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

Abstract

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

Quinoline Derivatives with Potential Activity Against Multidrug‐resistant Tuberculosis

Tuberculosis (TB), which affects primarily the lungs (pulmonary TB) apart from other vital organs, is a life‐threatening chronic deadliest infectious disease caused by members of Mycobacterium tuberculosis (MTB) complex and mainly by MTB itself. The emergence of MTB new virulent forms that are resistant to some or all first‐line and second‐line anti‐TB agents, including multidrug‐resistant (MDR), extensively drug‐resistant, and totally drug‐resistant strains has further aggravated the spread of this disease and was increased up to an alarming level in the recent decades. More than ever, it is imperative to develop novel, high effective, and fast acting anti‐TB drugs to prevent the spread of TB, particularly in its hard‐to‐kill MDR‐TB, extensively drug‐resistant‐TB, and totally drug‐resistant‐TB strains. In recent years, numerous compounds have been synthesized for this purpose, but only a handful of compounds have entered human trials after the discovery of rifampicin, reflecting the inherent difficulties of developing new anti‐TB agents. Despite of bedaquiline and delamanid have received approval from many countries for treatment of MDR‐TB infected patients, both drugs are associated with serious side effects and are only recommended for those MDR‐TB patients without other treatment options. All these aforementioned facts make it an urgent need to develop novel drugs. Quinoline‐based derivatives including quinolones ex biological activities, and some of them displayed excellent in vitro and in vivo activities against MDR‐TB. This review outlines the recent developments of quinoline‐based derivatives with potential activity against MDR‐TB as well as the structure–activity relationship.     

Heteronuclear 5‐Fluoroisatin Dimers: Design,Synthesis, and Evaluation of Their In Vitro Anti‐mycobacterial Activities

A series of novel heteronuclear 5‐fluoroisatin dimers 4a–j tethered through ethylene were designed, synthesized, and examined for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis H37Rv and multi‐drug resistant tuberculosis (MDR‐TB). All hybrids exhibited potential anti‐mycobacterial activities against the tested two strains with minimum inhibitory concentration (MIC) in a range of 25 to 256 μg/mL. In particular, the heteronuclear 5‐fluoroisatin dimer 4a (MIC: 25 and 32 μg/mL) was most active against Mycobacterium tuberculosis H37Rv and MDR‐TB strains, which was twofold and greater than fourfold more potent than rifampicin (MIC: 64 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR‐TB, warrant further optimization.     

Design,Synthesis, and Antimycobacterial Activities of Diethylene Glycol Tethered Moxifloxacin–Isatin Hybrids

A new class of diethylene glycol tethered moxifloxacin–isatin hybrids 5a–l was designed, synthesized, and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant tuberculosis (MDR‐TB) strains. Our results showed that all hybrids with higher lipophilicity than the parent moxifloxacin exhibited promising activity against the tested strains with minimum inhibitory concentration (MIC) in a range of 0.2–16 μg/mL. In particular, hybrid 5h (MIC: 0.20 and 0.5 μg/mL), which was found to be most active against MTB H37Rv and MDR‐TB, was twofold more potent than isoniazid (MIC: 0.39 μg/mL) against MTB H37Rv and ≥64‐fold more active than isoniazid and rifampicin (MIC: >128 and 32 μg/mL, respectively) against MDR‐TB.     

Design,Synthesis, and in vitro Anti‐mycobacterial Activities of Propylene‐tethered Heteronuclear Bis‐isatin Derivatives

A series of novel propylene‐tethered heteronuclear bis‐isatin derivatives were designed, synthesized, and assessed for their in vitro and anti‐mycobacterial activities. All hybrids exhibited considerable antibacterial and anti‐mycobacterial activities against Mycobacterium tuberculosis H37Rv and multi‐drug‐resistant tuberculosis (MDR‐TB) with minimum inhibitory concentration (MIC) ranging from 16 to 256 μg/mL. In particular, the heteronuclear bis‐isatin 4i (MIC: 25 and 16 μg/mL) was most active against M. tuberculosis H₃₇Rv and MDR‐TB strains, which was fourfold and greater than eightfold more potent than the first‐line anti‐tubercular agents rifampicin (MIC: 64 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR‐TB, could act as a lead for further optimization.     

