Potent Antitubercular Activity Research Articles

Current Insights into the Chemistry and Antitubercular Potential of Benzimidazole and Imidazole Derivatives.

Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtb), affecting millions of people worldwide. The emergence of drug resistance is a major problem in the successful treatment of tuberculosis. Due to the commencement of MDR-TB (multi-drug resistance) and XDR-TB (extensively drug resistance), there is a crucial need for the development of novel anti-tubercular agents with improved characteristics such as low toxicity, enhanced inhibitory activity and short duration of treatment. In this direction, various heterocyclic compounds have been synthesized and screened against Mycobacterium tuberculosis. Among them, benzimidazole and imidazole containing derivatives have been found to have potential anti-tubercular activity. The present review focuses on various imidazole and benzimidazole derivatives (from 2015-2019) with their structure-activity relationships in the treatment of tuberculosis.

Design, Synthesis, Pharmacological Evaluation, In silico Modeling, Prediction of Toxicity and Metabolism Studies of Novel 1-(substituted)-2-methyl- 3-(4-oxo-2-phenyl quinazolin-3(4H)-yl)isothioureas.

Although exhaustive efforts to prevent and treat tuberculosis (TB) have been made, the problem still continues due to multi-drug-resistant (MDR) and extensively drugresistant TB (XDR-TB). It clearly highlights the urgent need to develop novel "druggable" molecules for the co-infection treatment and strains of MDR-TB and XDR-TB. In this approach, a hybrid molecule was created by merging two or more pharmacophores. The active site of targets may be addressed by each of the pharmacophores and proffers the opportunity for selectivity. In addition, it also reduces undesirable side effects and drug-resistance. In this study, a novel quinazolinone analog was designed and synthesized by substituting thiourea nucleus and phenyl ring at N-3 and C-2 position of quinazoline ring, respectively. All title compounds were tested for antitubercular activity by in vitro M. tuberculosis and anti-human immunodeficiency virus (HIV) activity by MT-4 cell assay method. The agar dilution method was used to test the antibacterial potency of entire prepared derivatives against various strains of grampositive and gram-negative microorganisms. The title compounds, 1-(substituted)-2-methyl-3-(4-oxo-2-phenyl quinazolin-3(4H)-yl) isothioureas (QTS1 - QTS15) were synthesized by the reaction between key intermediate 3-amino- 2-phenylquinazolin-4(3H)-one with various alkyl/aryl isothiocyanates followed by methylation with dimethyl sulphate. Among the series, compound 1-(3-chlorophenyl)-2-methyl-3-(4-oxo-2-phenyl quinazolin- 3(4H)-yl) isothioureas (QTS14) showed the highest potency against B. subtilis, K. pneumonia and S. aureus at 1.6 μg/mL. The compound QTS14 exhibited the most potent antitubercular activity at the MIC of 0.78 μg/mL and anti-HIV activity at 0.97 μg/mL against HIV1 and HIV2. The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities. The new scaffolds proffer a plausible lead for further development and optimization of novel antitubercular and anti-HIV drugs.

Synthesis of isoniazid‐1,2,3‐triazole conjugates: Antitubercular, antimicrobial evaluation and molecular docking study

AbstractIn the present study, a series of new isoniazid‐1,2,3‐triazole conjugates (5a‐k) was synthesized via click chemistry approach. The newly synthesized compounds were assessed for their in vitro antitubercular and antimicrobial activities. The compound 5g has displayed potent antitubercular activity against Mycobacterium tuberculosis H37Rv (Mtb) with MIC value 1.56 μg/mL. The active compounds were screened for their cytotoxicity profile by MTT assay against RAW 264.7 cell line. The four compounds have shown good in vitro antimicrobial activities against both antibacterial and antifungal pathogens. A molecular docking study was accomplished to identify the probable mode of action of synthesized derivatives. These compounds have shown excellent binding affinity toward Enoyl‐acp reductase (INHA) and DNA gyrase.

Novel isoniazid embedded triazole derivatives: Synthesis, antitubercular and antimicrobial activity evaluation

In the present study, a series of new isoniazid embedded triazole derivatives have been synthesized. These compounds were evaluated for their in vitro antitubercular and antimicrobial activities. Among the screened compounds, six have exhibited potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC value 0.78 μg/mL, whereas, three compounds have displayed activity with MIC value ranging from 1.56 to 3.125 μg/mL. The cytotoxicity of the active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed even at 25 μg/mL concentration. The five compounds have displayed good antimicrobial activities. Molecular docking have been performed against mycobacterial InhA enzyme to gain an insight into the plausible mechanism of action which could pave the way for our endeavor to identify potent antitubercular candidates. We believe that further optimization of these molecules may lead to potent antitubercular agents.

