- Chagas Disease Drug Discovery: Multiparametric Lead Optimization against Trypanosoma cruzi in Acylaminobenzothiazole Series
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Acylaminobenzothiazole hits were identified as potential inhibitors of Trypanosoma cruzi replication, a parasite responsible for Chagas disease. We selected compound 1 for lead optimization, aiming to improve in parallel its anti-T. cruzi activity (IC50 = 0.63 μM) and its human metabolic stability (human clearance = 9.57 mL/min/g). A total of 39 analogues of 1 were synthesized and tested in vitro. We established a multiparametric structure-activity relationship, allowing optimization of antiparasite activity, physicochemical parameters, and ADME properties. We identified compound 50 as an advanced lead with an improved anti-T. cruzi activity in vitro (IC50 = 0.079 μM) and an enhanced metabolic stability (human clearance = 0.41 mL/min/g) and opportunity for the oral route of administration. After tolerability assessment, 50 demonstrated a promising in vivo efficacy.
- Fleau, Charlotte,Padilla, Angel,Miguel-Siles, Juan,Quesada-Campos, Maria T.,Saiz-Nicolas, Isabel,Cotillo, Ignacio,Cantizani Perez, Juan,Tarleton, Rick L.,Marco, Maria,Courtemanche, Gilles
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p. 10362 - 10375
(2019/11/29)
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- Synthesis and molecular docking of new roflumilast analogues as preferential-selective potent PDE-4B inhibitors with improved pharmacokinetic profile
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In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5.67 mL/min/kg) and moderate % plasma protein binding (53.71%). This was reflected onto increased in vivo exposure with a half-life greater than roflumilast by 3 folds (21 h) and a Cmax value of 113.958 ng/mL. Molecular docking attributed its good activity to its key binding interactions in PDE-4B active site with additional hydrogen bonding with amino acids lining the metal pocket. Summing up, 6c can be considered as suitable candidate for further investigation for the treatment of COPD.
- Moussa, Bahia A.,El-Zaher, Asmaa A.,El-Ashrey, Mohamed K.,Fouad, Marwa A.
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p. 477 - 486
(2018/02/28)
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- Novel Piperine Derivatives with Antidiabetic Effect as PPAR-γ Agonists
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Piperine is an alkaloid responsible for the pungency of black pepper. In this study, piperine isolated from Piper nigrum L. was hydrolyzed under basic condition to obtain piperic acid and was used as precursor to carry out the synthesis of twenty piperine derivatives containing benzothiazole moiety. All the benzothiazole derivatives were evaluated for their antidiabetic potential by OGT test followed by assessment of active derivatives on STZ-induced diabetic model. It was observed that nine of twenty novel piperine analogues (5b, 6a-h), showed significantly higher antidiabetic activity in comparison with rosiglitazone (standard). Furthermore, these active derivatives were evaluated for their action as PPAR-γ agonists demonstrating their mechanism of action. The effects on body weight, lipid peroxidation, and hepatotoxicity after administration with active derivatives were also studied to further establish these derivatives as lead molecules for treatment of diabetes with lesser side-effects.
- Kharbanda, Chetna,Alam, Mohammad Sarwar,Hamid, Hinna,Javed, Kalim,Bano, Sameena,Ali, Yakub,Dhulap, Abhijeet,Alam, Perwez,Pasha, M. A. Qadar
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p. 354 - 362
(2016/10/19)
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- Catalytic N-formylation for synthesis of 6-substituted-2-benzothiazolylimino-5-piperazinyl-4-thiazolidinone antimicrobial agents
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A new class of piperazine-based 2-benzothiazolylimino-4-thiazolidinones has been efficiently prepared via highly accelerated N-formylation of N-isopropylpiperazine by the use of a mild heterogeneous catalyst, sulfated tungstate. Heterocyclization of N-(benzo[d]thiazol-2-yl)-2-chloroacetamides (3a-j) by use of NH4SCN in ethanol under reflux efficiently furnished the intermediates 2-benzothiazolyliminothiazolidin-4-ones (4a-j). These were treated with 4-isopropylpiperazine-1-carbaldehyde (2) to prepare the final products 5a-j. The structures of the new derivatives were confirmed by elemental analysis and use of spectroscopic data (FTIR and 1H NMR). Their pharmacological potential as promising antimicrobial agents was determined in vitro against bacteria and a fungus; the lowest minimum inhibitory concentrations (MIC) observed were in the range 4-8 μg/mL.