Design,Synthesis and In Vitro Antitubercular Evaluation of Isatin‐ciprofloxacin Hybrids with Hydrogen Bonding Capacity

A series of novel isatin‐ciprofloxacin hybrids inhaling oxime, semicarbazone, and thiosemicarbazone groups with hydrogen bonding capacity were designed, synthesized, and evaluated for their in vitro antitubercular activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant‐TB (MDR‐TB). All hybrids endowed with potential activities against the tested MTB H37Rv and MDR‐TB strains with minimum inhibitory concentration (MIC) in a range of 0.20 to 128 μg/mL. In particular, the most active hybrid 5e (MIC: 0.20 and 0.5 μg/mL) was four and two times more active than the parent ciprofloxacin (MIC: 0.78 μg/mL) and rifampicin (MIC: 0.39 μg/mL) against MTB H37Rv, and 4–>256 times more potent than the three references ciprofloxacin (MIC: 2.0 μg/mL), rifampicin (MIC: 32 μg/mL), and isoniazid (>128 μg/mL) against MDR‐TB. Thus, this kind of hybrids holds great promise as future anti‐TB agents against both drug‐sensitive and drug‐resistant MTB strains infection.     

Antimycobacterial 3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones substituted on phenyl and benzoxazine moiety in position 6

A series of forty-five derivatives of 3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and forty-five derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones was synthesised. The compounds exhibited in-vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains), and M. avium. The most active derivatives were more active than isonicotinhydrazide (INH). The quantitative relationships between the structure and antimycobacterial activity were calculated. The activity against M. tuberculosis increased with the lipophilicity of the substituents.     

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

Abstract

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

Tetraethylene Glycol Tethered Heteronuclear Bis‐isatin Derivatives: Design,Synthesis, and In Vitro Anti‐mycobacterial Activities

A series of novel tetraethylene glycol tethered heteronuclear bis‐isatin derivatives 7a – l were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant TB (MDR‐TB) as well as cytotoxicity in VERO cell line. All hybrids exhibited potential anti‐mycobacterial activities against MTB H37Rv and MDR‐TB, and acceptable cytotoxicity. Among them, the heteronuclear bis‐isatin 7l [minimum inhibitory concentration (MIC): 16 and 16 μg/mL] was found to be most active against MTB H37Rv and MDR‐TB strains, which was 2‐fold and >8‐fold, respectively, more potent than were the first‐line anti‐tubercular agents rifampicin (MIC: 32 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR‐TB, also demonstrated acceptable cytotoxicity profile (CC₅₀: 62.5 μg/mL), could act as a starting point for further optimization.     

A convenient route to α-amido-β-lactams

Dedicated to Professor John C. Sheehan on the occasion of his sixty-fifth birthday. A method for the synthesis of α-amido-β-lactams without the intermediacy of an α-amino-β-lactam is described. The appropriate β-keto ester is used for preparing a vinylamino β-lactam via a “Dane salt” by a previously reported method. Oxidation with ruthenium tetroxide and periodic acid of this product leads directly to the desired “V”, or “G” or analogous α-amido side chain.     

