- Synthesis and biological evaluation of new imidazo[1,2-a]pyridine derivatives designed as mefloquine analogues.
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This paper describes the synthesis and the in vitro antimalarial profile of two new imidazo[1,2-a]pyridine derivatives 4HCl and 13HCl, structurally proposed as mefloquine (1) analogues, by exploring bioisosterism and molecular simplification tools. The synthetic route employed to access the title compounds used, as starting material, the previously described ethyl 2-methylimidazo[1,2-aJpyridine-3-carboxylate derivative (5). These novel heterocyclic derivatives 4HCl and 13HCl presented modest antimalarial activity against the W-2 and D-6 clones of Plasmodium falciparum as well as inhibitors of in vitro heme polymerization compared to mefloquine.
- Lima, Patricia C,Avery, Mitchell A,Tekwani, Babu L,de Alves, Helio M,Barreiro, Eliezer J,Fraga, Carlos A M
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- Structural modification of zolpidem led to potent antimicrobial activity in imidazo[1,2-: A] pyridine/pyrimidine-1,2,3-triazoles
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Ambien (zolpidem), an imidazo[1,2-a]pyridine derivative, is a commercial drug to treat insomnia which also possesses antitubercular activity against Mycobacterium tuberculosis H37Rv. In this paper, we describe the synthesis of three diverse lead series of imidazo[1,2-a]pyridine/pyrimidine-1,2,3-triazoles (IPTs) which are designed by specific structural modifications of zolpidem. Most of the IPTs exhibited remarkable in vitro antitubercular activity with an MIC of 1.56 μg mL-1, which is two-fold higher than the MIC of zolpidem. Further, the synthesized IPTs displayed moderate inhibitory activity against several bacterial and fungal strains as well, and also showed an acceptable safety profile as verified through in vitro cytotoxicity assessment against Vero cells. In addition, the potent IPTs exhibited promising binding interactions within the active site of the InhA enzyme. An interesting correlation between the in vitro inhibitory activity and the binding mode was observed: most of the potent molecules (MIC = 1.56 μg mL-1) interact through a H-bond with the Tyr 158 residue of the target enzyme. These efforts toward the structural modification of zolpidem could be helpful for further optimization of the IPT core to develop new anti-TB drugs.
- Reddyrajula, Rajkumar,Dalimba, Udaya Kumar
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p. 16281 - 16299
(2019/11/03)
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- NBS mediated protocol for the synthesis of N-bridged fused heterocycles in water
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A facile and environmental friendly protocol for the synthesis of N-bridged fused bicyclic compounds such as imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and imidazo[2,1-b]thiazole, from commercially available starting materials has been developed.
- Bhagat, Saket B.,Telvekar, Vikas N.
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p. 3662 - 3666
(2017/08/23)
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- Microwave-assisted synthesis and photophysical studies of novel fluorescent N-acylhydrazone and semicarbazone-7-OH-coumarin dyes
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A microwave-assisted synthesis of novel N-acylhydrazone and semicacarbazone-7-hidroxy-coumarins derivatives, starting from 3-acetyl-7-hydroxy-2H-chromen-2-one, is described. This optimized protocol led to higher yields and considerable reduction in reaction time from ~24 to ~1 hour. Aqueous solutions of these compounds showed bright blue to cyan emission and maximum quantum yields of 0.244. The stereoelectronic effects of the attached groups led to modulation of the spectral characteristics by favoring syn or anti amide conformers. The synthesized compounds showed pH dependent luminescence and a strong batochromic shift up to 65 nm in a low polarity medium (methanol) due to a better stabilization of the syn-conformer promoting this redshifted emission. These characteristics can be exploited for designing new luminescent probes for pH as well as polar microenvironments.
- Pereira, Thiago Moreira,Vitório, Felipe,Amaral, Ronaldo Costa,Zanoni, Kassio Papi Silva,Murakami Iha, Neyde Yukie,Kümmerle, Arthur Eugen
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p. 8846 - 8854
(2016/10/11)
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- 2-Aminopyridines as an α-Bromination Shuttle in a Transition Metal-Free One-Pot Synthesis of Imidazo[1,2-a]pyridines
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A wide range of imidazo[1,2-a]pyridines are accessible from cheap and readily available 2-aminopyridines and 1,3-dicarbonyl compounds using a unique CBrCl3/2-aminopyridine system for bromination at the α-carbon. 2-Aminopyridine is not only the substrate but also acts as a bromination shuttle, transferring the bromine atom from CBrCl3 to the α-carbon of the 1,3-dicarbonyl. The reaction mechanism involves a series of reversible steps, including an addition reaction with cyclic transition state, to form a bromo-hemiaminal intermediate. Isolated yields of up to 97% were obtained under mild conditions and at short reaction times in this transition metal-free, one-pot synthesis.
