Good Antitubercular Activity Research Articles

6-aryloxy-2-aminopyrimidine-benzonitrile hybrids as anti-infective agents: Synthesis, bioevaluation, and molecular docking.

This report explores the potential of novel 6-aryloxy-2-aminopyrimidine-benzonitrile scaffolds as promising anti-infective agents in the face of the increasing threat of infectious diseases. Starting from 2-amino-4,6-dichloropyrimidine, a series of 24 compounds inspired from the antiviral drugs dapivirine, etravirine, and rilpivirine were designed and synthesized via a two-step reaction sequence in good yields. Biological testing of synthetic analogs revealed potent inhibition against both viral and tuberculosis targets. Notably, compounds 5p (2,4-dimethyl substitution; IC50 = 44 ± 4.9 µM; selectivity index [SI] = 20) and 5 s (3-thiophenphenyl; IC50 = 6 ± 1 µM; SI = 120) showed significant antiviral activity against pandemic influenza virus A/Puerto Rico/8/34 (H1N1) with positive toxicity profiles and also exhibited good IC50 values (5p, IC50 = 10 ± 2 µM; SI = 9 and 5 s, IC50 = 16 ± 2 µM; SI = 60) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Wuhan strain) compared with favipiravir. In addition, analogs 5a, 5r, 5t, and 5u showed good antitubercular activity against Mycobacterium tuberculosis H37Rv strain and compounds 3, 5f, 5n, and 5q showed moderate antibacterial activity against gram+ve and gram-ve bacterial strains, suggesting that this scaffold has a broad spectrum of therapeutic effects.

Synthesis and in silico studies of some new pyrrolylbenzamide derivatives as antitubercular and antimicrobial agents

Eighteen new pyrrolylbenzamide derivatives (6a-6r) were synthesized by reacting N-(2,5-dimethyl- 1H-pyrrol-1-yl)-4-(2-hydrazineyl-2-oxoethoxy)benzamide (4) with substituted benzoic acids (5a-5r) in the presence of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, diisopropyl ethylamine and dimethyl formamide. The produced compounds were subjected to molecular docking studies against the dihydrofolate reductase (DHFR) and InhA mycobacterial enzymes. The compounds were biologically screened for antimycobacterial, and antibacterial activities along with InhA and DHFR enzyme inhibition studies. The compounds were also analyzed for ADMET parameters. The compounds 6j, 6l, 6q, and 6r exhibited good antitubercular activity, and compounds 6j, 6l, 6q, and 6r were effective against the Gram-negative Escherichia coli strain. The compounds 6b, 6f, 6j, 6l, and 6q showed good InhA inhibition and compounds 6b, 6c, 6j, 6l, and 6q were effective against DHFR enzyme. Among the synthesized compounds 6j and 6l exhibited promising antitubercular, antibacterial, and effective InhA and DHFR enzyme inhibition values.. KEYWORDS :Benzamide, Dimethylpyrrole, Antimycobacterial activity, Antibacterial activity.

Microwave-Assisted Synthesis of 2-(Arylidene)-1-thia-4-azaspiro[4.5]decan-3-ones and their Antibacterial, Antitubercular, and In Silico Screening

2-(Arylidene)-1-thia-4-azaspiro[4.5]decan-3-ones (3a-e, 4a-e) were synthesized from the 1-thia-4-azaspiro[4.5] decan-3-one through Knoevenagel reaction using the microwave method. In vitro, antibacterial and antitubercular screening of synthetic derivatives 3a-e and 4a-e revealed that compounds 3a and 4b are considerably potent as antibacterial agents against Escherichia coli with MIC = 50 μg/mL and MIC = 50 μg/mL, respectively. Compounds 3e and 4e possessed very good antitubercular activity with MIC = 0.47 μg/mL and MIC = 0.43 μg/mL. The results of molecular docking analysis supported the results of in vitro evaluation as against antibacterial protein compound 3a showed the lowest binding energy and against antitubercular protein, while 3e and 4e were highly attached?

