5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines as dual inhibitors of Mycobacterium tuberculosis and influenza virus: Synthesis and evaluation

This study describes synthesis and evaluation of novel 5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines 7a-o as dual inhibitors of Mycobacterium tuberculosis and influenza virus. Huisgen’s [3+2] dipolar cycloaddition of 6-(azidomethyl)-5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline 5 with various alkynes 6a-o using sodium ascorbate and copper sulphate gave new dihydroquinoline-1,2,3-triazoles 7a-o in good to excellent yields. The new compounds were evaluated for in vitro antimycobacterial against M. tuberculosis H37Rv (Mtb) and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1). Among the fifteen new analogs, compounds 7a (MIC: 3.12 µg/mL), 7j and 7k (MIC: 6.25 µg/mL) were identified as potent antitubercular agents. The virus-inhibiting activity of all the fifteen compounds was found to be moderate, and among them the compound 7l, bearing thiophene moiety appeared the most active with good selectivity index (IC₅₀ = 19.5 µg/mL; SI = 15). The results presented here will help developing newer dual inhibitors of tuberculosis and influenza virus.     

Dibenzofuran,dibenzothiophene and N-methyl carbazole tethered 2-aminothiazoles and their cinnamamides as potent inhibitors of Mycobacterium tuberculosis

Herein described the design, synthesis and antitubercular evaluation of novel series of dibenzofuran, dibenzothiophene and N-methyl carbazole tethered 2-aminothiazoles and their cinnamamide analogs. One pot condensation of N-methyl carbazole, dibenzofuran and dibenzothiophene methyl ketones with thiourea in the presence of Iodine and CuO gave respective 2-aminothiazoles 4–6 in very good yields. Aminothiazoles were further coupled with substituted cinnamic acids using acid-amine coupling conditions to give desired cinnamamide analogs 8a–e, 9a–e and 10a–e. All the newly synthesized compounds were fully characterized by their NMR and mass spectral analysis. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv (Mtb) resulted 8c, 10d and 10e (MIC: 0.78?µg/mL) and 2-aminothiazoles 5 and 6 (MIC: 1.56?µg/mL) as potent compounds with lower cytotoxicity profile.     

Design,synthesis and in vitro anti-mycobacterial evaluation of gatifloxacin-1H-1,2,3-triazole-isatin hybrids

A set of novel gatifloxacin-1H-1,2,3-triazole-isatin hybrids 6a-l was designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H₃₇Rv and MDR-TB as well as cytotoxicity. The results showed that all the targets (MIC: 0.025–3.12 μg/mL) exhibited excellent inhibitory activity against MTB H₃₇Rv and MDR-TB, but were much more toxic (CC₅₀: 7.8–62.5 μg/mL) than the parent gatifloxacin (GTFX) (CC₅₀: 125 μg/mL). Among them, 61 (MIC: 0.025 μg/mL) was 2–32 times more potent in vitro than the references INH (MIC: 0.05 μg/mL), GTFX (MIC: 0.78 μg/mL) and RIF (MIC: 0.39 μg/mL) against MTB H₃₇Rv. The most active conjugate 6 k (MIC: 0.06 μg/mL) was 16–>2048 times more potent than the three references (MIC: 1.0–>128 μg/mL) against MDR-TB. Both of the two hybrids warrant further investigations.     

Design,synthesis, and bioevaluation of a novel class of (E)-4-oxo-crotonamide derivatives as potent antituberculosis agents

A series of novel (E)-4-oxo-2-crotonamide derivatives were designed and synthesized to find potent antituberculosis agents. All the target compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H₃₇Rv(MTB). Results reveal that 4-phenyl moiety at part A and short methyl group at part C were found to be favorable. Most of the derivatives displayed promising activity against MTB with MIC ranging from 0.125 to 4?µg/mL. Especially, compound IIIa16 was found to have the best activity with MIC of 0.125?μg/mL against MTB and with MIC in the range of 0.05–0.48?µg/mL against drug-resistant clinical MTB isolates.     

Synthesis,antimicrobial activity and acid dissociation constants of methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives

In this study, a series of polysubstituted methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives were designed and synthesized by the cyclization reaction of methyl 1-(benzoylcarbamothioyl)-5,5-diphenylpyrrolidine-2-carboxylates and 2-bromo-1-(4-substituted phenyl)ethanones in 70–96% yield. The starting pyrrolidine derivatives were synthesized via a 1,3-dipolar cycloaddition reaction in 83–88% yield. The stereochemistry of one of these methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives was characterized by a single crystal X-ray diffraction study and the acid dissociation constants of these compounds were determined. An antimicrobial screening was performed against different bacterial and fungal strains and against the M. tuberculosis H37Rv strain. Interesting antibacterial activity was observed for two compounds against the A. baumannii strain with MIC values of 31.25?µg/mL (Ampicillin: 125?µg/mL) and against the M. tuberculosis H37Rv strain with MIC values of 0.98–1.96?µg/mL (Isoniazid: 0.98?µg/mL, Ethambutol: 1.96?µg/mL). Therefore, these structures can be considered as good starting points for the development of new powerful antimycobacterial agents.     