- Roslan, Irwan Iskandar,Ng, Kian-Hong,Chuah, Gaik-Khuan,Jaenicke, Stephan
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supporting information
p. 364 - 369
(2016/04/26)
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- CBr4 Mediated Oxidative C-N Bond Formation: Applied in the Synthesis of Imidazo[1,2-α]pyridines and Imidazo[1,2-α]pyrimidines
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The carbon tetrabromide mediated oxidative carbon-nitrogen bond formation of 2-aminopyridines or 2-aminopyrimidines with β-keto esters or 1,3-diones, leading to a variety of complex imidazo[1,2-α]pyridines or imidazo[1,2-α]pyrimidines, is reported. The re
- Huo, Congde,Tang, Jing,Xie, Haisheng,Wang, Yajun,Dong, Jie
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supporting information
p. 1016 - 1019
(2016/03/15)
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- Identification and development of 2-methylimidazo[1,2-a]pyridine-3- carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors
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In the present study, we used crystal structure of mycobacterial pantothenate synthetase (PS) bound with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)- 5-methoxy-1H-indol-1-yl) acetic acid inhibitor for virtual screening of antitubercular compound database to identify new scaffolds. One of the identified lead was modified synthetically to obtain thirty novel analogues. These synthesized compounds were evaluated for Mycobacterium tuberculosis (MTB) PS inhibition study, in vitro antimycobacterial activities and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, N′-(1-naphthoyl)- 2-methylimidazo[1,2-a]pyridine-3-carbohydrazide (5b) was found to be the most active compound with IC50 of 1.90 ± 0.12 μM against MTB PS, MIC of 4.53 μM against MTB with no cytotoxicity at 50 μM. The binding affinity of the most potent inhibitor 5b was further confirmed biophysically through differential scanning fluorimetry.
- Samala, Ganesh,Nallangi, Radhika,Devi, Parthiban Brindha,Saxena, Shalini,Yadav, Renu,Sridevi, Jonnalagadda Padma,Yogeeswari, Perumal,Sriram, Dharmarajan
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p. 4223 - 4232
(2014/08/18)
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- Lead optimization of a novel series of imidazo[1,2-a]pyridine amides leading to a clinical candidate (Q203) as a multi- and extensively-drug- resistant anti-tuberculosis agent
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A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-a]pyridine amide (IPA) lead compound 1, which led to the design and synthesis of Q203 (50). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs 49 and 50 showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log10 reduction at 10 mg/kg dosing level, respectively) in mouse lung.
- Kang, Sunhee,Kim, Ryang Yeo,Seo, Min Jung,Lee, Saeyeon,Kim, Young Mi,Seo, Mooyoung,Seo, Jeong Jea,Ko, Yoonae,Choi, Inhee,Jang, Jichan,Nam, Jiyoun,Park, Seijin,Kang, Hwankyu,Kim, Hyung Jun,Kim, Jungjun,Ahn, Sujin,Pethe, Kevin,Nam, Kiyean,No, Zaesung,Kim, Jaeseung
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p. 5293 - 5305
(2014/07/08)
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- A novel solvent-free approach to imidazole containing nitrogen-bridgehead heterocycles
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A very simple domino reaction under solvent-free conditions of various pyridine-like heterocycles with 1,2-diaza-1,3-dienes produces in good yields imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines, and imidazo[2,1-a] isoquinolines. The advantage of this one-pot transformation lies in the use of simple pyridine-like compounds without prefunctionalization of the starting heterocycles.
- Attanasi, Orazio A.,Bianchi, Luca,Campisi, Linda A.,Crescentini, Lucia De,Favi, Gianfranco,Mantellini, Fabio
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supporting information
p. 3646 - 3649
(2013/08/23)
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- Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors
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Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
- Kümmerle, Arthur E.,Schmitt, Martine,Cardozo, Suzana V. S.,Lugnier, Claire,Villa, Pascal,Lopes, Alexandra B.,Romeiro, Nelilma C.,Justiniano, Hélène,Martins, Marco A.,Fraga, Carlos A. M.,Bourguignon, Jean-Jacques,Barreiro, Eliezer J.