- Patel, Rahul V.,Park, Se Won
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p. 5599 - 5609
(2015/07/08)
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- Chrysin-benzothiazole conjugates as antioxidant and anticancer agents
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7-(4-Bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one, obtained from chrysin with 1,4-dibromobutane, was combined with a wide range of 6-substituted 2-aminobenzthiazoles, which had been prepared from the corresponding anilines with potassium thiocyanate. Free radical scavenging efficacies of newer analogues were measured using DPPH and ABTS assays, in addition to the assessment of their anticancer activity against cervical cancer cell lines (HeLa and CaSki) and ovarian cancer cell line (SK-OV-3) implementing the SRB assay. Cytotoxicity of titled compounds was checked using Madin-Darby canine kidney (MDCK) non-cancer cell line. Overall, 6a-r indicated remarkable antioxidant power as DPPH and ABTS+ scavengers; particularly the presence of halogen(s) (6g, 6h, 6j-6l) was favourable with IC50 values comparable to the control ascorbic acid. Unsubstituted benzothiazole ring favored the activity of resultant compounds (6a and 6r) against HeLa cell line, whereas presence of chlorine (6g) or a di-fluoro group (6k) was a key to exert strong action against CaSki. Moreover, a mono-fluoro (6j) and a ketonic functionality (6o) were beneficial to display anticipated anticancer effects against ovarian cancer cell line SK-OV-3. The structural assignments of the new products were done on the basis of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis.
- Mistry, Bhupendra M.,Patel, Rahul V.,Keum, Young-Soo,Kim, Doo Hwan
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supporting information
p. 5561 - 5565
(2015/11/17)
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- Synthesis and anticonvulsant activity evaluation of 7-alkoxy[1,2,4] triazolo[3,4-b]benzothiazol-3(2H)-ones
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A new series of 7-alkoxy[1,2,4]triazolo[3,4-b]benzothiazol-3(2H)-ones were synthesized and evaluated for their anticonvulsant activities. Among these compounds, 7-propoxy[1,2,4]triazolo[3,4-b]benzothiazol-3(2H)-one (4c) and 7-butoxy[1,2,4]triazolo[3,4-b]benzothiazol-3(2H)-one (4d) showed the highest activity against maximal electroshock (MES)-induced tonic extension [effective dose (ED)50: 11.4 and 13.6 mg/kg, respectively]. It is worth mentioning that compound 4d showed especially low neurotoxicity, which led to a high protective index (PI >51). The orally anticonvulsant activity data of compound 4d further confirmed its efficacy, in an MES test, and its high safety with a PI value of 50.2. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-induced seizure tests suggested that compound 4d may exert its anticonvulsant activity through affecting the GABAergic system.
- Liu, Da-Chuan,Deng, Xian-Qing,Wang, Shi-Ben,Quan, Zhe-Shan
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p. 268 - 275
(2014/04/17)
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- In vitro biological investigations of novel piperazine based heterocycles
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Eleven N.phenyl- and 11 N.benzothiazolyl-2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)acetamides have been synthesised by a simple and efficient method. The 22 novel compounds were tested for their in vitro biological efficacy against two Grampositive bacteria, three Gram-negative bacteria, two fungi and Mycobacterium tuberculosis H37Rv. The bioassay results revealed that the majority of the N.benzothiazole-substituted piperazine derivatives exhibited moderate to good bioefficacies with encouraging MICs. The influence of the presence or absence of various electron-withdrawing or -donating functional groups on the aryl acetamide moiety on the different bioassay results is discussed.
- Chhatriwala, Nirmal M.,Patel, Amit B.,Patel, Rahul V.,Kumari, Premlata
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p. 611 - 616
(2015/02/02)
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- Access to a new class of biologically active quinoline based 1,2,4-triazoles
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As an aspect of our ongoing research in search of new antimicrobial armamentarium, a series of 1,2,4-triazol-3-ylthio-acetamides was constructed and in vitro analyzed for their antimicrobial activity against several bacteria and fungi. Aiming to establish an increased potency, the bioassay results were matched to those of 1,3,4-oxadiazoles, utilized previously. Remarkably, 1,2,4-triazoles were found to possess a good spectrum of antifungal potency, which eventually suggested the azole template as an essential pharmacophore to diversify the biological occupations of the attendant molecules. However, it was noticed that the potency of final analogs against each strain placed reliance on the type of substituent present on benzothiazole ring. The structures of final compounds were confirmed with the aid of IR, 1H NMR, 13C NMR spectroscopy and CHN analysis.