Structure-based design of some isonicotinic acid hydrazide analogues as potential antitubercular agents

New pyridine derivatives were designed and synthesized as Isonicotinic acid hydrazide (INH) analogues. The synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis strain H₃₇R_v. Ten compounds (3c, 3e-g, 5a-c, 6h, 10 and 11b) showed promising antitubercular activity with MIC range 7.30 µM–19.39 µM. Compounds 3e, 3g, 5b and 11b were the most potent analogues, with MIC 7.30–8.74 µM. They were equipotent to the standard drug Ethambutol (MIC 7.64 µM) and more active than the standard drug Pyrazinamide (MIC 50.77 µM). They were further examined for cytotoxicity in human embryonic kidney (HEK) cell line at the concentration of 50 µg/mL using MTT assay. Results declared that most compounds showed acceptable safety margin. Molecular Docking studies into 2-trans-enoyl-acyl carrier protein reductase, called InhA have been conducted for compounds 3e, 3g, 5b and 11b using Molecular Operating Enviroment software (MOE 2016.0802), where reasonable binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration and Osiris software.     

Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria

Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a?6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125?µg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5?µg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC₅₀ value of 91.04?μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.     

Design and synthesis of new fused carbazole-imidazole derivatives as anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and in silico studies

Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC₅₀?=?750.0?±?1.5?µM) against yeast α-glucosidase with IC₅₀ values in the range of 74.0?±?0.7–298.3?±?0.9?µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (K_i value?=?75?µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase.     

Ultrasonication-ionic liquid synergy for the synthesis of new potent anti-tuberculosis 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines

The aim of the study is to design and synthesis of a new series of potent anti-TB 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines with their safety profile. A synergetic effect of ultrasonication and ionic liquid was shown successfully as a green methodology for the synthesis of title compounds 6a–t. These derivatives were obtained in shorter reaction time with good yields and well characterized by various spectroscopic methods, single-crystal X-ray diffraction (6f). The in vitro anti-tuberculosis activity for newly-synthesized derivatives has been screened against Mycobacterium tuberculosis. Among all, six compounds 6e, 6k, 6l, 6n, 6q and 6r exhibited equal potent activity compared to standard drug ethambutol (MIC: 1.56 µg/mL) and another compound 6h exhibited outstanding activity (MIC: 0.78 µg/mL) than the standard drug ethambutol. Cytotoxic nature of the anti-TB active compounds was evaluated against RAW 264.7 cells. The 6h, 6e, 6k, 6l, 6n, 6q and 6r exhibited lower toxicity which could be promising hits for anti-tuberculosis.     

Design,synthesis and in vitro anti-tuberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives

A series of novel benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole hybrids (7a–j & 8a–j) have been designed and synthesized in excellent yields by Huisgen’s [3+2] cyclo addition reaction of 3-(azidomethyl)-2-methyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine (5) with various alkynes 6 in presence of copper sulphate and sodium ascorbate and their structures were confirmed by IR, ¹H NMR, ¹³C NMR and HRMS. The newly synthesized compounds 7a–j & 8a–j were evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Among the compounds tested, the compounds 7i and 8g displayed most potent activity with MIC value of 1.56?µg/mL with low cytotoxicity.     

Antimicrobial,anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4-dihydropyridine derivatives

