of siderophores, their role in transporting iron into the tubercular cell, biosynthesis of mycobactins, viability of siderophore as a therapeutic target and also focuses on overview on various approaches to target siderophore. The approaches encompass mutation effect on genes involved in siderophore recycling, synthetic as well as natural compounds that can inhibit further spread of bacterium by targeting siderophore. Graphical abstract Image 1 Highlights • The role of siderophore in transporting iron into the tubercular cell. • Biosynthesis of mycobactins and viability of siderophore as a therapeutic target. • Approaches for targeting Mtb siderophore. [ABSTRACT FROM AUTHOR]

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III , endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date ( K i  = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC 99  = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition. [ABSTRACT FROM AUTHOR]

Using a classical hybridization approach, a series of 1 H -benzo[ d ]imidazoles and 3,4-dihydroquinazolin-4-ones were synthesized (39 examples) and evaluated as inhibitors of Mycobacterium tuberculosis growth. Chemical modification studies yielded potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.24 μM against M. tuberculosis H37Rv strain. Further, the synthesized compounds were active against four drug-resistant strains containing different levels of resistance for the first line drugs. These molecules were devoid of apparent toxicity to HepG2, HaCat, and Vero cells with IC 50s  > 30 μM. Viability in mammalian cell cultures was evaluated using MTT and neutral red assays. In addition, some 3,4-dihydroquinazolin-4-ones showed low risk of cardiac toxicity, no signals of neurotoxicity or morphological alteration in zebrafish ( Danio rerio ) toxicity models. 3,4-Dihydroquinazolin-4-ones 9q and 9w were considered the lead compounds of these series of molecules with MIC values of 0.24 μM and 0.94 μM against M. tuberculosis H37Rv, respectively. Taken together, these data indicate that this class of compounds may furnish candidates for future development of novel anti-TB drugs. [ABSTRACT FROM AUTHOR]

The development of novel drugs is essential for the treatment of tuberculosis and other mycobacterial infections in future. A series of N -alkyl-2-isonicotinoylhydrazine-1-carboxamides was synthesized from isoniazid (INH) and then cyclized to N -alkyl-5-(pyridin-4-yl)-1,3,4-oxadiazole-2-amines. All derivatives were characterised spectroscopically. The compounds were screened for their in vitro antimycobacterial activity against susceptible and multidrug-resistant Mycobacterium tuberculosis ( Mtb. ) and nontuberculous mycobacteria (NTM; M. avium , M. kansasii ). The most active carboxamides were substituted by a short n -alkyl, their activity was comparable to INH with minimum inhibitory concentrations (MICs) against Mtb. of 0.5–2 μM. Moreover, they are non-toxic for HepG2, and some of them are highly active against INH-resistant NTM (MICs ≥4 μM). Their cyclization to 1,3,4-oxadiazoles did not increase the activity. The experimentally proved mechanism of action of 2-isonicotinoylhydrazine-1-carboxamides consists of the inhibition of enoyl-ACP reductase (InhA) in a way similar to INH, which is blocking the biosynthesis of mycolic acids. N -Dodecyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amine as the most efficacious oxadiazole inhibits growth of both susceptible and drug-resistant Mtb. strains with uniform MIC values of 4–8 μM with no cross-resistance to antitubercular drugs including INH. The mechanism of action is not elucidated but it is different from INH. Obtained results qualify these promising derivatives for further investigation. [ABSTRACT FROM AUTHOR]

We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way. [ABSTRACT FROM AUTHOR]

Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity. As the most emblematic example, 4-nitroimidazole delamanid has already received approval for treatment of multidrug-resistant tuberculosis infected patients. Thus, imidazole-containing derivatives have caused great interests in discovery of new anti-tubercular agents. Numerous of imidazole-containing derivatives were synthesized and screened for their in vitro and in vivo anti-mycobacterial activities against both drug-sensitive and drug-resistant Mycobacterium tuberculosis pathogens. This review aims to outline the recent advances of imidazole-containing derivatives as anti-tubercular agents, and summarize the structure-activity relationship of these derivatives. The enriched structure-activity relationship may pave the way for the further rational development of imidazole-containing derivatives as anti-tubercular agents. [ABSTRACT FROM AUTHOR]