Design, Synthesis, Molecular Docking, Antitubercular, Antimicrobial and Antioxidant Studies of Some Novel 3-(((1H-Benzo[d]imidazol-2- yl)methyl)thio)-5H-[1,2,4] Triazino[5,6-b]indole Derivatives

A series of novel 3-(((1H-benzo[d]imidazol-2-yl)methyl)thio)-5H-[1,2,4]triazino[5,6-b]indole derivatives (3a-3j) were synthesized by reacting different substituted 5H-[1,2,4]triazino[5,6-b]indole-3-thiols with substituted (2-chloromethyl)-1H-benzo(d)imidazoles in the presence of KOH and water in good yields. The structures of the newly synthesized compounds were confirmed by spectroscopic techniques such as 1H-NMR, 13C-NMR, IR and mass spectrometry. The in-vitro antitubercular activity of the synthesized compounds was evaluated against Mycobacterium tuberculosis (Mtb) H37Rv (ATCC 27294) using MABA (Microplate Alamar Blue Assay) method. Compounds 3b, 3c, and 3i showed good antitubercular activity against Mtb with MIC value of 6.25 ± 0.00 μg/mL. Also, the in-vitro antimicrobial activities of the compounds were evaluated against various bacterial and fungal strains using the two-fold serial dilution technique and most of the compounds exhibited moderate activities with MIC values in the range of 63.33 ± 1.44 to >500 ????g/mL against the tested microorganisms. The compounds (3a-3j) were also tested for their in-vitro antioxidant activities by DPPH radical scavenging activity method and among the series, compounds 3e, 3a, and 3g exhibited strong antioxidant activity with IC50 values of 10.85 ± 0.05, 12.18 ± 0.13 and 12.57 ± 0.17????g/mL respectively compared to the standard ascorbic acid (IC50 value, 5.85 ± 0.04 ????g/mL). Further, molecular docking studies were performed to investigate the binding affinities as well as the interaction of these compounds with Mtb InhA target protein. In-silico ADME predictions showed that all the synthesized compounds have drug-like properties and exhibited good oral bioavailability.

Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects 10 million people each year and the emergence of resistant TB augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the type II fatty acid synthase system (FAS-II) are involved in the biosynthesis of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. INH acts as a prodrug requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD+/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.

Synthesis, biological screening and in silico studies of new N-phenyl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine derivatives as potential antifungal and antitubercular agents

A new series of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) have been synthesized by a cyclo-condensation reaction of 2-bromo-1-(1,3-diphenyl-1H-pyrazol-4-yl)ethanone (6a-f) with N-aryl thiourea, (7a-d). The structure of newly synthesized N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives was analyzed by 1H NMR, 13C NMR and Mass spectral analysis. The compounds 8a-x were screened for in vitro antimicrobial activity against Escherichia coli, Proteus mirabilis, Bacillus subtilis, Staphylococcus aureus, Candida albicans and Aspergillus niger. and antitubercular activity against M. tuberculosis H37Rv strain. Among the twenty-four pyrazolyl-thiazole derivatives, six compounds 8a, 8b, 8j, 8n, 8o and 8s showed good activity against S. aureus. Against A. niger, all synthesized derivatives showed good antifungal activity. Fifteen pyrazolyl-thiazole derivatives 8a, 8f, 8g, 8h, 8j, 8k, 8n, 8o, 8p, 8q, 8r, 8s, 8t, 8w and 8x showed good antitubercular activity with MIC 1.80–7.34 μM (0.8–3.12 μg/mL), these derivatives have showed more activity than the drugs isoniazid and ethambutol. The active compounds were further screened for cytotoxicity activity against the mouse embryonic fibroblast cells (3t3l1) cell lines at 12.5 and 25 μg/mL concentrations and found less or non-cytotoxicity. To know the plausible mode of action, the synthesized pyrazolyl-thiazole derivatives were studied for pharmacokinetics, toxicity profiles and binding interactions along with an in-depth analysis of structural dynamics and integrity using prolonged molecular dynamics (MD) simulation. The compounds have shown significant docking scores in the range of −7.98 to −5.52 and −9.44 to −7.2 kcal/mol with the M. tuberculosis enoyl reductase (M. tb. InhA) and C. albicans sterol 14-α demethylase (C. ab. CYP51), respectively. Thus, the significant antifungal and antitubercular activity of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives incited that, these scaffolds could assist in the development of lead compounds to treat fungal and antitubercular infections.

Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation

Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198–0.096 μM, compared to IC50 value of 0.19420 μM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 μM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.

Investigation of new 1,2,3-triazolyl-quinolinyl-propan-2-ol derivatives as potential antimicrobial agents: in vitro and in silico approach

A new series of 1-((1-(4-substituted benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(2-substituted quinolin-4-yl)propan-2-ol (9a-x) have been synthesized. The newly synthesized 1,2,3-triazolyl-quinolinyl-propan-2-ol (9a-x) derivatives were screened for in vitro antimicrobial activity against M. tuberculosis H37Rv, E. coli, P. mirabilis, B. subtilis, and S. albus. Most of the compounds showed good to moderate antibacterial activity and all derivatives have shown excellent to good antitubercular activity with MIC 0.8-12.5 μg/mL. To know the plausible mode of action for antibacterial activity the docking study against DNA gyrase from M. tuberculosis and S. aureus was investigated. The compounds have shown significant docking scores in the range of −9.532 to −7.087 and −9.543 to −6.621 Kcal/mol with the DNA gyrase enzyme of S. aureus (PDB ID: 2XCT) and M. tuberculosis (PDB ID: 5BS8), respectively. Against the S. aureus and M. tuberculosis H37Rv strains, the compound 9 l showed good activity with MIC values of 62.5 and 3.33 μM. It also showed significant docking scores in both targets with −8.291 and −8.885 Kcal/mol, respectively. Molecular dynamics was studied to investigate the structural and dynamics transitions at the atomistic level in S. aureus DNA gyrase (2XCT) and M. tuberculosis DNA gyrase (5BS8). The results revealed that the residues in the active binding pockets of the S. aureus and M. tuberculosis DNA gyrase proteins that interacted with compound 9 l remained relatively consistent throughout the MD simulations and thus, reflected the conformation stability of the respective complexes. Thus, the significant antimicrobial activity of derivatives 9a-x recommended that these compounds could assist in the development of lead compounds to treat for bacterial infections. Communicated by Ramaswamy H. Sarma

Design, synthesis and biological evaluation of phenanthridine amide and 1,2,3-triazole analogues against Mycobacterium tuberculosis.

The phenanthridine core exhibits antitubercular activity, according to reports from the literature. Several 1,2,3-triazole-based heterocyclic compounds are well-known antitubercular agents. A series of twenty-five phenanthridine amide and 1,2,3-triazole derivatives are synthesized and analyzed using ESI-MS, 1HNMR, and 13CNMR on the basis of our earlier findings that phenanthridine and 1,2,3-triazoles shown good antitubercular activity. The synthesized phenanthridine amide and 1,2,3-triazole analogues were tested in vitro against Mycobacterium tuberculosis H37Rv and minimum inhibitory concentration (MIC) values were determined utilizing non-replicating and replicating low-oxygen recovery assay (LORA) and microplate Alamar Blue assay (MABA) methodologies. The phenanthridine amide derivative PA-01 had an MIC of 61.31 μM in MABA and 62.09 μM in the LORA technique, showing intense anti-TB activity. Amongst the phenanthridine triazole derivatives, PT-09, with MICs of 41.47 and 78.75 μM against the tested strain of Mtb in both MABA and LORA was the most active one. The final analogues' drug-likeness is predicted using absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies. The most active compounds PA-01 and PT-09 were further subjected to in silico docking studies. Using the Glide module of Schrodinger, molecular docking analysis was carried out to estimate the plausible binding pattern of PA-01 and PT-09 at the active site of Mycobacterial DNA topoisomerase II (PDB code: 5BS8). Further, molecular dynamics studies of PA-01 and PT-09 were also carried out.

Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: Hit–to–lead optimization and release of a novel antitubercular chemotype via scaffold derivatization

Tuberculosis is one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extensively drug-resistant strains is a reason for concern. We have previously reported a series of substituted 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides with growth inhibitory activity against Mycobacterium tuberculosis strains and low propensity to be substrate of efflux pumps. Encouraged by these preliminary results, we have undertaken a medicinal chemistry campaign to determine the metabolic fate of these compounds and to delineate a reliable body of Structure–Activity Relationships. Keeping intact the (thiazol-4-yl)isoxazole-3-carboxamide core, as it is deemed to be the pharmacophore of the molecule, we have extensively explored the structural modifications able to confer good activity and avoid rapid clearance. Also, a small set of analogues based on isostere manipulation of the 2-aminothiazole were prepared and tested, with the aim to disclose novel antitubercular chemotypes. These studies, combined, were instrumental in designing improved compounds such as 42g and 42l, escaping metabolic degradation by human liver microsomes and, at the same time, maintaining good antitubercular activity against both drug-susceptible and drug-resistant strains.

New quinoline-thiolactone conjugates as potential antitubercular and antibacterial agents

Tuberculosis and bacterial infections are major challenges because of elevated infection rates and drug resistance. New chemical agents need to be developed to address them. Thiolactomycin and quinolines are promising lead molecules in the design of new antitubercular and antibacterial agents. Herein, we report the design and synthesis of series of new quinoline-thiolactone conjugates as potential antitubercular and antibacterial agents. Two of the conjugates, 6b and 6d, exhibited good antitubercular activity with MIC value of 8 µg/mL. Docking studies showed that the conjugates, 6b and 6d, exhibited good binding affinity towards the target protein KasA of M. tuberculosis. Two other conjugates also showed decent antibacterial activity with MIC value of 8 µg/mL. Further, the docking of conjugate 7a was better than standard drug, linezolid against three different molecular receptors.

Investigation of quinolone-tethered aminoguanidine as novel antibacterial agents.

A recent study identified quinolone-based thiosemicarbazone with an MIC90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC90 values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating >50% growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non-pan-assay interfering compound.

Novel 2-arylthiazolidin-4-one-thiazole hybrids with potent activity against Mycobacterium tuberculosis

Substituted aldehydes, ethyl 2-(2-amino-thiazol-4-yl)acetate), and 2-mercaptoacetic acid, in a three-component one-pot green synthetic approach afforded 2-arylthiazolidin-4-one- thiazole hybrids(T1-T13). Compounds showed good anti-tubercular activity towards sensitive M. tuberculosis strain. Compound T8 was as potent as isoniazide (INH) with MIC = 0.12 μg/ml. Compounds T2 and T13 showed potent activity with MIC = 0.48 μg/ml. Other compounds showed moderate to good anti-tubercular activity towards MDR M. tuberculosis strain with MIC range 1.95–125 μg/ml. Compounds T2, T8, T9, and T13 showed anti-tubercular activity towards XDR M. tuberculosis strain with MIC range 7.81–125 μg/ml. Compounds T2 and T8 were capable of inhibiting M. tuberculosis InhA enzyme in-vitro with IC50 = 1.3 ± 0.61 µM and 1.06 ± 0.97 µM, respectively. Molecular docking simulation showed that T2 and T8 were also capable of interacting at the catalytic site of InhA enzyme in a similar mode to the native ligand through binding with NAD+ and Tyr158. The 3D- QSAR study highlighted the relevance of substitution of phenyl group at position-2 of thiazolidin-4-one where bulky electronegative substitution at position-4 of the phenyl ring favored the activity against M. tuberculosis H37R. Additionally, compounds showed good antibacterial activity against bronchitis causing bacteria M. pneumoniae, S. pneumonia, K. pneumonia, and B. pertussis compared to Azithromycin. In-silico studies of ADMET descriptors and drug-likeness were conducted for all synthesized compounds. Compounds showed good oral bioavailability, good gastrointestinal absorption and showed no signs of adverse effects to the liver or CNS. Compounds showed no potential carcinogenicity as well.