- Patel, Rahul V.,Park, Se Won
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- Discovery of the highly potent Fluoroquinolone-based Benzothiazolyl-4- thiazolidinone hybrids as antibacterials
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A new series of fluoroquinolone-based benzothiazolyl-4-thiazolidinone hybrids has been yielded via sulfated tungstate-promoted highly accelerated N-formylation at a piperazine residue of ciprofloxacin and norfloxacin entities. The formylated fluoroquinolone moieties were then coupled with substituted 2-aminobenzothiazoles, which were generated from their respective para-substituted amines to form corresponding Schiff base intermediates. The Schiff bases were then treated with thioglycolic acid to equip a new class of 4-thiazolidinones to be analyzed for their antibacterial effects against two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and were found highly potent with lowest Minimum inhibitory concentrations (MIC), 1-2 μg/mL, that is, more potent than control drugs ciprofloxacin (3.12-6.25 μg/mL). Initial outcomes provided for these novel molecular systems will aid researchers to design and develop new antibacterial drugs. The structural assignments of the new products were done on the basis of FT-IR, 1H NMR and 13C NMR spectroscopy, and elemental analysis. A truly rationalized design of a new class of 4-thiazolidinones revealed potent antibacterial efficacies with lowest MICs 1-2 μg/mL when compared to control drug ciprofloxacin at 3.12-6.25 μg/mL. Combination of electron-withdrawing substituent on the benzothiazole ring and norfloxacin entity furnished anti-Gram-positive effects, as well as combination of electron-releasing substituent with ciprofloxacin entity furnished anti-Gram-negative potency. Two thiazole rings positively enhanced the potency of the final scaffolds.
- Patel, Rahul V.,Park, Se Won
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p. 123 - 129
(2014/07/07)
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- Synthesis of coumarin-based 1,3,4-oxadiazol-2ylthio-N-phenyl/benzothiazolyl acetamides as antimicrobial and antituberculosis agents
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In an attempt to find new agents to fight against microbial infections, a series of coumarin-based 1,3,4-oxadiazol-2ylthio-N-phenyl/benzothiazolyl acetamides was synthesized starting from coumarin-3-carboxylic acid ethyl ester obtained through Knoevenagel and Pinner reaction. In vitro antimicrobial activity against several bacteria (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain was assessed. This study shows to what extent the presence of various electron withdrawing/donating substituents on the phenyl or benzothiazole ring affects the activity profiles of the newer molecules. The relationship between activity profiles (MICs, 3.12-25 μg/mL) and the lipophilic character (LogP) of the prepared products is also discussed and the MIC values of the active conjugates seem to correlate to some extent with the lipophilicity profiles. Two (5e and 6c) of the final analogues displayed promising antimycobacterial activity at 12.5 μg/mL of MIC, half fold potent to the standard drug pyrazinamide (6.25 μg/mL). Compounds were characterized by IR, 1H NMR, 13C NMR spectroscopy and elemental analysis.
- Patel, Rahul V.,Kumari, Premlata,Rajani, Dhanji P.,Chikhalia, Kishor H.
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p. 195 - 210
(2013/03/13)
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- New quinolinyl-1,3,4-oxadiazoles: Synthesis, in vitro antibacterial, antifungal and antituberculosis studies
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In order to generate hybrid antimicrobial remedies with novel mode of action, two series of quinoline based 1,3,4-oxadiazole derivatives condensed with N-aryl/benzothiazolyl acetamides were synthesized and the MIC values of the compounds towards eight reference bacterial strains (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), four fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and Mycobacterium tuberculosis H37Rv were assayed in vitro. Quinoline-6-carboxlic acid was treated with thionyl chloride in refluxing methanol to obtain the corresponding ester derivative to be hydrazinolyzed by 99% hydrazine hydrate in ethanol to produce carbohydrazide intermediate. The carbohydrazide precursor underwent cyclization by carbon disulfide and ethanolic KOH to construct 5-quinolinyl-6-yl-1,3,4- oxadiazol-2-thiol. Substituted 2-chloro-N-phenyl(benzothiazolyl)aceta-mide derivatives were then condensed to 1,3,4-oxadiazole nucleus via sulphur linkage to yield the desired products. Target products bearing N-benzothiazolyl-2- chloroacetamides displayed good inhibitory potential. The biological screening identified that many final analogues exhibited a significant inhibition of the growth of microorganisms at 3.12-25 μg/mL of MIC, which were comparable to control drugs. The influence of the presence of various functional groups to the phenyl/benzothiazolyl ring on activity profiles was investigated. The proposed structures of the newly prepared products were confirmed with the aid of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. These results may provide new insights in the design of a novel pool of bioactive templates.