Four series of primaquine (PQ) derivatives were screened for antitubercular and antiplasmodial activity: amides 1a-k , ureas 2a-s , semicarbazides 3a-c and bis -ureas 4a-u . Antimycobacterial activity of PQ derivatives against Mycobacterium tuberculosis (MTB), M. avium complex (MAC) and M. avium subsp. paratuberculosis (MAP) were evaluated in vitro and compared with PQ and the standard antitubercular drugs. In general, the PQ derivatives showed higher potency than the parent compound. Most of the compounds of series 1 and 2 showed high activity against MAP, comparable or even higher than the relevant drug ciprofloxacin, and weak or no activity against MTB and MAC. bis -Trifluoromethylated cinnamamide 1k showed low cytotoxicity and high activity against all three Mycobacterium species and their activities were comparable or slightly higher than those of the reference drugs. PQ urea derivatives with hydroxyl, halogen and trifluoromethyl substituents on benzene ring 2f-p exerted very strong antimycobacterial activity towards all tested mycobacteria, stronger than PQ and the relevant standard drug(s). Unfortunately, these compounds had relatively high cytotoxicity, except bromo 2l and trifluoromethyl 2m , 2n derivatives. In general, meta- substituted derivatives were more active than analogues para- derivatives. Phenyl ureas were also more active than cycloalkyl or hydroxyalkyl ureas. Semicarbazide 3a showed similar activity as PQ, while the other two semicarbazides were inactive. Bis -urea derivatives 4 were generally less active than the urea derivatives sharing the same scaffold, differing only in the spacer type. Out of 21 evaluated bis -urea derivatives, only p -Cl/ m -CF 3 phenyl derivative 4p , benzhydryl derivatives 4t and 4u and bis -PQ derivative 4s showed high activity, higher than all three reference drugs. After comparison of activity and cytotoxicity, urea 2m and bis -urea 4u could be considered as the most promising agents. Antimalarial potential of PQ derivatives in vitro against the liver stage of P. berghei was evaluated as well. 3-(4-Chlorophenyl)-1-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]urea ( 4l ) was the most active compound (IC 50 = 42 nM; cytotoxicity/activity ratio >2000). Our results bring new insights into development of novel anti-TB and antimalarial compounds. [ABSTRACT FROM AUTHOR]

A limited number of novel 3-nitrotriazole- and 2-nitroimidazole-linked quinolines and quinazolines were synthesized and screened for in vitro antitrypanosomal and antitubercular activities as well as cytotoxicity in normal cells. All compounds were active against T. cruzi amastigotes, while all but one were active or moderately active against T. b. rhodesiense . However, only two chloroquinolines exhibited satisfactory selectivity indices (SI) against T. cruzi and only one of them demonstrated a satisfactory SI against T. b. rhodesiense . All tested compounds demonstrated a Minimum Inhibitory Concentration (MIC) ≥ 200 μM against aerobic Mtb. However, the 2-nitroimidazole-based analogs were active against hypoxic Mtb with MIC values 2.89–9.18 μM. The present data support our previous observations that 2-nitroimidazole-based aromatic amines are selectively active against nonreplicating Mtb , while 3-nitrotriazole-based aromatic amines are potent antichagasic agents. [ABSTRACT FROM AUTHOR]

In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1 H )-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentrations against Mycobacterium tuberculosis H37Ra below 10 μM and against Mycobacterium bovis AN5A below 15 μM but were inactive against faster growing mycobacterial species. None of these selected derivatives showed significant acute toxicity against MRC-5 cells or early signs of genotoxicity in the Vitotox™ assay at the active concentration range. The structure activity study relation provided some insight in the further favourable substitution pattern at the 4-hydroxyquinolin-2(1 H )-one scaffold and finally 6-fluoro-4-hydroxy-3-phenylquinolin-2(1 H )-one ( 38 ) was selected as the most promising member of the library with a MIC of 3.2 μM and a CC 50 against MRC-5 of 67.4 μM. [ABSTRACT FROM AUTHOR]

Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have generated extended research interest in natural products in the hope of devising new antitubercular leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards various resistant strains of M. tuberculosis . Extensive applications of alkaloids in the field of therapeutics is well-established and nowday's researches being pursued to develop new potent drugs from natural sources for tuberculosis. Alkaloids are categorized in quite a few groups according to their structures and isolation from both terrestrial and marine sources. These new drugs might be a watershed in the battle against tuberculosis. This review summarizes alkaloids, which were found active against Mycobacteria since last ten years with special attention on the study of structure-activity relationship (SAR) and mode of action with their impact in drug discovery and development against tuberculosis. [ABSTRACT FROM AUTHOR]

In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis , including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects. 2-Substituted 5-(3,5-dinitrophenyl)-2 H -tetrazole regioisomers, which are the dominant products of 5-(3,5-dinitrophenyl)-1 H -tetrazole alkylation, showed better properties with respect to antimycobacterial activity and cytotoxicity than their 1-substituted counterparts. The 2-substituent of 5-(3,5-dinitrophenyl)-2 H -tetrazole can be easily modified and can thus be used for the structure optimization of these promising antitubercular agents. The introduction of a tetrazole-5-thioalkyl moiety at position 2 of the tetrazole further increased the antimycobacterial activity. These compounds showed outstanding in vitro activity against M. tuberculosis (MIC values as low as 0.03 μM) and high activity against non-tuberculous mycobacterial strains. [ABSTRACT FROM AUTHOR]

Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1 H -tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis , including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 μM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents. [ABSTRACT FROM AUTHOR]

A collection of 1,2,3-triazoles unsaturated fatty acid mimics were efficiently synthesized by click chemistry. The 1,4-disubstituted analogs prepared covered different alkyl chain lengths and triazole positions. The compounds were subsequently tested against Mycobacterium tuberculosis , being most of them active with some of the analogs displaying activity at micromolar concentration. The most potent member of the series has the triazole moiety on the C-2 position with a carbon chain of eight or ten carbon atoms. The 1,5-isomers of the most active analog were significantly less active than the original isomer. The activity of the selected hit was assayed on several clinical MTB multi-drug resistant strains providing the same MIC. [ABSTRACT FROM AUTHOR]

A series of rhodanine incorporated quinoline derivatives were efficiently synthesized using reusable DBU acetate as ionic liquid and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) (ATCC 25177) and Mycobacterium bovis BCG (ATCC 35743) both in active and dormant state. Compounds 3e , 3f , 3g , 3h and 3i exhibited very good antitubercular activity. The active compounds were studied for cytotoxicity against HUVEC, THP-1, macrophages, A549, PANC-1 and HeLa cell lines using modified MTT assay and were found to be noncytotoxic. Inactivity of all these compounds against Gram positive and Gram negative bacteria indicates their specificity towards the MTB. Further, the synthesized compounds have been screened for their in vitro antifungal activity. In addition, the molecular docking studies revealed the binding modes of these compounds in active site of Zmp1 enzyme, which in turn helped to establish a structural basis of inhibition of mycobacteria. The results of present study clearly indicate the identification of some novel, selective and specific inhibitors against MTB that can be explored further for potential antitubercular drug. [ABSTRACT FROM AUTHOR]

Small molecules with antitubercular activity containing the pyrimidine motif in their structure have gained more attention after three drugs, namely GSK 2556286 (GSK-286), TBA-7371 and SPR720, have entered clinical trials. This review provides an overview of recent advances in the hit-to-lead drug discovery studies of antitubercular pyrimidine-containing compounds with the aim to highlight their structural diversity. In the first part, the review discusses the pyrimidine compounds according to their targets, pinpointing the structure-activity relationships of each pyrimidine family. The second part of this review is concentrated on antitubercular pyrimidine derivatives with a yet unexplored or speculative target, dividing the compounds according to their structural types. [Display omitted] • Pyrimidine represents a valuable scaffold in the discovery of antitubercular agents. • There are currently investigated three clinical candidates with pyrimidine core. • Pyrimidine-based drugs are sub-classified according to their mechanism of action. [ABSTRACT FROM AUTHOR]

Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (Mt InhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity relationships led to novel submicromolar inhibitors of Mt InhA and potent antitubercular agents. The lead compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals, satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-aminoquinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug-resistant tuberculosis treatments. [Display omitted] • InhA enzyme inhibition and thermodynamics of ligand binding of best candidates. • 4-aminoquinolines that inhibit in vitro Mycobacterium tuberculosis growth. • 4-aminoquinolines against drug-resistant strains of Mycobacterium tuberculosis. • High selectivity index of 4-aminoquinolines. • Bacteriostatic effect of 4-aminoquinoline in M. tuberculosis mouse infection model. [ABSTRACT FROM AUTHOR]

The practice of polypharmacology is not a new concept but the approaches which are being adopted for administering the two or more drugs together are varied from time to time. Taking two or more drugs simultaneously, co-formulation of two or more active agents in a single tablet and development of hybrid molecular entities capable to modulate multiple targets are the three popular approaches for multidrug therapy. The simultaneous use of more than one drug for the chemotherapy of a single disease demands a lot of patient compliance. Hence the present form of polypharmacology is gaining popularity in the form of hybrid molecules (multiple ligand approach). From the last 1-2 decades, the synthesis of hybrid molecules by the combination of different biologically relevant moieties has been under constant escalation along with their evaluation as diverse range of pharmacological agents and as potent drugs. This review is focused on the biological potential of hybrid molecules with particular mention of those exhibiting anti-fungal, anti-tuberculosis, anti-malarial, anti-inflammatory and anti-cancer activities. A comparison of the drug potency of the hybrid molecules with their individual counterparts is discussed for quantifying the significance of the concept of molecular hybridisation. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2- N -oxide) (compounds 4a-c , 8a-c and 14a-c ) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTB) H 37 Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC 90 values ranging from 1.03 to 62 μM (H 37 Rv) and 7.0–50.0 μM (MDR-TB). For the most active compounds ( 8c , 14a , 14b and 14c ) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25–34.78 (J774A.1 cells). In addition, it was characterized for those compounds log P o/w values between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c ) were the best NO-donor with the lowest MIC 90 values. The most active compound ( 14c ) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis. [ABSTRACT FROM AUTHOR]