Synthesis of novel antipyrine-azole-S-alkyl derivatives antimicrobial activity, molecular docking, and computational studies

In this investigation, we synthesized the newly antipyrine-azole-S-alkyl and their reduction derivatives that were screened for their antimicrobial activity and compared them with molecular docking and computational Studies. The nucleophilic substitution reaction between antipyrine-azole derivatives 1a, 1b and (2,4-dichlorophenyl) acetyl chloride (2) in presence of Na metal to afforded the corresponding 2-(2,4-dichlorophenyl)-2-oxoethyl)thio)-4H-1,2,4-triazol-3-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one derivatives 3a, 3b in excellent yield. The reduction process of compounds 3a,3b were utilized via NaBH4 act as reducing agent which convert the C=O group to OH group to afford the corresponding 2-(2,4-dichlorophenyl)-2-hydroxyethyl)thio)-4H-1,2,4-triazol-3-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one derivatives 4a, 4b. The investigated compounds were exhibited against in vitro antimicrobial activity. Compound 3a was determined to be the most effective against all strains. In addition, it was observed that compound 4a showed very good antitubercular activity (Mycobacterium smegmatis ATCC607) and showed equivalent activity to Staphylococcus aureus ATCC 25923 against the standard drug from gram-positive bacteria. Compound 3b with allyl group in its structure was found to be effective against Pseudomonas aeruginosa ATCC 27853, one of the gram-negative bacteria. Furthermore, molecular docking studies were carried out on one of the investigated compounds with (PDB ID:3t88), (PDB ID:2wje), (PDB ID:4ynt), and (PDB ID:1tgh), which attached with different proteins with different energies and short bond distance. Furthermore, the comprehensive theoretical and physical characterization studies of compounds 3a, 3b,4a, and 4b were examined via DFT/ B3LYP/6–31 G (d) level to elucidate their activities.

Design, Synthesis and Biological Investigation of Some Novel Quinazolin-4(3H)-One Tethered 1, 3, 4-Thiadiazole-Thiol Motifs as Direct Enoyl Acyl Carrier Protein Reductase Inhibitors

Aims: In this study was two noteworthy pharmacophores quinazolin-4(3H)-one and 1,3,4-thiadiazole through methylene bridge were utilized to design, synthesize and characterize some novel 2-methyl quinazolin-4(3H)-one and 6-chloro-2-methyl quinazolin-4(3H)-one tethered S-substituted-1,3,4-thiadiazole-thiol structural analogs respectively as direct Mycobacterium Tuberculosis (MTB) enoyl acyl carrier protein reductase (InhA) inhibitors.
 Study Design: Design of structural analogs of quinazolin-4(3H)-one tethered 1,3,4-thiadiazole-thiol through methylene bridge by functional group modifications in core scaffold followed by computational studies to select promising compounds. Synthesis of some novel compounds, structural characterization and screening of biological activity of the same.
 Methodology: The molecular docking of designed compunds was carried out using schrodinger Glide XP into the active site of MTB InhA with protein data bank code (PDB ID: 2H7M). The interactions were evaluated based on the glide G score compared with reference standard isoniazid. Ten new compounds 7(A1-A10) were synthesized, characterized and screened for their in-vitro antitubercular activity by Microplate Almar Blue Assay (MABA) method followed by cytotoxicity evaluation of compounds 7A4 and 7A10 using Vero cell line.
 Results: All the designed compounds of series 7(A1-A10) had drug-like characteristics and were non-toxic to normal cells. In the molecular docking studies, compounds 7A4, 7A5, and 7A10 demonstrated strong binding affinity in the active region of MTB InhA protein and retained necessary amino acid interaction, similar to co-crystal 2H7M. Synthesized compounds 7(A1-A10) were found to have good antitubercular activity. Out of the series the compounds 7A4 and 7A10 were found to possess excellent antitubercular activity equipotent to reference standard streptomycin with minimum inhibitory concentration (MIC) value of 6.25µg/ml. The cytotoxic potential of compounds 7A4 and 7A10 showed remarkable selectivity index against Vero cell line.
 Conclusion: The findings of this study highlights the importance of tethering two pharmacophoric motifs in one compound to develop novel antitubercular agents that can be exploited as promising leads as direct InhA inhibitors.