Synthesis and Antimycobacterial Evaluation on Arylsulfonyl and Arylcarbonyl Derivatives of Ofloxacin

Four ofloxacin derivatives 3, 5, 6 , and 11 were found to exhibit > 90% inhibition on the growth of M. tuberculosis at a concentration of 6.25 μg/mL. Compounds 3, 5 and 11 have also exhibited a broad spectrum of antibacterial activities while 8‐fluoro‐3‐methyl‐9‐[4‐(4‐nitrophenylsulfonyl)piperazin‐1‐yl)‐6‐oxo‐2,3‐dihydro‐6H‐1‐oxo‐3a‐azaphenalene‐5‐carboxylic acid ( 6 ), which exhibited potent activity against the growth of TB with the MIC of 2.23 μg/mL and a selectivity index (SI) of > 14.80, was inactive against the growth of G(+)‐ and G(‐)‐bacteria. Selective anti‐TB activity was achieved by the introduction of an arylsulfonyl group at C‐7 piperazin‐4‐yl of N‐demethyl ofloxacin. Compound 6 is species‐specific, exhibiting no significant activity against the growth of bacterial species other than M. tuberculosis, which implied the possibility of developing new specific anti‐TB drug candidates without inducing cross resistance with other currently used antibacterial drugs. Structural optimization of 6 is on‐going.     

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

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

Bioactives of Microbes Isolated from Western Ghat Belt of Kerala Show β-Lactamase Inhibition along with Wide Spectrum Antimicrobial Activity

The present study describes the exploitation of microbial biodiversity from Western Ghats of Kerala for screening of bioactives having β-lactamase inhibitory activities. A total of 700 pure cultures were isolated and were screened for antibacterial activity against a β-lactam resistant Bacillus cereus strain (PL 10) isolated from the same niche. Bioactive extracts made from 45 isolates showed inhibitory activities against PL 10, of which two strains showed inhibition of extended spectrum β-lactamase (ESBL) producing Klebsiella ESBL1101 and three strains inhibited methicillin-resistant Staphylococcus aureus (MRSA) strain MRSA831. All these five strains showed wide spectrum antimicrobial activity against various fungi and bacteria. These five cultures were identified by 16S rRNA sequencing and biochemical tests and the preliminary characterizations of their bioactive extracts were carried out. This study suggests the potential of bioactives from two inhibitor–producer strains, NII 167 and NII 1054, for being developed as inhibitors against wide spectrum β-lactam resistant strains.     

Cluster‐based molecular docking study for in silico identification of novel 6‐fluoroquinolones as potential inhibitors against Mycobacterium tuberculosis

A classical protein sequence alignment and homology modeling strategy were used for building three Mycobacterium tuberculosis‐DNA gyrase protein models using the available topoII‐DNA‐6FQ crystal structure complexes originating from different organisms. The recently determined M. tuberculosis‐DNA gyrase apoprotein structures and topoII‐DNA‐6FQ complexes were used for defining the 6‐fluoroquinolones (6‐FQs) binding pockets. The quality of the generated models was initially validated by docking of the cocrystallized ligands into their binding site, and subsequently by quantitative evaluation of their discriminatory performances (identification of active/inactive 6‐FQs) for a set of 145 6‐FQs with known biological activity values. The M. tuberculosis‐DNA gyrase model with the highest estimated discriminatory power was selected and used afterwards in an additional molecular docking experiment on a mixed combinatorial set of 427 drug‐like 6‐FQ analogs for which the biological activity values were predicted using a prebuilt counter‐propagation artificial neural network model. A novel three‐level Boolean‐based [T/F (true/false)] clustering algorithm was used to assess the generated binding poses: Level 1 (geometry properties assessment), Level 2 (score‐based clustering and selection of the (T)‐signed highly scored Level 1 poses), and Level 3 (activity‐based clustering and selection of the most “active” (T)‐signed Level 2 hits). The frequency analysis of occurrence of the fragments attached at R₁ and R₇ position of the (T)‐signed 6‐FQs selected in Level 3 revealed several novel attractive fragments and confirmed some previous findings. We believe that this methodology could be successfully used in establishing novel possible structure‐activity relationship recommendations in the 6‐FQs optimization, which could be of great importance in the current antimycobacterial hit‐to‐lead processes. © 2012 Wiley Periodicals, Inc.     