The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index. [ABSTRACT FROM AUTHOR]

A structure based medium throughput virtual screening campaign of BITS-Pilani in house chemical library to identify novel binders of Mycobacterium tuberculosis gyrase ATPase domain led to the discovery of a quinoline scaffold. Further medicinal chemistry explorations on the right hand core of the early hit, engendered a potent lead demonstrating superior efficacy both in the enzyme and whole cell screening assay. The binding affinity shown at the enzyme level was further corroborated by biophysical characterization techniques. Early pharmacokinetic evaluation of the optimized analogue was encouraging and provides interesting potential for further optimization. [ABSTRACT FROM AUTHOR]

Novel pyrrolyl hydrazones and their copper complexes have been synthesized and characterized using analytical and spectral techniques to show the tetrahedral geometry for Cu(II) complexes. Biological activities of hydrazones have been assessed to understand the role of metal ion on their biological activity and the effect of pyrrolyl hydrazones. In vitro antitubercular activity against Mycobacterium tuberculosis of the metal complexes ( 13b and 13r ) exhibited the highest antitubercular activity that are quite close to rifampicin (0.4 μg/mL), giving a MIC of 0.8 μg/mL. All other compounds showed good activity with the MIC values ranging from 1.6 to 100 μg/mL. A comparative study of inhibition values of the ligands and their complexes showed higher antimicrobial activity of the complexes than the ligands. Some compounds have a good activity against InhA and in particular, compounds 12r , 13b and 13r exhibited more than 60% binding with the enzyme even at 5 μM (exhibited good IC50 upto 2.4 μM). Most of the active molecules have a very less cytotoxicity against the human lung cancer cell-line A549. The docking and 3D-QSAR studies have been carried out to provide some insights into the mechanism of action for this class of compounds. [ABSTRACT FROM AUTHOR]

Isoniazid is a cornerstone of modern tuberculosis (TB) therapy and targets the enoyl ACP reductase InhA, a key enzyme in mycolic acid biosynthesis. InhA is still a promising target for the development of new anti-TB drugs. Herein, we report the design, synthesis, and anti-tubercular activity of new isoniazid hybrids. Among these, 1 H -1,2,3 triazole-tethered quinoline-isoniazid conjugates 16a to 16g exhibited high activity against Mycobacterium tuberculosis with minimal inhibitory concentrations in the 0.25–0.50 μg/mL range and were bactericidal in vitro. Importantly, these compounds were well tolerated at high doses on mammalian cells, leading to high selectivity indices. The hybrids were dependent on functional KatG production to inhibit mycolic acid biosynthesis. Moreover, overexpression of InhA in M. tuberculosis resulted in high resistance levels to 16a - 16g and reduced mycolic acid biosynthesis inhibition, similar to isoniazid. Overall, these findings suggest that the synthesized quinoline-isoniazid hybrids are promising anti-tubercular molecules, which require further pre-clinical evaluation. [Display omitted] • Quinoline-based hydrazones were designed and assayed against mycobacteria. • Quinoline-isoniazid hybrids are promising compounds against M. tuberculosis. • They exhibit low MIC values and low toxicity on mammalian cells. • These compounds are bactericidal and target the enoyl ACP reductase InhA. • The compounds inhibit mycolic acid biosynthesis. [ABSTRACT FROM AUTHOR]

The benzo[ d ]thiazol-2-yl(piperazin-1-yl)methanones scaffold has been identified as new anti-mycobacterial chemotypes. Thirty-six structurally diverse benzo[ d ]thiazole-2-carboxamides have been prepared and subjected to assessment of their potential anti-tubercular activity through in vitro testing against Mycobacterium tuberculosis H 37 Rv strain and evaluation of cytotoxicity against RAW 264.7 cell lines. Seventeen compounds showed anti-mycobacterial potential having MICs in the low (1–10) μM range. The 5-trifluoromethyl benzo[ d ]thiazol-2-yl(piperazin-1-yl)methanones emerged to be the most promising resulting in six positive hits (2.35–7.94 μM) and showed low-cytotoxicity (<50% inhibition at 50 μg/mL). The therapeutic index of these hits is 8–64. The quantitative structure activity relationship has been established adopting a statistically reliable CoMFA model showing high prediction ( r p r e d 2 = 0.718 , r n c v 2 = 0.995 ) . [ABSTRACT FROM AUTHOR]