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p. 7525 - 7545
(2012/11/06)
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- Identification of fused bicyclic heterocycles as potent and selective 5-HT2A receptor antagonists for the treatment of insomnia
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A series of fused bicyclic heterocycles was identified as potent and selective 5-HT2A receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
- Xiong, Yifeng,Ullman, Brett,Choi, Jin-Sun Karoline,Cherrier, Martin,Strah-Pleynet, Sonja,Decaire, Marc,Feichtinger, Konrad,Frazer, John M.,Yoon, Woo H.,Whelan, Kevin,Sanabria, Erin K.,Grottick, Andrew J.,Al-Shamma, Hussien,Semple, Graeme
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scheme or table
p. 1870 - 1873
(2012/04/17)
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- Toward versatile methods leading to highly functionalized imidazo[1,2-a]pyridines
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A convenient and general method of preparation of polyfunctionalized imidazo[1,2-a]pyridines is reported. This methodology involves activation of secondary amides leading to the formation of the corresponding amidines 9. Different activating reagents have
- Basilio-Lopes, Alexandra,De Aquino, Thiago Mendon?a,Mongeot, Alexandre,Bourguignon, Jean-Jacques,Schmitt, Martine
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scheme or table
p. 2583 - 2587
(2012/07/01)
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- Thermal and microwave-assisted rapid syntheses of substituted imidazo[1,2-a]pyridines under solvent- and catalyst-free conditions
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Thermal and microwave-assisted rapid syntheses of highly substituted imidazo[1,2-a]pyridine derivatives by reaction of aminopyridines and -bromo - keto esters under solvent-free conditions are described. Reactions carried out under microwave irradiation give the highest yields of products in reaction times of less than two minutes. Georg Thieme Verlag Stuttgart New York.
- Chunavala, Kaushik C.,Joshi, Girdhar,Suresh, Eringathodi,Adimurthy, Subbarayappa
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experimental part
p. 635 - 641
(2011/04/15)
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- FUSED IMIDAZOLE CARBOXAMIDES AS TRPV3 MODULATORS
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The present invention provides transient receptor potential vanilloid (TRPV) modulators of formula (I). In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPV3. Also provided
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Page/Page column 14
(2010/06/22)
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- FUSED IMIDAZOLE CARBOXAMIDES AS TRPV3 MODULATORS
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The present invention provides transient receptor potential vanilloid (TRPV) modulators of formula (I). In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPV3. Also provided
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Page/Page column 32
(2010/08/05)
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- CHEMICAL COMPOUNDS
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The present invention provides compounds of formula (I) including salts, solvates, and pharmaceutically acceptable derivatives thereof, pharmaceutical formulations containing them, processes for their preparation, and methods of treatment using them.
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Page/Page column 73-74
(2010/11/28)
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- Synthesis and antinociceptive properties of new structurally planned imidazo[1,2-a]pyridine 3-acylarylhydrazone derivatives
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This paper describes recent results of a research program aiming at the synthesis and pharmacological evaluation of new N-heterocyclic functionalized acylarylhydrazone compounds, belonging to 3-acyl-(2-methyl-imidazo[1,2-a]pyridinyl)-arylhydrazone 2 series. These compounds were structurally planned applying classical ring bioisosterism strategies on previously described 4-acyl-(N-phenylpyrazolyl)-arylhydrazone 1, which presented important analgesic properties, in order to identify the pharmacophore contribution of the acylarylhydrazone moiety and investigate the structure-activity relationship (SAR) in these series. The results herein disclosed indicate that this strategy of molecular modification gave rise to a new series of analgesic and anti-inflammatory agents, where the activity seems to be more dependent on the nature of the para-substituent at the pharmacophore acylarylhydrazone (AAH) moiety, than the N-heterocyclic acyl-ring pattern.
- Ribeiro, Izabella G.,Da Silva, Kelly Christine M.,Parrini, Sergio C.,De Miranda, Ana Luisa P.,Fraga, Carlos A. M.,Barreiro, Eliezer J.
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p. 225 - 235
(2007/10/03)
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- Synthesis and biological activity of 3-substituted imidazo[1,2-a]pyridines as antiulcer agents
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New imidazo[1,2-a]pyridines substituted at the 3-position have been synthesized as potential antisecretory and cytoprotective antiulcer agents. The synthetic routes began with cyclization of aminopyridines 5a,b and chloro ketones 6a,b to give imidazo[1,2-
- Starrett Jr.,Montzka,Crosswell,Cavanagh
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p. 2204 - 2210
(2007/10/02)
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