Design,Synthesis and In Vitro Anti‐mycobacterial Activities of 8‐OMe Ciprofloxacin‐1H‐1,2,3‐triazole‐isatin‐(thio) Semicarbazide/Oxime Hybrids

A series of novel 8‐OMe ciprofloxacin (8‐OMe CPFX)‐1H‐1,2,3‐triazole‐isatin‐(thio) semicarbazide/oxime hybrids 6a – l with the capacity to form hydrogen bond were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and MDR‐TB as well as cytotoxicity. All the synthesized hybrids (MIC: 0.39–16 μg/mL) exhibited excellent activities against MTB H₃₇Rv and MDR‐TB, and the majority of them were more potent than the parent 8‐OMe CPFX (MIC: 1.56 and 2.0 μg/mL, respectively). In particular, the most active conjugate 6h (MIC: 0.39 and 1.0 μg/mL, respectively) was two to eight times more potent in vitro than the references CPFX (MIC: 3.12 and 4.0 μg/mL, respectively) and 8‐OMe CPFX against the tested strains and was comparable with or 64‐folds more potent than RIF (MIC: 0.39 and 64 μg/mL, respectively) against MTB H₃₇Rv and MDR‐TB, respectively. In addition, all conjugates (CC₅₀: 16–64 μg/mL) showed acceptable cytotoxicity, although most of them were more toxic than the parent (CC₅₀: 64 μg/mL) in VERO cell line.     

Design,Synthesis, and In Vitro Anti‐mycobacterial Activities of Propylene‐Tethered Gatifloxacin‐Isatin Hybrids

A series of propylene‐tethered mono‐/bis‐isatin‐gatifloxacin hybrids 3a–f and 4a–f were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug‐resistant tuberculosis (MDR‐TB) as well as cytotoxicity against VERO cell line. The results indicated that all hybrids exhibited promising anti‐mycobacterial activities against MTB H37Rv and MDR‐TB with MIC ranging from 0.25 to 16 μg/mL. In particular, the mono‐isatin‐gatifloxacin hybrid 3e (MIC: 0.25 and 0.25 μg/mL) was found to be most active against MTB H₃₇Rv and MDR‐TB strains, which was twofold more active than the parent gatifloxacin (MIC: 0.5 μg/mL) and comparable with rifampicin ( RIF ) (MIC: 0.25 μg/mL) against MTB H₃₇Rv, and 4‐ > 512 times more potent than the three references gatifloxacin (MIC: 1.0 μg/mL), RIF (MIC: 64 μg/mL), and isoniazid (>128 μg/mL) against MDR‐TB, could act as a starting point for further optimization.     

Identification and further development of thiazolidinones spiro-fused to indolin-2-ones as potent and selective inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B

Tuberculosis continues to be a major cause of morbidity and mortality throughout the world. Protein tyrosine phosphatases from Mycobacterium tuberculosis are attractive targets for developing novel strategies in battling tuberculosis due to their role in the intracellular survival of M. tuberculosis in various infection models. Here, we report on the identification and further development of thiazolidinones spiro-fused to indolin-2-ones as a new class of potent and selective inhibitors of M. tuberculosis protein tyrosine phosphatase B. Detailed structure-activity relationship (SAR) studies revealed that a nitro-substituted 2-oxoindole core together with a dihalogenated anilide and a halogenated N-benzyl moiety are essential for strong inhibitory activity against MptpB (M. tuberculosis protein tyrosine phosphatase B). Small structural modification of the identified compounds led to significant improvement of compound solubility and cell permeability retaining inhibitory activity in the micromolar range. The configuration of the spiro-center was found to be crucial for the inhibitory activity and the separation of the racemate revealed the R-(−)-enantiomers as the biologically active component. The reported MptpB inhibitors show excellent selectivity against a selected panel of protein tyrosine phosphatases, including MptpA (M. tuberculosis protein tyrosine phosphatase A), PTP1B (protein tyrosine phosphatase 1B), SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase), PTPN2, h-PTPβ (human protein tyrosine phosphatase β), and VHR (Vaccinia virus VH1-related dual-specific protein phosphatase) and further highlight the identified thiazolidinones spiro-fused to indolin-2-ones as a promising class of new compounds that might prove useful for chemical biology research to dissect MptpB function and eventually foster the development of next generation antibiotics.     