Molecular hybridization is an emerging approach to design novel ligands by combination of two or more pharmacophoric subunits of known bioactive compounds. In the present study, we have designed a novel series of diarylpiperazine analogues, synthesized, characterized using FTIR, 1 H NMR, Mass, Elemental analysis and evaluated their in-vitro anti-tubercular activity. Among the reported sixteen diarylpiperazines, eleven analogues exhibited significant anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC values below 6.25 μg/mL and good selectivity index. Structure activity relationship studies concluded that, ortho-para directing group (except para chloro) substitution on ortho and para position of piperazine attached phenyl ring favored anti-tubercular activity. [ABSTRACT FROM AUTHOR]

Tuberculosis, caused by Mycobacterium tuberculosis , remains a serious global health threat, highlighting the urgent need for novel antituberculosis drugs. The shikimate pathway, responsible for aromatic amino acid biosynthesis, is required for the growth of Mycobacterium tuberculosis and is a potential drug target. 3-deoxy-D- arabino -heptulosonate 7-phosphate synthase (mtDAH7Ps) catalyzes the first step in shikimate pathway. E-pharmacophore models for inhibitors of mtDAH7Ps - tyrosine, phenylalanine, phosphoenolpyruvate and (2S)-2,7-bis(phosphonooxy)heptanoic acid were screened against ZINC synthetic and natural compounds databases. The shortlisted compounds were subjected to induce fit docking and validated by Prime/Molecular Mechanics Generalized Born Surface Area calculation to predict ligand binding energy and ligand strain energy for ligand and receptor. The lead compounds were screened for their inhibitory activity against purified mtDAH7Ps enzyme. Lead compounds inhibited mtDAH7Ps in a concentration-dependent manner; with an IC 50 value of 21 μM, 42 μM and 54 μM for α-Tocopherol, rutin and 3-Pyridine carboxyaldehyde respectively. Molecular Dynamics analysis for 50 ns of the active compounds–mtDAH7Ps complexes showed that the backbone of mtDAH7Ps was stable. These results suggest that α-tocopherol, 3 - Pyridine carboxyaldehyde and rutin could be novel drug leads to inhibit mtDAH7Ps in M. tuberculosis . [ABSTRACT FROM AUTHOR]

TB, caused by Mycobacterium tuberculosis , is one of the deadliest infections worldwide. The co-infection with HIV and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains have further increased the burden for this disease. In the attempt to respond to the constant need of novel therapeutic options, we herein report the discovery of 2,4-diphenyl-1 H -imidazoles as effective antitubercular agents, with MIC in the low micromolar range against actively replicating and persistent M. tuberculosis strains. The good activity, along with the lack of toxicity and the feasible synthesis, underscore their value as novel scaffolds for the development of new anti-TB drugs. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is still a challenging worldwide health problem and mycobacterium tuberculosis ( MTB ) remains one of the most deadly human pathogens. TB is the second leading infectious cause of mortality today behind only HIV/AIDS. The impetus for developing new structural classes of antituberculosis drugs comes from the emergence of multi-drug resistant (MDR) strains. The development of MDR strains to commonly used drugs is due to, longer durations of therapy as results of resistance, and the resurgence of the disease in immune compromised patients. Therefore, there is an urgent need to explore new antitubercular (anti-TB) agents. Ironically, the low number of potentially new chemical entities which can act as anti-TB candidates is of great importance at present situation. Considering the severity of the problem, WHO has prepared a strategic plan in Berlin declaration 2007 to stop TB, globally. Among the oxygen heterocycles, coumarin derivatives are important motifs, which can be widely found in many natural products, and many of them displaying diverse biological activities. This spectacular spectrum of applications has intrigued organic and medicinal chemists for decades to explore the natural coumarins or their synthetic analogs for their applicability as anti-TB drugs. To pave the way for the future research, there is a need to collect the latest information in this promising area. In the present review, we collated published reports on coumarin derivatives to shed light on the insights on different types of methods reported for their preparations, characterizations and anti-TB applications, so that its full therapeutic potential class of compounds can be utilized for the treatment of tuberculosis. Therefore, the objective of this review is to focus on important coumarin analogs with anti-TB activities, and structure-activity relationships (SAR) for designing the better anti-TB agents. It is hoped that, this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic coumarin-based anti-TB drugs. [ABSTRACT FROM AUTHOR]