Synthesis and Antimicrobial, Antiproliferative Evaluation of Novel Quinolone and Conazole Analogues via Conventional and Microwave Techniques

Abstract1,2,4‐Triazole‐3‐one (3), acquired from cinnamaldehyde was converted to the corresponding carbox(thio)amides via several steps (6 a–c). Their reaction with sodium hydroxide gave the 1,2,4‐triazole derivatives (7 a–c). Compound 3 treatment with 2‐bromo‐1‐(4‐chlorophenyl) ethanone or 2‐chloro‐1‐(2,4‐dichlorophenyl)ethanone afforded the compounds 8 a,b and by reducing these compounds reduction products were obtained (9 a,b). The synthesis of (10 a–e) was carried out by the reaction compounds 9 a,b with different benzyl chlorides. Then oxadiazole derivative (12) was obtained by ring closure from hydrazide compound 5. Subsequently compounds 3, 7 a–c, and 12 were treated with various amines in the presence of formaldehyde to yield Mannich bases (11 a–e, 14 a–e, 13 a,b). Microwave‐assisted and conventional techniques were utilized for the syntheses. The structures of newly synthesized compounds were illuminated by spectroscopic methods. Their antimicrobial (MIC method), and anticancer activities (Abay's method) were examined. Results showed that most of the compounds exhibited good antimicrobial activities. Especially compounds 14 a–e which is a mannich base showed very good antitubercular activity against Mycobacterium smegmatis compared with Streptomycin standard drug. Also compounds 8 a and 9 b have been found to have strong antiproliferative effects on the HeLa cervical cancer cells and also these compounds did not have a cytotoxic effects on a normal cells.

Design, Synthesis and Antitubercular Evaluation of New Benzimidazole Scaffolds

Background: To overcome one of the resistance mechanisms of Isoniazid (INH), there is a need for an antitubercular agent that can inhibit InhA enzyme by circumventing the formation of INH-NAD+ adduct. Objective: The objective of the study is the development of novel antitubercular agents that target Mycobacterium tuberculosis InhA (Enoyl Acyl Carrier Protein Reductase). Methods: A small-molecule chemical library was used for the identification of the novel InhA inhibitors using primary screening and molecular docking studies followed by the scaffold hopping approach. The designed molecules, 2-(2-(hydroxymethyl)-1H- benzo[d] imidazole-1-yl)- N- substituted acetamides were synthesized by reacting (1H- benzo[d]imidazole -2-yl)methanol with appropriate 2-chloro-N-substituted acetamides / dialkylamino carbonyl chlorides respectively in good yields (42-65%). The antitubercular activity of synthesized compounds was determined by Microplate Alamar Blue Assay (MABA) against Mycobacterium tuberculosis H37Rv strain. The selected compounds were screened for cytotoxicity on normal cell lines. Results: The antitubercular activity data revealed that the 4-chlorophenyl substituted derivative (3b) showed good MIC value at 6.25 μg/mL and, dimethylacetamide substituted derivative (3i) showed MIC at 25 μg/mL among the tested compounds. The substitution of dimethylacetamide (3i) group on the 1st position of benzimidazole has good antitubercular activity (25μg/mL) in comparison to the diethyl acetamide group (3j, 100μg/mL). Conclusion: The antitubercular activity data indicated that the tested compounds exhibited well to moderate inhibition of the H37Rv strains. The compounds (3b) with electronegative substitution on the phenyl moiety exhibited better antitubercular activity than that of the other substitutions. The active compounds have displayed a good safety profile on normal cell lines.