A new series of 1,4-dihydropyridine derivatives (2a–h, 3a–e, and 4a–e) were systematically designed and synthesized via ultrasound irradiation methods with easy work-up and good yields. Compounds structures were confirmed by IR, ¹H NMR, ¹³C NMR, and mass spectra. The synthesized compounds were screened for both antimicrobial and anticoagulant activities. Compound 2e (MIC: 0.25?μg/mL) was highly active against Escherichia coli and compound 2c (MIC: 0.5?μg/mL) was also highly active against Pseudomonas aeruginosa compared with ciprofloxacin. (MIC: 1?μg/mL) The antifungal activity of 2c (MIC: 0.5?μg/mL) against Candida albicans was high relative to that of clotrimazole (MIC: 1?μg/mL). Anticoagulant activity was determined by activated partial thromboplastin time (APTT) and prothrombin time (PT) coagulation assays. Compound 4-(4-hydroxyphenyl)-2,6-dimethyl-N³,N⁵-bis(5-phenyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyridine-3,5-dicarboxamide 3d (>1000?s in APTT assays) was highly active in anticoagulant screening compared with the reference of heparin.Cytotoxicity was evaluated using HepG2 (liver), HeLa (cervical), and MCF-7 (breast) cancer cell lines, with high toxicities observed for 2c (GI₅₀?=?0.02?μm) against HeLa cell line and 2e (GI₅₀?=?0.03?μm) equipotant against MCF-7 cell line. Therefore, the compounds 2e, 2c and 3d can serve as lead molecules for the development of new classes of antimicrobial and anticoagulant agent.     

Synthesis and in vitro antimicrobial activity of new 4-phenyl-5-methyl-4H-1,2,4-triazole-3-thione derivatives

This study presents the synthesis, spectral analysis and antimicrobial evaluation of a new series of substituted 1,2,4-triazole (5a–i) and 1,3,4-thiadiazole derivatives (9a, c, g, h). New compounds were obtained by cyclization reaction of acyl thiosemicarbazide derivatives in the presence of alkaline and acidic media. All synthesized compounds were screened for their in vitro antimicrobial activities. Nine of the compounds had potential activity against Gram-positive bacteria (MIC?=?3.91–500 µg/mL). Some compounds showed good activity especially against: Micrococcus luteus ATCC 10240 (MIC?=?3.91?31.25 µg/mL), Bacillus subtilis ATCC 6633 (MIC?=?15.63? 62.5 µg/mL), and Staphylococcus aureus ATCC 25923 (MIC?=?15.63?125 µg/mL).     

Ciprofloxacin-1,2,3-triazole-isatin hybrids tethered via amide: Design,synthesis, and in vitro anti-mycobacterial activity evaluation

The purpose of this study was to prepare various novel amide tethered ciprofloxacin-1,2,3-triazole-isatin hybrids 7a-l, and evaluate their in vitro anti-mycobacterial activity as well as cytotoxicity in VERO cells. The synthesized hybrids showed considerable in vitro activity against both MTB H₃₇Rv and MDR-MTB with MIC of 0.12 to 32 μg/mL, and acceptable cytotoxicity in VERO cells (CC₅₀: 8.0–>128.0 μg/mL). In particular, the most active hybrid 7a (MIC_{MTB H37Rv}: 0.5 μg/mL and MIC_MDR-MTB: 0.12 μg/mL) had the activity in the same level with the first-line anti-tubercular agents isoniazid (MIC: 0.12 μg/mL) and rifampicin (MIC: 0.25 μg/mL), and it was 2-fold more active than the parent ciprofloxacin (MIC: 1.0 μg/mL) against MTB H₃₇Rv, and ≥16 folds more potent than ciprofloxacin (MIC: 2.0 μg/mL), isoniazid (MIC: >64 μg/mL) and rifampicin (MIC: >64 μg/mL) against MDR-MTB. Moreover, hybrid 7a (CC₅₀: 16.0 μg/mL) also displayed considerable cytotoxicity towards VERO cells. Thus, hybrid 7a could act as a platform for further investigations.     

Benzofuran-isatin hybrids tethered via different length alkyl linkers and their in vitro anti-mycobacterial activities

A series of novel benzofuran-isatin hybrids 6a–m tethered through different length alkyl linkers propylene, butylene, pentylene and hexylene were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against both drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (MTB) and cytotoxicity towards VERO cells. All hybrids with acceptable cytotoxicity in VERO cells (CC₅₀: 64 to >1024 μg/mL) also exhibited considerable anti-mycobacterial activities against both drug-susceptible and MDR-MTB strains with MIC in a range of 0.125–4 μg/mL. The SAR indicated that the length of the linker played a pivotal role on the activity, and the longer linker could enhance the activity. The most active hybrid 6d (MIC: 0.125 and 0.125 μg/mL) was comparable to or better than rifampicin (MIC: 0.5 μg/mL) and isoniazid (MIC: 0.06 μg/mL) against MTB H₃₇Rv, and was ≥256 folds more potent than rifampicin (MIC: 64 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR-MTB strain, but was less active than TAM16 (MIC: <0.06 μg/mL against the tested two strains). The hybrid 6d also showed low cytotoxicity towards VERO cell (CC₅₀: 128 μg/mL), but it was inferior to TAM16 in metabolic stability and in vivo pharmacokinetic profiles.     