Meridianins are marine-derived indole alkaloids, known to possess kinase inhibitory and antimalarial activities. A series of N -aryl and heteroaryl sulfonamide derivatives of meridianins were prepared and screened for antimalarial activity against D6 and W2 strains of Plasmodium falciparum . 2-Nitro-4-trifluoromethyl sulfonamide derivative 14v displayed promising antiplasmodial activity against both strains with IC 50 values of 2.56 and 3.41 μM, respectively. These compounds were not cytotoxic to mammalian cell lines including VERO (monkey kidney fibroblasts), LLC-PK1 (pig kidney epithelial cells) and four cancer cell lines; SK-MEL (human malignant, melanoma), KB (human epidermal carcinoma), BT-549 (ductal carcinoma), SK-OV-3 (human ovary carcinoma) up to 25 μg/ml. Furthermore, all sulfonamide derivatives along with acyl, alkyl and C-ring modified derivatives of meridianins were screened for antitubercular activity against a sensitive strain (H 37 Rv) of Mycobacterium tuberculosis (Mtb), wherein several compounds showed MIC values in the range of 5.2–304.8 μM. Meridianin C ( 3 ) and meridianin G ( 7 ) showed anti-tubercular activity with MIC values of 111.1 and 304.8 μM, respectively. The C-ring modified analog 12 exhibited potent anti-tubercular activity against H 37 Rv strain of Mtb with MIC of 5.2 μM. Furthermore, the most potent analogs 11b and 12 were screened against two clinical isolates of M. tuberculosis INH R and MDR and one laboratory generated mutant strain Rif R . These two analogs 11b and 12 displayed promising activity against these resistant strains with MIC values in the range of 5.2–187.7 μM. This is the first report on the anti-tubercular activity of this scaffold. [ABSTRACT FROM AUTHOR]

The synthesis and anti-tuberculosis activity for three series of 2,4-disubstituted quinolines is reported. The synthesized compounds were evaluated for activity against M. tuberculosis H37Rv strain; most promising compounds from the series exhibited MIC 99 values ranged between 3.125 and 6.25 μg/mL. None of the compounds exhibited cytotoxicity up to the highest test concentration of 200 μg/mL. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). Atom-fit alignment provided the best model, and allowed prediction of the activity of molecules in the test sets leading to the rationalization of the relationship between structure and activity. [ABSTRACT FROM AUTHOR]

A series of novel 1 H -benzo[ d ]imidazole derivatives and analogues ( 1 – 25 ) have been synthesized and evaluated for tuberculostatic activity. Benzimidazoles substituted at the C-2 position with cyclohexylethyl, cyclohexylpropyl and phenylpropyl moiety or 4-phenylpyridine system were obtained. Compounds 3 , 4 , 6 and 7 bearing halogen atoms or methyl groups at the benzimidazole system and cyclohexylethyl substituent at the C-2 position showed an excellent tuberculostatic activity against Mycobacterium tuberculosis and Mycobacterium bovis strains with MIC values ranging from 0.75 to 1.5 μg/mL. More importantly, derivatives 4 (5-Bromo-2-(2-cyclohexylethyl)-1 H -benzo[ d ]imidazole) and 6 (2-(2-cyclohexylethyl)-5,6-dimethyl-1 H -benzo[ d ]imidazole) appeared selective for M. tuberculosis and M. bovis as compared with non-malignant eukaryotic cells (LLC-PK1 pig kidney epithelial cell line). These compounds may thus represent a novel, selective class of anti-tubercular agents. [ABSTRACT FROM AUTHOR]

Various classes of natural products and synthetic compounds were tested against reference strains and clinical multidrug resistant isolates of Mycobacterium tuberculosis . Vermelhotin ( 19 ), a natural tetramic acid from fungi, was the most active toward clinical MDR TB isolates (MIC 1.5–12.5 μg/mL). Synthetic compounds (i.e. benzoxazocines, coumarins, chromenes, and pyrrolodiquinoline derivatives) were prepared by green chemistry approaches. Under microwave irradiation, a one-pot synthesis of pyrrolodiquinoline 85 was achieved by homocoupling of 1-methylquinolinium iodide; the structure of 85 was confirmed by single-crystal X-ray analysis. Compound 85 and its derivative 86 exhibited potent anti-tubercular activity (MIC 0.3–6.2 μg/mL) against clinical MDR TB isolates, and they displayed weak cytotoxicity toward normal cell line. The scaffold of 85 and 86 is potential for antimycobacterial activity. [ABSTRACT FROM AUTHOR]

In this communication, we synthesized a series of twenty four novel 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[ d ]isoxazole analogues, characterized using various spectroscopic techniques and evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) H 37 Rv strain. The titled compounds exhibited Minimum inhibitory concentration (MIC) between 3.125 and >50 μg/mL. Among the tested compounds, 5c , 6a , 6j and 6p exhibited moderate activity (MIC = 12.5 μg/mL), while 5a and 6i exhibited good activity (MIC = 6.25 μg/mL) and 6b (MIC = 3.125 μg/mL) exhibited very good anti-tubercular activity. In addition, the analogues 5a , 5c , 6a , 6b , 6i , 6j and 6p were subjected to toxicity studies against mouse macrophage (RAW 264.7) cell lines to analyse the selectivity profile of the newly synthesized compounds and selectivity index of the most active compound was found to be >130 indicating suitability of the compound for further drug development. Structure of 6b was further substantiated through single crystal XRD. [ABSTRACT FROM AUTHOR]