Novel Aminopyrazole Tagged Hydrazones as Anti-Tubercular Agents: Synthesis and Molecular Docking Studies.

Pyrazole derivatives have been reported to possess numerous pharmacological activities viz., anti-inflammatory, antipsychotic, etc. Our group has disclosed that pyrazole benzamides display potent antibacterial and anti-tubercular activities. Synthesis of new pyrazole acetamides which possess hydrazone group to be evaluated for antitubercular activity. The key intermediate 5-aminopyrazole was synthesized with the known procedure, which is then converted into chloroacetamide. This compound than resulted in hydrazine derivative and finally converted into aromatic hydrazones. All the compounds were screened for antitubercular activity. All the synthesized compounds have been characterized by their spectral data obtained and subjected to anti-tubercular activity. Among all the twenty tested compounds, three compounds, 5a5, 5b5 and 5b7 have demonstrated MIC value of 3.12 μg/mL against MTB H37Rv. Docking studies revealed important hydrogen bonding interactions with InhA. Three compounds 5a5, 5b5 and 5b7 were found to be most potent among the series of compounds. Docking studies of compounds explained the presence of hydrogen bonding and π- π stacking interactions with InhA. Further synthesis of more such derivatives with optimized groups would produce compounds with more potent anti-tubercular activity.

In-silico Druggability Studies of 4-hydroxy-α-tetralone and its Derivatives with RND Efflux pump of E. coli

The compound 4-hydroxy-α-tetralone (1) has been reported to possess potent anti-tubercular, anti-diabetic and anti-leishmanial activities. In our earlier studies the compound 1 and its various semi-synthetic derivatives showed potent bioenhancing activity in combination with nalidixic acid (NAL) and tetracycline (TET) reducing the minimum inhibitory concentration (MIC) of antibiotics up to 8 folds by inhibition of ABC efflux pump. However, in gram negative bacteria, resistance nodulation division (RND) family are considered as major efflux pump responsible for multidrug resistance (MDR). Hence, the current study was carried out to access the in-silico docking potential of compound 1 and its cinnamoyl (1a), 3, 4, 5-trimethoxybenzoyl (1b) derivatives against RND efflux pump target proteins AcrA, AcrB, TolC of E. coli. The docking study showed that the test compounds have good binding affinity with target proteins. The derivative 1a showed highest interaction with AcrA followed by AcrB showing binding energies -8.7 and -8.2 kcal/mol respectively. The low molecular weight ≤500, high hydrogen bonding, high log p value (>1) with hydroxy, methoxy and aromatic group of ligands make these compounds as effective efflux pump inhibitor. In drug likeliness studies, these compounds pass the safety criteria with enhanced bioavailability and absorption, less acute oral toxicity, less hepatotoxicity. This study promises that the compound 1 and its derivatives (1a & 1b) might be RND efflux pump inhibitors providing the initial platform for development of safer and cost-effective antibacterial drug to manage MDR infections.

Resistance of Mycobacterium Tuberculosis to Indole 4-Carboxamides Occurs Through Alterations in Drug Metabolism and Alterations in Tryptophan Biosynthesis

Tryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.

Design, Synthesis and Evaluation of Aryloxybenzylidene Hydrazinyl-Benzoxazoles/Benzothiazoles Analogs as Antimycobacterial Agents

Substituted 2-(2-(4-aryloxybenzylidene)hydrazinyl)benzothiazole/benzoxazoles series were designed through molecular hybridization and synthesized in condensation reaction of hydrazinylbenzothiazole/benzoxazole with substituted aryloxy benzaldehydes. All the synthesized compounds were assigned structure based on spectral data and were evaluated for antimycobacterial activity. Among both benzothiazole and benzoxazole derivatives, the compounds 8f and 9e were found to show most potent antitubercular activity with MIC value of 0.89 and 0.92 μM which are on a par with those of standard antitubercular drugs. In order to know the binding interactions of all the compounds were docked within the mycobacterial pantothenate synthetase, which showed interactions with Asp88, Arg200, Ser196, Asn199, Met 195 and Lys 160 of pantothenate synthetase.

