RESUMO
We report the synthesis of a series of imidazo[1,2-a]pyridine-based molecules as anthelmintic against the livestock parasite Haemonchus contortus. The molecules were tested by using Larval Paralysis Test (LPT), in order to target ionic channels, as most of the prominent marketed anthelminthics present such mechanism of action. The most active compound (5e) displayed paralysis on H. contortus stage 3 larvae until 31.25⯵M. Effect of 5e on H. contortus cholinergic receptors (L-AChR1 and 2) was characterized via electrophysiological measurement and a rare antagonist mode of action was unveiled.
Assuntos
Anti-Helmínticos/farmacologia , Descoberta de Drogas , Haemonchus/efeitos dos fármacos , Piridinas/farmacologia , Receptores Colinérgicos/metabolismo , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/química , Relação Dose-Resposta a Droga , Haemonchus/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
The diastereoselective carbocupration reaction of cyclopropenylmethyl ethers followed by addition of oxenoid leads to the formation of diastereo- and enantiomerically enriched 2,2,3,3-tetrasubstituted cyclopropanol derivatives. Ring fragmentation of the copper cyclopropanolate leads to acyclic butenal derivatives possessing enantiomerically enriched α-quaternary carbon stereocenters in a single-pot operation.
RESUMO
Most of the efforts of organic chemists have been directed to the development of creative strategies to build carbon-carbon and carbon-heteroatom bonds in a predictable and efficient manner. In this Review, we show an alternative approach where challenging molecular skeletons could be prepared through selective cleavage of carbon-carbon bonds. We demonstrate that it has the potential to be a general principle in organic synthesis for the regio-, diastereo-, and even enantioselective preparation of adducts despite the fact that C-C single bonds are among the least reactive functional groups. The development of such strategies may have an impact on synthesis design and can ultimately lead to new selective and efficient processes for the utilization of simple hydrocarbons.
RESUMO
The copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 1 leads to various substituted cyclopropanes species 3 in good yields with very high diastereoselectivities. The reaction proceeds through a syn-chelated carbomagnesiation reaction and could be extended to various cyclopropenylmethyl ester derivatives 5. The potential of this approach was illustrated by the preparation of two consecutive all-carbon quaternary stereocenters. However, the carbometalation reaction needs to be performed at temperature ranging from -35 to -20 °C to avoid subsequent fragmentation reaction into stereodefined ß,γ-nonconjugated unsaturated esters 4. Alternatively, the carbocupration reaction with organocopper species could also be performed to leads to configurationally stable cyclopropyl copper speciesâ 2[Cu]. Additionally, when the Lewis acid character of the copper center is decreased (i.e., RCuCNLi), the reaction proceed with an anti-selectivity. The diastereodivergent behavior of these organometallic species is of synthetic interest, since both diastereomers syn-3 and anti-3 can be obtained, at will, from the same precursor cyclopropenyl esters 1.
RESUMO
Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2-b]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis, the prime causative agent of eumycetoma, with IC50 ≤ 5 µM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC50 of 0.9 µM, in the same order then itraconazole (IC50 = 1.1 µM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies.
Assuntos
Antifúngicos , Imidazóis , Micetoma , Doenças Negligenciadas , Piridazinas , Piridazinas/farmacologia , Piridazinas/química , Piridazinas/síntese química , Micetoma/tratamento farmacológico , Camundongos , Animais , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/síntese química , Relação Estrutura-Atividade , Doenças Negligenciadas/tratamento farmacológico , Estrutura Molecular , Madurella/efeitos dos fármacos , Células NIH 3T3 , Testes de Sensibilidade Microbiana , Relação Dose-Resposta a Droga , Humanos , Sobrevivência Celular/efeitos dos fármacosRESUMO
Imidazo[1,2-b]pyridazine scaffold represents an important class of heterocyclic nucleus which provides various bioactives molecules. Among them, the successful kinase inhibitor ponatinib led to a resurgence of interest in exploring new imidazo[1,2-b]pyridazine-containing derivatives for their putative therapeutic applications in medicine. This present review intends to provide a state-of-the-art of this framework in medicinal chemistry from 1966 to nowadays, unveiling different aspects of its structure-activity relationships (SAR). This extensive literature surveil may guide medicinal chemists for the quest of novel imidazo[1,2-b]pyridazine compounds with enhanced pharmacokinetics profile and efficiency.
Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Piridazinas/farmacologia , Anti-Infecciosos/química , Anti-Inflamatórios/química , Antineoplásicos/química , Química Farmacêutica , Humanos , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/químicaRESUMO
Herein, we report the design, synthesis and evaluation of novel bioinspired imidazo[1,2-a:4,5c']dipyridines. The structural optimization identified four anti-proliferative compounds. Compounds 11, 18, 19 and 20 exhibited excellent anticancer activities in vitro with IC50 of 0.4-5⯵M against three human cancer cell lines (MDA-MB-468, MDA-MB-435s and MDA-MB-231). These four compounds induced apoptosis in MDA-MB-231â¯cells in a dose-dependent manner, targeting different apoptotic proteins expression: 11 increased the expression of pro-apoptotic Bax protein while 18-20 reduced the level of anti-apoptotic Bcl-2 protein. Compounds 18 and 19 also reduced MDA-MB-231â¯cells proliferation as measured by Ki-67 staining. Furthermore, compounds were also tested for the ability to inhibit cell migration in the highly aggressive human MDA-MB-435s cell line. Six compounds of this series (8, 15, 18, 22, 23, 24) inhibited cell migration by 41-50% while four compounds (20, 25, 27, 30) inhibited the migration by 53-62% in wound-healing experiments. Interestingly, compound 20 presented both antiproliferative and anti-migration activities and might be a promising anti-metastatic agent for cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
An improved enantioselective total synthesis of (-)-linderol A has been achieved via a five-step reaction with a 21% overall yield, starting from phloroacetophenone and (-)-alpha-phellandrene, two commercially available reagents. In the diastereoselective epoxidation step, the analysis of the two endocyclic epoxide intermediates reveals a hindered sp(2)-sp(3) rotation, which results in rotational diastereoisomers.
Assuntos
Benzofuranos/química , Benzofuranos/síntese química , Rotação , Cromatografia em Camada Fina , Compostos de Epóxi/química , Espectroscopia de Ressonância Magnética , Estereoisomerismo , Especificidade por SubstratoRESUMO
The synthesis of an optically pure proline-based tryptophan mimetic is described. The strategy involves the in situ generation of an unprecedented allylmetal species containing the indole moiety, and its coupling with a chiral imine. The construction of the 3-substituted proline skeleton is then achieved through a hydrozirconation/iodination sequence applied to the resulting homoallylic amine.
Assuntos
Materiais Biomiméticos/síntese química , Prolina/química , Triptofano/química , Iodo/química , Estrutura Molecular , EstereoisomerismoRESUMO
A spectacular inversion of α- to γ-regioselectivity in the allylzincation of imines can be achieved by fine-tuning of the N-side chain. This approach allows easy preparation of regioisomeric amines, in racemic as well as enantiopure forms. The usefulness of the method is illustrated by the parallel asymmetric syntheses of 2,3- and 2,5-diphenylpyrrolidines.