Substituted sulfonamide bioisosteres of 8-hydroxyquinoline as zinc-dependent antibacterial compounds

A series of substituted sulfonamide bioisosteres of 8-hydroxyquinoline were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus uberis, Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc. Compounds 9a-e, 10a-c, 11a-e, 12 and 13 were demonstrated to have MICs of 0.0625 µg/mL against S. uberis in the presence of 50 µM ZnSO₄. Against S. aureus compounds 9g (MIC 4 µg/mL) and 11d (MIC 8 µg/mL) showed the greatest activity, whereas all compounds were found to be inactive against E. coli (MIC > 256 µg/mL); again in the presence of 50 µM ZnSO₄. All compounds were demonstrated to be significantly less active in the absence of supplementary zinc. Compound 9g was subsequently confirmed to be bactericidal, with an MBC (≥3log₁₀ cfu/mL reduction) of 0.125 µg/mL against S. uberis in the presence of 50 µM ZnSO₄. To validate the sanitising activity of compound 9g in the presence of supplementary zinc, a quantitative suspension disinfection (sanitizer) test was performed. In this preliminary test, sanitizing activity (>5log₁₀ reduction of CFU/mL in 5 min) was observed against S. uberis for compound 9g at concentrations as low as 1 mg/mL, validating the potential of this compound to function as a topical sanitizer against the major environmental mastitis-causing microorganism S. uberis.     

1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design,synthesis and biological evaluation

A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (IC₅₀s = 0.06–6.80 µM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31–155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu²⁺ ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells.     

Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA)

Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125–8 µg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC₅₀ = >10–>100 µg/mL) and exhibited favourable selectivity index (SI = 40–>200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.     

Constituents of Desmodium salicifolium (Poir.) DC (Fabaceae) with antifungal activity

Phytochemical investigation of the roots of Desmodium salicifolium led to the isolation of two new compounds (Desmoflavanone A: 5,2',4'-trihydroxy-4'',4''-dimethyl-2H-dihydropyranoisoflavanone (1) and desmodioside A: (22R)-3β,22,23-trihydroxyolean-12-en-3-O-α- _L-rhamnopyranosyl-(1→2)-β-_D-glucopyranosyl-(1→2)-β-_D-glucuronopyranoside (2)) together with nine known secondary metabolites including kaikasaponin III (3), spinosin (4), isovitexin (5), β-sitosterol 3-O-β-_D-glucopyranoside (6), neorautenol (7), kaempferol (8), oleanolic acid (9), betulinic acid (10), and lupeol (11). The structures of these compounds were elucidated mainly by extensive spectroscopic analysis, particularly 1D and 2D NMR spectroscopy, electrospray ionization-mass spectrometry and by comparison of their spectroscopic data with those of related compounds reported in the literature. The methanolic extract, EtOAc and n-BuOH fractions as well as some isolated compounds were assessed for their antifungal activities against two fungi using microdilution method. The methanolic extract displayed weak activity against Candida albicans (MIC = 512 µg/mL). The EtOAc fraction also exhibited weak inhibitory effect with MIC of 256 µg/mL against Candida albicans and Candida glabrata. Compound 3 showed moderate effect against Candida glabrata with MIC value of 16 µg/mL while 1 was inactive against both fungi.     

Synthesis and characterization of pyridoxine,nicotine and nicotinamide salts of dithiophosphoric acids as antibacterial agents against resistant wound infection

The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(–)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(–)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10?µM (6?µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC₅₀?=?48.6 and 57.6?µM, respectively, 72?h), encouraging their further investigation as potential antimicrobials against skin and wound infections.     

A novel synthesis of 2-arylbenzimidazoles in molecular sieves-MeOH system and their antitubercular activity

Arylbenzimidazoles have been synthesized as antimycobacterial agents. An efficient synthesis has been developed for 2-arylbenzimidazoles from o-phenylenediamines and aromatic aldehydes in molecular sieves-methanol system. The methodology is straightforward to get 2-arylbenzimidazoles (3a–3z) in excellent yields with high chemoselectivity over 2-aryl-1-benzylbenzimidazoles (4a–4z). All these benzimidazole analogues were evaluated against M. tuberculosis in BACTEC radiometric assay. The compounds 4y and 4z exhibited potential antitubercular activity against M. tuberculosis H₃₇R_V, MIC at 16?µM and 24?µM respectively. The best compound of the series i.e. compound 4y was well tolerated by Swiss-albino mice in acute oral toxicity. Compound 4y possessing a diarylbenzimidazole core, can further be optimized for better activity.