- Patel, Rahul V.,Kumari, Premlata,Chikhalia, Kishor H.
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p. 596 - 607
(2013/07/28)
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- 2-Aminobenzothiazole derivatives: Search for new antifungal agents
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A new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4-8 μg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells.
- Catalano, Alessia,Carocci, Alessia,Defrenza, Ivana,Muraglia, Marilena,Carrieri, Antonio,Van Bambeke, Fran?oise,Rosato, Antonio,Corbo, Filomena,Franchini, Carlo
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p. 357 - 364
(2013/07/27)
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- Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as antibacterial, antifungal and antituberculosis agents
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To affiliate multiple bioactivities in a compact heteronuclei, two series of benzimidazole based 1,3,4-oxadiazoles were synthesized and assessed in vitro for their efficacy as antimicrobial agents against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv and best results were observed amongst the N-benzothiazolyl aetamide series. The lipophilicity (LogP) influence on the biological profile (MICs) of the prepared products was also discussed. Upon biological screening, it was observed that the majority of the compounds were found to possess a significant broad spectrum antimicrobial (3.12-25 μg/mL of MIC) and antitubercular (6.25-25 μg/mL of MIC) potential. The structural assignments of the new products were done on the basis of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis.
- Patel, Rahul V.,Patel, Paresh K.,Kumari, Premlata,Rajani, Dhanji P.,Chikhalia, Kishor H.
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experimental part
p. 41 - 51
(2012/07/30)
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- Combination of bioactive moieties with different heteroatom(s): Application of the Suzuki cross-coupling reaction
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Two series of thiophene/benzothiophene-linked quinolinyl oxadiazoles condensed to the substituted N-benzothiazolyl acetamides have been synthesized via the Suzuki cross-coupling reaction. The ester derivative of 6-bromo-substituted quinoline was reacted via the Suzuki cross-coupling reaction with commercially available (benzo)thiophen-2-ylboronic acid at optimized temperature in 1,2-dimethoxy ethane and water in the presence of potassium carbonate and palladium tetrakis. The resulting derivatives were then hydrazinolized using 99% hydrazine hydrate followed by cyclization using carbon disulfide in ethanolic KOH to furnish the corresponding oxadiazoles, which were then condensed with various substituted 2-chloro-N-benzothiazolyl acetamides to produce the final scaffolds involving a unique combination of four heterocycles to be examined for their antimicrobial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae), and two fungal species (Aspergillus niger and Candida albicans). The investigation of biological screening data revealed that the majority of the compounds tested have demonstrated excellent activity (minimum inhibitory concentrations; 6.25-50 μg/mL) against most of the microorganisms as compared with the standard and hence they warrant more consideration as prospective antimicrobial agents. New products (9a-10i) were characterized by physicochemical, elemental, and spectral (IR, 1H NMR, and 13C NMR) data.
- Patel, Rahul V.,Patel, Jigar K.,Kumari, Premlata,Chikhalia, Kishor H.
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experimental part
p. 399 - 410
(2012/08/28)
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- Visible light photocatalytic synthesis of benzothiophenes
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The photocatalytic reaction of o-methylthio-arenediazonium salts with alkynes yields substituted benzothiophenes regioselectively through a radical annulation process. Green light irradiation of eosin Y initiates the photoredox catalysis. The scope of the reaction was investigated by using various substituted diazonium salts and different alkynes.
- Hari, Durga Prasad,Hering, Thea,Koenig, Burkhard
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supporting information
p. 5334 - 5337,4
(2012/12/12)
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- Facile synthesis of bioactive 4H-[1,4]-benzothiazines under solvent free conditions
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An efficient method for synthesis of 4H-[1,4]-benzothiazines under solvent free conditions has been developed. The oxidative condensation of 2-aminobenzenethiols with β-diketones/β-ketoesters in presence of catalytic amount of hydrazine hydrate yields the 4H-[1,4]-benzothiazines. The reaction is accelerated by microwave irradiation under solvent free conditions in presence of an energy transfer agent DMF to get the product in high yield. The 2-aminobenzenethiazole required for the synthesis of 4H-[1,4]-benzothiazines are also obtained by a new method instead of presently used time consuming and low yielding method. The structure of the synthesized compounds has been characterized by IR, NMR, mass spectral studies and elemental analysis.