Synthesis and in vitro Evaluation of Dihydrobenzimidazole Thiopyranooxazinone Derivatives as a Potent Biological Agents

In the present study, dihydrobenzimidazole thiopyranooxazinone derivatives were efficiently synthesized, which were further characterized and authenticated by means of TLC and different spectral analysis such as IR and 1H NMR. The synthesized compounds DPK2d2 to DPK2d8 were screened for their in vitro antimicrobial, antitubercular and anticancer activities. The results showed that the titled compounds DPK3d1, DPK3d2 and DPK3d4 exhibited potent antimicrobial activity, shows a broadspectrum activity against Bacillus subtilis, Escherichia coli (antibacterial) and Aspergillus niger (antifungal) as compared to ciprofloxacin and fluconazole, respectively. Compounds DPK3d1, DPK3d3 and DPK3d5 exhibited potent antitubercular activities against Mycobacterium tuberculosis as compared to pyrazinamide, ciprofloxacin and streptomycin. Compounds DPK3d3, DPK3d4 and DPK3d5 showed highly potent cytotoxic activity against human lung cancer cell line (A549) as compared to adriamycin. In silico molecular docking studies shown that all the ligands highest binding affinity range -6.7 to -8.7 for selected 1CB4 PDB of superoxide dismutase, which recognized that ligands having antioxidant activity.

Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents.

Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.

3,4-Dihydropyrimidin-2(1H)-One Analogues: Microwave irradiated Synthesis with Antimicrobial and Antituberculosis Study

Background:For rapid and sustainable synthesis, microwave irradiation method is serviceable. This present study deals with the preparation of oxadiazole and pyridine bearing 1,2,3,4- tetrahydro pyrimidine derivatives by microwave irradiation.Objective:The present study aims to carry out rapid synthesis of chloro-acetamides of oxadiazoles of Biginelli product and amino cyano derivative of pyridine by microwave-assisted heating. Our efforts are focused on the introduction of chemical diversity in the molecular framework in order to synthesize pharmacologically interesting compounds.Methods::Microwave irradiation was used for the synthesis of 2-((3-cyano-4-(3,4-dichloro phenyl)- 6-(4-hydroxy-3-methoxyphenyl) pyridin-2-yl) amino)-N-(5-(substituted) -(6-methyl-2-oxo -1,2,3,4- tetrahydro pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetamide by using Biginelli reaction. New structural analogues were confirmed by spectral studies followed by their screening for in vitro antibacterial activity against Staphylococcus aureus, Staphylococcus Pyogenus, Escherichia coli and Pseudomonas aeruginosa bacterial strains and for antifungal activity against Candida albicans, Aspergillus niger and Aspergillus clavatus by micro-broth dilution method. In vitro antimycobacterial activity determined out against (Mycobacterium tuberculosis) H37Rv strain using Lowenstein-Jensen medium.Results:As compared to the conventional method, microwave irradiation method is advantageous for the synthesis of 1,2,3,4-tetrahydropyrimidin derivatives. Potent antimicrobial activities and antitubercular activity were found for some of the compounds.Conclusion:Microwave irradiation method provided an effective way to discover a novel class of antimicrobial and antituberculosis agents. 1,2,3,4-tetrahydropyrimidin derivatives showed improved antimicrobial and good antituberculosis activity.

Revisiting the β-Lactams for Tuberculosis Therapy with a Compound-Compound Synthetic Lethality Approach.