In the search for new therapeutic tools against tuberculosis and to further address the therapeutic potential of pyridine-2-thiol 1-oxide (Hmpo) metal complexes, two new octahedral [M III (mpo) 3 ] complexes, with M = Ga or Bi, were synthesized and characterized in the solid state and in solution. Attempts to crystallize [Ga III (mpo) 3 ] in CH 2 Cl 2 led to single crystals of the reaction product [GaCl(mpo) 2 ], where the gallium(III) ion is in a square basis pyramidal environment, trans -coordinated at the basis to two pyridine-2-thiolato 1-oxide anions acting as bidentate ligands through their oxygen and sulfur atoms. The biological activity of the new [M III (mpo) 3 ] complexes together with that of the previously reported Fe(III) analogous compound and the pyridine-2-thiol 1-oxide sodium salt (Na mpo) was evaluated on Mycobacterium tuberculosis . The compounds showed excellent activity, both in the standard strain H 37 Rv ATCC 27294 (pan-susceptible) and in five clinical isolates that are resistant to the standard first-line anti-tuberculosis drugs isoniazid and rifampicin. These pyridine-2-thiol 1-oxide derivatives are promising compounds for the treatment of resistant tuberculosis. [ABSTRACT FROM AUTHOR]

A new series of new diphenylamine containing 1,2,4-triazoles were synthesized from 4-arylideneamino-5-[2-(2,6-dichlorophenylamino) benzyl]-2H-1,2,4-triazole-3(4H)-thiones 3a-f. The synthesized compounds were screened for in-vitro antimycobacterial and antibacterial activities. The synthesized compounds 4a, 4e and 4d have shown potential activity against Mycobacterium tuberculosis H37Rv strain with MIC of 0.2, 1.6 and 3.125 µM respectively. To investigate the SAR of diphenylamine containing 1,2,4-triazole derivatives in more details, CoMFA (q²-0.432, r²-0.902) and CoMSIA (q²-0.511, r²-0.953) models on M. tuberculosis H37Rv were established. The generated 3D-QSAR models are externally validated and have shown significant statistical results, and these models can be used for further rational design of novel diphenylamine containing 1,2,4-triazoles as potent antitubercular agents. [ABSTRACT FROM AUTHOR]

Mycobacterial resistance is a rapidly increasing phenomenon requiring the identification of new drugs effective against multidrug-resistant pathogens. The inhibition of protein tyrosine phosphatase B (MptpB), which interferes with host immune responses, may provide a new strategy to fight tuberculosis (TB), while preventing cross-resistance issues. On this basis, starting from a virtual screening (VS) campaign and subsequent structure elucidation studies guided by X-ray analyses, an unexpected γ-lactone derivative (compound 1) with a significant enzymatic activity against MptpB was identified. The structural characterization of compound 1 was described by means of NMR spectroscopy, HRMS, single crystal X-ray diffraction and Hirshfeld surface analysis, allowing a detailed conformational investigation. Notably, the HPLC separation of (±)- 1 led to the isolation of the most active isomer, which emerged as a very promising MptpB inhibitor, with an IC 50 value of 31.1 μM. Overall, the new chemotype described herein might serve as a basis for the development of novel treatments against TB infections. [Display omitted] • Novel MptpB inhibitors were identified through a receptor-based virtual screening study. • X-ray studies revealed an unexpected chiral structure for the most active inhibitor 1. • HPLC separation allowed the isolation of the eutomer, which proved to be a valuable lead MptpB inhibitor. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para -Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis , has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N -acetylation and fluorination of the aryl ring of PAS to attenuate N -acetylation by electronically deactivating the para -amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug. [Display omitted] • p -Aminosalicylic acid (PAS), a potent anti-tubercular agent, has limiting oral bioavailability. • Prodrugs and structural analogs improve pharmacokinetic properties of drugs. • Pivoxyl PAS prodrug quantitatively improves oral bioavailability of PAS. • PAS analogs show a 5 to 430-fold improvement in oral bioavailability, but result in a loss of potency. • Increased exposures of 5-Fluoro PAS and N-Methyl PAS are due to poor substrate specificities towards N-acetyl transferase 1. [ABSTRACT FROM AUTHOR]

