5(4H)‐Oxazolones as Novel Antitubercular Agents: Synthesis,Characterisation and Structure Activity Study

In search of novel anti tubercular agents, a series of twelve 4‐(substituted benzylidene)‐2‐p‐tolyloxazol‐5(4H)‐ones (5a – 5l) has been synthesized, characterised and subjected to evaluate their antitubercular activity for the first time against Mycobacterium tuberculosis H37Rv (ATCC 27294). The out‐put of these studies disclosed that all the synthesized target molecules of the series displayed good to moderate activity with MIC values ranging 2–32 μg/mL in comparison with the standard first line antitubercular drugs Rifampicin and Isoniazid. Compound 5e with three methoxy groups meta to each other, is the most distinctive compound identified amongst the series, because of its remarkable in vitro antitubercular activity and thus may act as a promising lead molecule for further explorations.     

Synthesis,antitubercular evaluation and molecular docking studies of phthalimide bearing 1,2,3-triazoles

In a search for safer and potent antitubercular agents, here a library of newly substituted dioxoisoindolinylmethyl-triazolyl-N-phenylacetamide derivatives (5a–l) has been synthesized via click chemistry approach. All synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB). Among the screened compounds, 5d, 5e, 5h, and 5l showed good antitubercular activity. The compounds 5d and 5l have shown very effective antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB) with MIC 12.5?μg/mL. All the newly synthesized compounds were thoroughly characterized by ¹H NMR, ¹³C NMR, and HRMS spectral data. We further performed exploratory docking studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase to demonstrate the mechanism of antitubercular activity.     

Salicylaldehyde and dihydroisobenzofuran derivatives from the marine fungus Zopfiella marina

Two salicylaldehyde derivatives (1 and 2), a hydroxymethylphenol (3), five dihydroisobenzofuran (4–8) derivatives, and a 5-chloro-3-deoxyisoochracinic acid (9), together with a known 3-deoxyisoochracinic acid (10) were isolated from the marine fungus Zopfiella marina BCC 18240 (or NBRC 30420). The structures of these compounds were elucidated by extensive spectroscopic analysis. Compound 1 showed weak antituberculous activity against Mycobacterium tuberculosis H37Ra, and antibacterial activity against Bacillus cereus with MIC values of 25 and 12.5 μg/mL, respectively.     

Synthesis and Antitubercular Evaluation of New Bis-1,2,3-Triazoles Derived from D-Mannitol

Five new bis-1,2,3-triazole derivatives from D-mannitol, namely 2,3,4,5-tetra-O-acetyl-1,6-dideoxy-1,6-bis-(4-substituted-1H-1,2,3-triazol-1-yl)-D-mannitol (4), have been synthesized from 2,3,4,5-tetra-O-acetyl-1,6-diazido-1,6-dideoxy-D-mannitol (3) and alkynes, employing copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) methodology. Evaluation of their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Rv using the Alamar Blue susceptibility test indicated poor activities. However, this study has provided information about the SAR of D-mannitol derivatives in the search for new anti-TB drugs based on this carbohydrate.     

Synthesis and in vitro activity of 6-amino-2,9-diarylpurines for Mycobacterium tuberculosis

A mild method was developed to synthesize 6-amino-2-phenolic-9-alkyl and 9-arylpurines. The new compounds were screened for antibacterial activity against Mycobacterium tuberculosis strain H₃₇Rv. The 9-tolyl derivatives with a dimethylamino or a piperidine substituent in C6 and the 3-hydroxyphenyl or 4-hydroxyphenyl substituent in C2 were highly active against the bacilli.     

Synthesis,bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1,2,3-triazoles

Abstract

In search of more potent new antitubercular agents, a library of novel piperazine tethered dimeric 1,2,3-triazoles were designed by assembling 1,2,3-triazoles and piperazine in a single molecular architectural framework. The titled compounds (3a–m) were synthesized by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1) and various azides (2a–m) using click chemistry approach with good yields. All the synthesized compounds (3a–m) have been screened for their in vitro antitubercular, antifungal and antioxidant activities against their respective strains. Among them, 3b, 3d, and 3i have revealed promising antitubercular activity against Mycobacterium tuberculosis (Mtb) H37Rv with MIC 12.5?µg/mL. Molecular docking results provided well-clustered solutions to the mode of binding for these molecules into the active site of Mtb enoyl reductase (InhA). In addition to this, most of synthesized compounds were found to have potential antifungal as well as antioxidant activity.     