Gatifloxacin–Isatin Hybrids and Their Antimycobacterial Activities

We report herein the design, synthesis, and antimycobacterial activity of a series of diethylene glycol tethered gatifloxacin–isatin hybrids 5a – o in this paper. Results revealed that all hybrids showed promising activity against both drug‐sensitive and multidrug‐resistant Mycobacterium tuberculosis strains with minimum inhibitory concentration (MIC) in a range of 1–128 μg/mL. Particularly, hybrid 5j with low cytotoxicity in VERO cell line was comparable with the parent gatifloxacin (MIC: 0.78 and 1 μg/mL) against MTB H37Rv and MDR‐TB strains, and ≥32‐fold more potent than isoniazid and rifampicin (MIC: >128 and 32 μg/mL, respectively) against MDR‐TB, suggesting it may serve as a new and promising candidate for further study.     

Synthesis and biological evaluation of new 4‐(4‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)phenyl)‐2‐phenylthiazole derivatives

A novel series of 4‐(4‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)phenyl)‐2‐substitutedthiazole derivatives ( 8a‐l) have been synthesized by [3 + 2] cycloaddition reaction of 4‐(4‐ethynylphenyl)‐2‐substitutedthiazole with substituted benzyl azide in aqueous DMF. Starting compounds 4‐(4‐ethynylphenyl)‐2‐substitutedthiazole ( 6a‐d ) were synthesized by reaction of 4‐(2‐substitutedthiazol‐4‐yl)benzaldehyde with Ohira‐Bestmann reagent in methanol. The structures of these novel triazole‐thiazole clubbed derivatives were confirmed by the spectral analysis. The title compounds ( 8a‐l ) were tested for antimycobacterial activity against Mycobacterium tuberculosis H37Ra active and dormant (MTB, ATCC 25177) and antimicrobial activity against standard Gram‐positive bacteria, Staphylococcus aureus (NCIM 2602) and Bacillus subtilis (NCIM 2162), and Gram‐negative bacteria, Escherichia coli (NCIM 2576) and Pseudomonas flurescence (NCIM 2059). Compounds 8a , 8b , 8c , and 8h reported good activity against B subtilis, compounds 8a , 8b , and 8c showed good activity against S aureus, and compound 8b showed good activity against dormant M tuberculosis H37Rv strain. Compounds 8b and 8c found more potent against Gram positive and dormant M tuberculosis H37Rv strains. These novel triazole‐thiazole clubbed analogues found to be a capable leads for further optimization and development.     

Design,Synthesis, and in vitro Anti‐mycobacterial Evaluation of Propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered (Thio)semicarbazone‐isatin‐moxifloxacin Hybrids

A new class of propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered (thio)semicarbazone‐isatin‐moxifloxacin hybrids 6a – h was designed, synthesized, and screened for their in vitro anti‐mycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and MDR‐TB as well as cytotoxicity in VERO cell line. All the synthesized hybrids (MIC: 0.05–2.0 μg/mL) exhibited excellent activities against M. tuberculosis H₃₇Rv and MDR‐TB; in particular, conjugate 6c (MIC: 0.05 and 0.12 μg/mL) was no inferior to the three references MXFX (MIC: 0.10 and 0.12 μg/mL), RIF (MIC: 0.39 and 32 μg/mL), and INH (MIC: 0.05 and >128 μg/mL) against the tested two strains. All hybrids (CC₅₀: 2–8 μg/mL) were much more cytotoxic than the parent MXFX (CC₅₀: 128 μg/mL) should be further optimized.