Abstract: In this work, a new class of highly potent antituberculosis agents, 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their oxa and selanyl analogs, is described. The minimal inhibitory concentration (MIC) values reached 1 μM (0.36–0.44 μg/mL) against Mycobacterium tuberculosis CNCTC My 331/88 and 0.25–1 μM against six multidrug-resistant clinically isolated strains of M. tuberculosis. The antimycobacterial effects of these compounds were highly specific because they were ineffective against all eight bacterial strains and eight fungal strains studied. Furthermore, these compounds exhibited low in vitro toxicity in four mammalian cell lines (IC50 > 30 μM). We also examined the structure–activity relationships of the compounds, particularly the effects on antimycobacterial activity of the number and position of the nitro groups, the linker between tetrazole and benzyl moieties, and the tetrazole itself. Relatively high variability of substituent R1 on the tetrazole in the absence of negative effects on antimycobacterial activity allows further structural optimization with respect to toxicity and the ADME properties of the 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles lead compounds. [Copyright &y& Elsevier]

Abstract: The disturbing emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has been driving the scientific community to urgently search for new and efficient antitubercular drugs. Despite the various drugs currently under evaluation, isoniazid is still the key and most effective component in all multi-therapeutic regimens recommended by the WHO. This paper describes the QSAR-oriented design, synthesis and in vitro antitubercular activity of several potent isoniazid derivatives (isonicotinoyl hydrazones and isonicotinoyl hydrazides) against H37Rv and two resistant Mtb strains. QSAR studies entailed RFs and ASNNs classification models, as well as MLR models. Strict validation procedures were used to guarantee the models' robustness and predictive ability. Lipophilicity was shown not to be relevant to explain the activity of these derivatives, whereas shorter N–N distances and lengthy substituents lead to more active compounds. Compounds 1, 2, 4, 5 and 6, showed measured activities against H37Rv higher than INH (i.e., MIC ≤ 0.28 μM), while compound 9 exhibited a six fold decrease in MIC against the katG (S315T) mutated strain, by comparison with INH (i.e., 6.9 vs. 43.8 μM). All compounds were ineffective against H37RvINH (ΔkatG), a strain with a full deletion of the katG gene, thus corroborating the importance of KatG in the activation of INH-based compounds. The most potent compounds were also shown not to be cytotoxic up to a concentration 500 times higher than MIC. [Copyright &y& Elsevier]

Abstract: The rapid generation and spread of the drug resistant tuberculosis has led to an ongoing demand for novel compounds for therapeutic use. Identification and study of compounds with the ability to inhibit Mycobacterium tuberculosis is of paramount importance. For this reason, a library of substituted 1,3-diaryltriazenes based on the acting component of the anti-trypanosomal drug, diminazene aceturate was created and evaluated for its potential as anti-tubercular agent. Several compounds were identified with sub-micro molar inhibitory concentrations against M. tuberculosis and other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. Although the library of the compounds showed a considerable acute cytotoxicity, a genotoxicity could not be observed. Finally, the triazene 14 was selected with the best biological properties (IC 50 = 3.26 μM, NI 50 = 24.22 μM, SI = 7.44). The compound 14 showed the ability to inhibit the growth of intracellular replicating and multi-drug resistant M. tuberculosis. The results suggest the molecule to be an interesting scaffold for further study and optimization. [Copyright &y& Elsevier]

Abstract: A series of benzfused heterocyclic derivatives such as amide conjugates of 2-(benzo[d]thiazol-2-ylthio)acetic acid with aromatic/aliphatic/cyclic secondary amines (5a–5o & 8a–8m); 1,2,3-triazole conjugates of 2-mercaptobenzothiazoles and amide conjugates of indole-3-glyoxalic acid with cyclic secondary amines (14a–14g) have been synthesized and were screened for their antitubercular activity against Mycobacterium tuberculosis H37Rv strain by broth microdilution assay method. Compounds 8b, 8f, 8g and 8l inhibited the growth of the H37Rv strain at concentrations of 8 μg/mL. These compounds (8b, 8f, 8g and 8l) have been further identified as bactericidal and are completely killing the microbes at 32–64 μg/mL concentrations. Molecular docking studies of the active compounds reveal that these compounds are targeting DprE1 and may act as DprE1 inhibitors. [Copyright &y& Elsevier]

Abstract: A series of new amidoalcohols and amidodiols were designed on the base of the camphor scaffold and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and MDR strain 43. Some of the new compounds show 25 times higher activity than the classical anti-TB drug ethambutol. Small structural changes in the side chain shift the activity from micromolar to nanomolar inhibitory concentrations. Quantitative structure–activity relationship (QSAR) model is derived to guide the further lead optimization. Two hydrogen bond donors and up to three rings in the molecules are optimal for nanomolar activity. The camphane-based amides present novel promising scaffolds for antimycobacterial agents. [Copyright &y& Elsevier]