Synthesis and in vitro Antimycobacterial Activity of Moxifloxacin Methylene and Ethylene Isatin Derivatives

A series of novel moxifloxacin methylene and ethylene isatin derivatives with remarkable improvement in lipophilicity, compared to the parent moxifloxacin, was designed, synthesized and characterized by 1H NMR, MS and HRMS. These derivatives were initially evaluated for their in vitro antimycobacterial activity against M. smegmatis CMCC 93202. Compounds 3a―3f, 5a, 5f and 5j were chosen for the further evaluation of their in vitro activity against Mycobacterium tuberculosis(MTB) H37Rv ATCC 27294 and MDR-MTB 09710. All the target compounds[ minimum inhibitory concentration(MIC): 0.39―>16 μg/mL] were far more active than rifampin(MIC: 2.0―>256 μg/mL), but less active than moxifloxacin(MIC: 0.1―1.0 μg/mL) against the three tested strains. The most active compounds 3a and 3c were found to be 2―64 fold more potent than isoniazid and rifampin against M. smegmatis CMCC 93202, 2 fold more potent than rifampin against MTB H37Rv ATCC 27294, and 16―>64 fold more potent than ethambutol, isoniazid and rifampin against MDR-MTB 09710.     

Zinc(II) and mercury(II) complexes with Schiff bases: syntheses,spectral, and structural characterization

Schiff bases o-vanilidene-1-aminobenzene (HL¹) and o-vanilidene-2-methyl-1-aminobenzene (HL²) lead to the formation of mono- and bis-[(Cl)Zn(L¹)] (1), [(Cl)Zn(L²)] (2), [(Cl)Hg(L¹)] (3), [(Cl)Hg(L²)] (4), [Zn(L¹)₂] (5), [Zn(L²)₂] (6), [Hg(L¹)₂] (7), and [Hg(L²)₂] (8) complexes by reactions of zinc(II) and mercury(II) chlorides in different mole ratio(s). Complexes 1–8 have been characterized by elemental analyses (Zn, Hg, C, H, Cl, and N), melting point and spectral (IR, ¹H-NMR), PXRD, molar conductivity measurement, and TGA. Conductivity measurements suggest non-electrolytes. Structural compositions have been assigned by mass spectral studies. Four-coordinate geometry may be assigned to these complexes tentatively. Structural study reveals that in 1–4 two metal centers are held together by two bridged (μ₂-Cl) chlorides, whereas 5–8 contain two bidentate Schiff-base ligands around one metal-producing monomers.     

Design,Synthesis, and Evaluation of Tetraethylene Glycol Tethered Ciprofloxacin–Isatin Hybrids as Novel Antitubercular Agents

A new set of tetraethylene glycol tethered ciprofloxacin–isatin hybrids 5a–l with greater lipophilicity than the parent ciprofloxacin was designed, synthesized, and screened for their in vitro antimycobacterial activity against drug‐sensitive Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant MTB strains as well as toxicity in a mammalian VERO cell line. The preliminary results revealed that all hybrids exhibited considerable activity against MTB H₃₇Rv with minimum inhibitory concentration in a range of 0.205–14.186 μg/mL. Especially, hybrid 5a with low cytotoxicity displayed highest activity against both drug‐sensitive MTB H₃₇Rv and two clinically isolates multidrug‐resistant MTB strains, suggesting that it may serve as a new and promising candidate for further study.     

Synthesis and antimicrobial activity of new 2-((1-furan-2-yl)ethylidene)hydrazono)-4-phenylthiazol-3(2H)-amine derivatives and their schiff bases with 4-nitrobenzaldehyde

Abstract

A new series of 2-((1-furan-2-yl)ethylidene)hydrazono)-4-substitutedphenylthiazol-3(2H)-amines (2a–2o) and their Schiff bases (3a–3o) from 4-nitrobenzaldehyde were synthesized. The chemical structures of all the synthesized compounds were confirmed by their IR, ¹H-NMR, ¹³C-NMR spectroscopy and mass spectrometry. They were screened for their antimicrobial and antifungal activities. Additionally, in vitro cytotoxic acivity of the most active antifungal compound (3o) and ketoconazole was determined in NIH/3T3 cells by MTT assay. Compound 2i (4-{3-Amino-2-[(1-(furan-2-yl)ethylidene)hydrazono]-2,3-dihydrothiazol-4-yl}phenol) showed the greatest antifungal activity among the newly synthesized derivatives. Schiff bases (3c-3n) displayed an undeniable fungicidal action against Candida parapsilosis ATCC 22019 as intense as the reference ketoconazole. In addition, the most active Schiff base 3o (2-[(1-(Furan-2-yl)ethylidene)hydrazono]-N-(4-nitrobenzylidene)-4-(2,3,4-trichloro phenyl)thiazol-3(2H)-amine) showed the highest antifungal activity against both Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019, and was as potent as ketoconazole. Moreover, compound 3o was found to be non-cytotoxic against NIH/3T3 cells.     