Synthesis of 2‐Chloro‐N‐(4‐(6‐chloroH‐imidazo[1,2‐a]pyridin‐2‐yl)phenyl) Acetamide Derivatives as Antitubercular Agents

AbstractThe present article reports the synthesis of 2‐chloro‐N‐(4‐(6‐chloroH‐imidazo[1,2‐a]pyridin‐2‐yl)phenyl)acetamide derivatives (PINRAc 1–12) using 5‐chloropyridin‐2‐amine and 2‐bromo‐1‐(4‐nitrophenyl)ethanone in a multi‐step protocol. The structures of all the compounds were characterized by NMR, FT‐IR and GCMS. The compounds were screened for their antitubercular activity against Mycobacterium tuberculosis H37Rv using the microplate Alamar Blue assay. Most of them exhibited good antitubercular activity with MIC in the range of 1.6–25 μg/mL and the cytotoxicity study carried out on human embryonic kidney cell line showed no toxicity on the normal cells. The docking study was performed on mycolic acid transporter protein MmpL3 from Mycobacterium smegmatis which supported the in vitro results.

Synthesis and biological evaluation of anti-tubercular activity of Schiff bases of 2-Amino thiazoles

Tuberculosis, an infectious disease, has been reported to cause the death of 1.5 million in 2018. Due to the emergence of Multi-Drug Resistant-TB, Extensively Drug Resistant-TB, and Totally Drug Resistant-TB, many first-line and second-line drugs have been found in-effective. New drugs introduced in TB regimens such as pretomanid, bedaquiline and linezolid have been associated with toxicities. Hence, there is an urgent need for introducing safe and cost-effective antitubercular drugs. In this study, a series of Schiff bases of 2-amino thiazoles were synthesized and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain by Microplate Alamar Blue assay (MABA) method. N-[4-(2-Amino-thiazol-4-yl)-phenyl]-benzamide derivative with 2-nitro (5c2), 4-hydroxy (5c4) substitution, 2-[4-(2-Amino-thiazol-4-yl)-phenyl]-isoindole-1,3-dione derivatives with 3,4,5-trimethoxy substitution (5b1) and the compound 1-[4-(2-Amino-thiazol-4-yl)-phenyl]-pyrrole-2,5-dione (4a) which is a maleic derivative bearing thiazole ring, exhibited good anti-tubercular activity (MIC 6.25 μg/ml). Drug likeness was also evaluated for all the synthesised compounds using Molinspiration software. All synthesized compounds fulfilled the parameters of the Lipinski rule of five and showed drug-like properties. Through this study, it was proved that thiazole analogues have good anti-tubercular potentials.

Synthesis, structural elucidation, pharmacological and molecular docking studies of terpolymer transition metal complexes

A novel monomer (terpolymer) was prepared by mixing of 2-amino-6-nitro-benzimidazole, 2,5-diaminophenol and formaldehyde. Based on the impressive material utilities and therapeutic potential, Cu2+, Ni2+, Co2+ and Zn2+ metal ions were mixed with terpolymer to form different metal chelates. UVVis., IR, 1H NMR, ESR spectral data analysis showed that the prepared metal chelates were of square planar geometry. The molecular mass of polymer was determined using gel permeation chromatography technique. Thermo gravimetric technique was utilized to measure the thermal withstanding ability of terpolymer chelates. The electron transfer mechanism of the metal complexes was investigated by the aid of cyclic voltammetry. The prepared compounds were also screened for antimicrobial efficiency against bacterial strains (B. subtilis, E. coli and S. aureus) and fungal strains (C. albicans, A. niger and A. flavus). The observed results indicated that the chelates showed greater antimicrobial efficiencies than terpolymer ligand. Furthermore, the SOD biomimetic activity of prepared metal chelates was accessed and copper complex was found to possess high antioxidant potential with IC50 value of 0.94 µM. Antituberculosis capacities of terpolymer and its metal chelates was assessed against M. tuberculosis H37Rv strain using MABA assay protocol. Copper complex was found to possess good antitubercular activity with MIC value of 6.20 mg/mL. Molecular docking study was conducted to assess the target for antitubercular activity. It was found that copper complex could be a potent inhibitor of pantothenate synthetase enzyme (a potential target for development of antitubercular drug) of M.tuberculosis with binding energy of -9.8 kcal/mol. Overall copper complex showed good antimicrobial, antioxidant and antitubercular activity when compared to other metal complexes and terpolymer ligand.