The suboptimal effectiveness of β-lactam antibiotics against Mycobacterium tuberculosis has hindered the utility of this compound class for tuberculosis treatment. However, the results of treatment with a second-line regimen containing meropenem plus a β-lactamase inhibitor were found to be encouraging in a case study of extensively drug-resistant tuberculosis (M. C. Payen, S. De Wit, C. Martin, R. Sergysels, et al., Int J Tuberc Lung Dis 16:558-560, 2012, https://doi.org/10.5588/ijtld.11.0414). We hypothesized that the innate resistance of M. tuberculosis to β-lactams is mediated in part by noncanonical accessory proteins that are not considered the classic targets of β-lactams and that small-molecule inhibitors of those accessory targets might sensitize M. tuberculosis to β-lactams. In this study, we screened an NIH small-molecule library for the ability to sensitize M. tuberculosis to meropenem. We identified six hit compounds, belonging to either the N-arylindole or benzothiophene chemotype. Verification studies confirmed the synthetic lethality phenotype for three of the N-arylindoles and one benzothiophene derivative. The latter was demonstrated to be partially bioavailable via oral administration in mice. Structure-activity relationship studies of both structural classes identified analogs with potent antitubercular activity, alone or in combination with meropenem. Transcriptional profiling revealed that oxidoreductases, MmpL family proteins, and a 27-kDa benzoquinone methyltransferase could be the targets of the N-arylindole potentiator. In conclusion, our compound-compound synthetic lethality screening revealed novel small molecules that were capable of potentiating the action of meropenem, presumably via inhibition of the innate resistance conferred by β-lactam accessory proteins. β-Lactam compound-compound synthetic lethality may be an alternative approach for drug-resistant tuberculosis.

Antitubercular metabolites from the marine-derived fungus strain Aspergillus fumigatus MF029

During the systematic screening of bioactive compounds from our marine natural product library, crude extract of the marine-derived fungus strain Aspergillus fumigatus MF029 exhibited moderate bioactivities against Bacillus subtilis, Staphylococcus aureus, methicillin-resistant S. aureus, and Mycobacterium bovis bacillus Calmette–Guérin (BCG). Further chemical investigation resulted in the identification of two new compounds, chaetominine A (1) and sphingofungin I (2), together with four known compounds, emodin (3), chaetominine (4), sphingofungin D (5) and trypacidin (6). Trypacidin displayed potential antitubercular activity with MIC value of 1.25 μg/mL.

Biosynthesis, Anti-TB Activity and Degradation of Dyes by Silver Nanoparticles using Fruits Peels

In the present work, waste materials such as pomegranate and orange peels were taken to synthesize nanoparticles by biological method. The method did not involve the use of toxic reducing and capping agents. It uses only the environmentally benign biomolecules for reduction of AgNO3 and subsequent stabilization of silver nanoparticles. The size of pomegranate and orange silver nanoparticles varied from 8-25 nm with nearly spherical morphology as analyzed by XRD and TEM studies. The synthesized nanoparticles were studied for their dye degrading property. Different dyes such as crystal violet, methylene blue, malachite green and Congo red were taken for the study. The results indicated the presence of two diverse mechanism of dye removal. Crystal violet, methylene blue, malachite green was removed by adsorption onto both the nanoparticles, whereas Congo red was reduced by NaBH4 in the presence of catalytic pomegranate silver nanoparticles. Moreover, pomegranate silver nanoparticles have exhibited potent antitubercular activity with MIC value of 6.25 μg/mL and orange silver nanoparticles are moderately active with MIC value of 25 μg/mL. It could be concluded that the pomegranate silver nanoparticles would a promising candidate for drug development and catalysis.

Synthesis and bioevaluation of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones

Curcumin is an active component of turmeric that has poor solubility, stability and bioavailability. The monocarbonyl curcumin analogues were modified from curcumin to achieve more stable and active compounds as compared to curcumin. Therefore, we have designed and synthesized a library of 18 compounds of α,α’-bis(1H-1,2,3-triazol-5-ylmethylene) ketones (8a–o) and evaluated them for their in vitro antitubercular and antioxidant activities against their respective strains. Results of biological activities reveal that some of the compounds from the series showed good antitubercular as well as antioxidant activities. The compound 8l was found as the most active antitubercular agent with MIC value 3.125 µg/mL, against Mtb H37Rv. Moreover, the compounds, 8c, 8d, 8e and 8g, also showed potent antitubercular activity. The compounds 8e and 8m displayed potent antioxidant activities with IC50 values 15.60 and 15.49 µg/mL, respectively. In support of the bioactivities, in silico ADME properties’ prediction has also been carried out in this study.

Anthraquinone Derivatives from a Marine-Derived Fungus Sporendonema casei HDN16-802.