Succinct and Facile Synthesis of Innovative Thiopyrimidines With Antimicrobial and Antitubercular Investigation

Abstract

To develop a series of bioactive heterocycles in minimum number of steps, 3-methyl- 4-(substituted phenyl)-1-phenyl-4,8-dihydropyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-5,7 (1H,6H)-dithione 2(a–j), 4-(4-substituted phenyl)-5-imino-3-methyl-1,6-diphenyl-4,5,6,8-tetrahydropyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-7(1H)-thione 3(a–j), and N-[4-(subs- tituted phenyl)-3-methyl-1-phenyl-7-thioxo-1,4,7,8-hexahydropyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-5-yl]thiourea 4(a–j) have been synthesized from amino nitrile functionality 1(a–j). The structures of the compounds were elucidated by IR, ¹H NMR, elemental analysis, and some representative ¹³C NMR and mass spectra. All the title compounds were screened for antimicrobial and antitubercular activities, while some representative compounds were tested for antioxidant activity. Out of synthesized compounds, compounds 1j (4-CH₃), 2d (4-F), 4c (4-OH), and 4i (3-Br) exhibited maximum inhibition against Mycobacterium Tuberculosis H₃₇Rv. Compound 3c (4-OH) revealed elevated efficacy against all tested bacterial strain, while compounds 1i (3-Br), 2c (4-OH), and 3h (3-NO₂) were found efficacious against Candida albicans as compared to standard drugs.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

In vitro and ex vivo antitubercular activity of diarylheptanoids from the rhizomes of Alpinia officinarum Hance

Phytochemical investigation of methanol extract of the rhizomes of Alpinia officinarum Hance afforded four known diarylheptanoids 1,7-diphenylhept-4-en-3-one (1), 5-hydroxy-1,7-diphenyl-3-heptanone (2), 5-hydroxy-7-(4″-hydroxy-3″-methoxyphenyl)-1-phenyl-3-heptanone (3), and 7-(4″-hydroxy-3″-methoxyphenyl)-1-phenyl heptan-3-one (4).The acetate derivative of (4), 7-(4″-actetate-3″-methoxy phenyl)-1-phenyl heptan-3-one (5), was prepared. These diarylheptanoids exhibited promising in vitro and ex vivo antitubercular activity for the first time against dormant Mycobacterium tuberculosis H37Ra with the IC₅₀ values between 0.34–47.69 and 0.13–22.91 μM, respectively. All compounds showed comparable activity against Mycobacterium bovis BCG (dormant phage) and did not show any activity against two gram + ve and two gram –ve bacterial strains. These compounds were also weakly cytotoxic up to 300 μM against three human cancer cell lines THP-1, Panc-1 and A549.     

Ciprofloxacin–Isatin Hybrids and Their Antimycobacterial Activities

A series of diethylene glycol tethered ciprofloxacin–isatin hybrids 5a–j were designed, synthesized, and evaluated for their in vitro antimycobacterial activity against both drug‐sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains in this paper. The preliminary results revealed that all hybrids with greater lipophilicity than the parent ciprofloxacin displayed considerable activity against the tested strains with minimum inhibitory concentration (MIC) in a range of 1.56–64 μg/mL. In particular, hybrid 5f (MIC: 1.56 and 2 μg/mL) with low cytotoxicity in VERO cell line was comparable with the parent ciprofloxacin (MIC: 0.78 and 2 μg/mL) against M. tuberculosis H₃₇Rv and MDR tuberculosis strains and ≥16‐fold more potent than isoniazid and rifampicin (MIC: >128 and 32 μg/mL, respectively) against MDR tuberculosis, suggesting that it may serve as a new and promising candidate for further study.     

Design,synthesis and biological evaluation of some 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives as selective DprE1 inhibitors

Abstract

Tuberculosis (TB) is an infectious disease and caused by various strains of mycobacteria. In the present study, pharmacophore model was developed using single ligand by ligand-based drug discovery approach. The key features responsible for DprE1 inhibitory activity were taken into consideration for developing pharmacophore. After the virtual screening, top 1000 hits were further subjected to docking study using GLIDE module, Schrödinger. Docking studies have shown promising interaction with amino residues with better glide score. Ligand-based drug design approach yielded a series of 15, 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives. All synthesized derivatives were characterized using NMR, mass, CHN analysis. The synthesized compounds were screened for In vitro antitubercular activity against Mycobacterium tuberculosis (H₃₇Rv). Four compounds, 5g (MIC-1.01?μM); 5i (MIC-0.91?μM); 5k (MIC-0.82?μM); and 5o (MIC-1.04?μM) has shown promising activity compared to MIC of standard isoniazid (INH) and DprE1 enzyme inhibition was compared to BTZ043. Two halogen-substituted compounds have exhibited drastic enzyme inhibition.     

Propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered Isatin‐coumarin Hybrids: Design,Synthesis, and In Vitro Anti‐tubercular Evaluation

A series of novel propylene‐1H‐1,2,3‐triazole‐4‐methylene‐tethered isatin‐coumarin hybrids 7a–l that were composed of three anti‐tubercular bioactive substances/pharmacophore coumarin, isatin, and I‐A09 were designed, synthesized, and assessed for their in vitro anti‐tubercular activity against Mycobacterium tuberculosis (MTB) H₃₇Rv. In spite of the hybrids were inactive against the tested MTB H₃₇Rv, the structure–activity relationship was enriched, and these hybrids may act as an ideal starting point for developing new isatin‐coumarin anti‐TB candidates with various linkers.     

Design,Synthesis, and in vitro Antimycobacterial Activity of Propylene‐tethered Isatin Dimmers

A set of propylene‐tethered isatin dimmers 2a–i was synthesized via click chemistry and screened for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant TB. In spite of all dimmers (minimum inhibitory concentration: 25– > 128 μg/mL) only exhibited weak to moderate activities against the tested MTB H₃₇Rv and multidrug‐resistant TB, the structure–activity relationship was enriched and the results warrant further development of the anti‐TB properties of this kind of dimmers.     

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.     

Synthesis, antibacterial and antifungal activities of 3-aryl-5-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamide derivatives

A new series of 3-aryl-5-(pyridin-3-yl)-1-thiocarbamoyl-2-pyrazoline derivatives (4a-j) were prepared by the reaction of azachalcons 3a-j with thiosemicarbazide in ethanolic sodium hydroxide. The structure of synthesized compounds were confirmed by ¹H NMR and Mass spectral data. Their antibacterial activities against Escherichia coli (CTP 7624), Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12229), Pseudomonas aeruginosa (ATCC 9027), Bacillus subtilis (ATCC 1156) and Micrococcus luteus (ATCC 9341) were investigated. Antifungal activity of compounds against Candida albicans and Candida globrata were found to be inactive. Compounds 4a-j were also evaluated for antituberculosis activity against Mycobacterium tuberculosis H ₃₇ Rv (ATCC 27294) in BACTEC 12B using a broth microdilution assay and Microplate Alamar Blue Assay (MABA). The preliminary results showed that compounds 4e, 4d and 4g had 87%, 93% and 92% inhibitory effect respectively.     

New 6-(4-Bromophenyl)-imidazo[2,1- b ]thiazole Derivatives: Synthesis and Antimicrobial Activity

 New 4-alkyl/aryl-1-((6-(4-bromophenyl)-imidazo[2,1-b]thiazol-3-yl)-acetyl)-3-thiosemicarbazides and 3-alkyl/aryl-2-(((6-(4-bromophenyl)-imidazo[2,1-b]thiazol-3-yl)-acetyl)-hydrazono)-4-thiazolidinones were synthesized from 6-(4-bromophenyl)-imidazo[2,1-b]thiazole-3-acetic acid hydrazide. Their structures were elucidated by elemental analyses and spectroscopic data. All compounds were tested for antibacterial and antifungal activities. The antimicrobial activities of the compounds were assessed by the microbroth dilution technique. The compounds were also evaluated for antituberculosis activity against Mycobacterium tuberculosis H₃₇Rv (ATCC 27294); they exhibited varying degrees of inhibition in the in vitro primary screening at 6.25 μg · cm⁻³. The most active compound was 3-(4-nitrophenyl)-2-(((6-(4-bromophenyl)-imidazo[2,1-b]thiazol-3-yl)-acetyl)-hydrazono)-4-thiazolidinone.     

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

A series of novel propylene tethered benzofuran–isatin hybrids 5a–j were designed, synthesized, and assessed for their in vitro anti‐mycobacterial activity against Mycobacterium tuberculosis (MTB) H₃₇Rv and multidrug‐resistant (MDR)‐MTB strains. All hybrids exhibited promising anti‐mycobacterial activities against the tested two pathogens with minimum inhibitory concentration (MIC) ranging from 2 to 32 μg/mL, and the resistance index for a significant part of the hybrids was ≤1, indicating their potential for the treatment of drug‐resistant tuberculosis. Hybrid 5g (MIC: 2 and 4 μg/mL) was found to be the most active against MTB H₃₇Rv and MDR‐MTB, which was eightfold and >32‐fold more active than the first‐line anti‐tuberculosis drugs rifampicin (MIC: 32 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR‐MTB, and it could act as a starting point for further optimization.