- Kalwania,Chomal,Choudhary, Savita
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experimental part
p. 5133 - 5136
(2012/06/18)
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- Synthesis of some new biologically active benzothiazole derivatives containing benzimidazole and imidazoline moieties
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Synthesis of N-(1H-benzimidazol-2-yl)-6-substituted-1,3-benzothiazol-2- amines and 6-substituted-N-(4,5-dihydro-1H-imidazol-2-yl)-1,3-benzothiazol-2- amines by the reaction of substituted 2-aminobenzothiazoles with carbon disulphide and methyl iodide followed by the reaction with o-phenylene diamine/ethylene diamine are reported. All the synthesized compounds were characterized by elemental analysis, IR spectra and 1H NMR spectral studies. The potent antibacterial and entomological (antifeedant, acaricidal, contact toxicity and stomach toxicity) activities of the synthesized compounds were investigated.
- Chaudhary, Manish,Pareek, Deepak,Pareek, Pawan K.,Kant, Ravi,Ojha, Krishan G.,Pareek, Arun
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body text
p. 131 - 136
(2011/11/01)
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- Synthesis of some new 1,4-benzothiazines and their anti psychotic activity
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1,4-Benzothiazines (1-28) have been synthesized by treating substituted aminothiophenols with various substituted β-diketones in the presence of piperidine in THF solution.
- Chaudhari,Shinde,Shingare
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p. 1250 - 1256
(2007/10/03)
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- Substituted 2-aminobenzothiazoles and derivatives useful as cerebrovascular agents
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A series of substituted 2-aminobenzothiazoles and derivatives useful for treating cerebrovascular disorders are disclosed. Also disclosed is a new method for treating such disorders.
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- Syntheses of 1,5-Benzothiazepines: Part III - Syntheses of 4-(p-Chlorophenyl)-2-(p-methoxyphenyl)-8-substituted-2,3-dihydro-1,5-benzothiazepines
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4-Methoxy-4'-chlorobenzalacetophenone (IV) on reaction with 5-substituted 2-aminothiophenols (IIIa-f) in toluene gives 4-(p-chlorophenyl)-2-(p-methoxyphenyl)-8-substituted-2,3-dihydro-1,5-benzothiazepines (Va-f).Their structures have been established by IR, PMR and mass spectral data.
- Pant, Umesh C.,Gaur, B. S.,Chugh, Manju
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p. 189 - 190
(2007/10/02)
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- Monoazo dyestuffs derived from benzothiazole
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A disperse dye of the formula, STR1 wherein R1 is an alkyl group having 5 to 6 carbon atoms, R2 is an alkyl group having 5 to 6 carbon atoms, a cyano-ethyl group, R3 is a hydrogen atom or a lower alkyl, amino or phenyl group, and Y1 and Y2 represent independently a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, a cyano group, a thiocyanate group or an alkylsulfonyl group, provided that both Y1 and Y2 are not hydrogen at the same time and Y1 is located at the 4- or 5-position, which is useful for dyeing hydrophobic fibers in brilliant red to violet shade with good fastnesses.
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- Hydrosoluble monoazoic cationic dyes and process for preparing same
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Hydrosoluble, cationic, azo dyes of the formula: SPC1 Wherein: R is an alkyl or aralkyl group; R' is an alkyl group having from 1 to 4 carbon atoms; R" is H, an alkyl group having from 1 to 4 carbon atoms or a halogen; R'" is an alkyl group having from 1 to 4 carbon atoms or a C1 -C4 alkyl group substituted by a halogen, cyano, hydroxy, alkoxy or acyloxy group; Y is a cyano, amido, acyloxy or carboalkoxy group; and X is an anion, are obtained by: A. diazotizing a 2-amino-6-alkoxybenzothiazole of the formula (II): SPC2 b. coupling the resultant diazo compound in an acid solution with a tertiary amine of the formula (III): SPC3 wherein R', R", R'" and Y are as defined above; and C. quaternizing the resultant dye.
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