Five new anthraquinone derivatives, auxarthrols D–H (1–5), along with two known analogues (6–7), were obtained from the culture of the marine-derived fungus Sporendonema casei. Their structures, including absolute configurations, were established on the basis of NMR, HRESIMS, and circular dichroism (CD) spectroscopic techniques. Among them, compound 4 represents the second isolated anthraquinone derivative with a chlorine atom, which, with compound 6, are the first reported anthraquinone derivatives with anticoagulant activity. Compounds 1 and 3 showed cytotoxic activities with IC50 values from 4.5 μM to 22.9 μM, while compounds 1, 3–4, and 6–7 showed promising antibacterial activities with MIC values from 12.5 μM to 200 μM. In addition, compound 7 was discovered to display potential antitubercular activity for the first time.

Novel Antimycobacterial Compounds Suppress NAD Biogenesis by Targeting a Unique Pocket of NaMN Adenylyltransferase.

Conventional treatments to combat the tuberculosis (TB) epidemic are falling short, thus encouraging the search for novel antitubercular drugs acting on unexplored molecular targets. Several whole-cell phenotypic screenings have delivered bioactive compounds with potent antitubercular activity. However, their cellular target and mechanism of action remain largely unknown. Further evaluation of these compounds may include their screening in search for known antitubercular drug targets hits. Here, a collection of nearly 1400 mycobactericidal compounds was screened against Mycobacterium tuberculosis NaMN adenylyltransferase ( MtNadD), a key enzyme in the biogenesis of NAD cofactor that was recently validated as a new drug target for dormant and active tuberculosis. We found three chemotypes that efficiently inhibit MtNadD in the low micromolar range in vitro. SAR and cheminformatics studies of commercially available analogues point to a series of benzimidazolium derivatives, here named N2, with bactericidal activity on different mycobacteria, including M. abscessus, multidrug-resistant M. tuberculosis, and dormant M. smegmatis. The on-target activity was supported by the increased resistance of an M. smegmatis strain overexpressing the target and by a rapid decline in NAD(H) levels. A cocrystal structure of MtNadD with N2-8 inhibitor reveals that the binding of the inhibitor induced the formation of a new quaternary structure, a dimer-of-dimers where two copies of the inhibitor occupy symmetrical positions in the dimer interface, thus paving the way for the development of a new generation of selective MtNadD bioactive inhibitors. All these results strongly suggest that pharmacological inhibition of MtNadD is an effective strategy to combat dormant and resistant Mtb strains.

Structure-based design, synthesis and biological evaluation of a newer series of pyrazolo[1,5-a]pyrimidine analogues as potential anti-tubercular agents

In-depth study of structure-based drug designing can provide vital leads for the development of novel, clinically active molecules. In this present study, twenty six novel pyrazolo[1,5-a]pyrimidine analogues (6a-6z) were designed using molecular docking studies. The designed molecules were synthesized in good yields. Structural elucidation of the synthesized molecules was carried out using IR, MS, 1H NMR and 13C NMR spectroscopy. All the synthesized compounds were evaluated for their in-vitro anti-tubercular activity against H37Rv strain by Alamar Blue assay method. Most of the synthesized compounds displayed potent anti-tubercular activities. Amongst all the tested compounds 6p, 6g, 6n and 6h exhibited promising anti-tubercular activity. Further, these potent compounds were gauged for MDR-TB, XDR-TB and cytotoxic study. None of these compounds exhibited potent cytotoxicity. Stability of protein ligand complex was further evaluated by molecular dynamics simulation for 10 ns. All these results indicate that the synthesized compounds could be potential leads for further development of new potent anti-tubercular agents.

Design, synthesis and in silico study of pyridine based 1,3,4-oxadiazole embedded hydrazinecarbothioamide derivatives as potent anti-tubercular agent

Development of novel, safe and effective drug candidates combating the emerging drug resistance has remained a major focus in the mainstream of anti-tuberculosis research. Here, we inspired to design and synthesize series of new pyridin-4-yl-1,3,4-oxadiazol-2-yl-thio-ethylidene-hydrazinecarbothioamide derivatives as potential anti-tubercular agents. The anti-tubercular bioactive assay demonstrated that the synthesized compounds exhibit potent anti-tubercular activity (MIC = 3.9–7.81 μg/mL) in comparison with reference drugs Rifampicin and Isoniazid.We employed pharmacophore probing approach for the identification of CYP51 as a possible drug target for the synthesized compounds. To understand the preferable binding mode, the synthesized molecules were docked onto the active site of Sterol 14 α-demethylases (CYP51) target. From the binding free energy of the docking results it was revealed that the compounds were effective CYP51 inhibitors and acts as antitubercular agent.

Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties.

8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters.