RESUMO
This study investigates the potential of click chemistry for the development of novel anti-tuberculosis agents. A targeted library of 1,4-dihydropyridine-1,2,3-triazole conjugates was synthesized and evaluated for their in vitro activity against Mycobacterium tuberculosis H37Ra using the resazurin microtiter assay (REMA). Among the synthesized derivatives, compounds J10, J11, J14, J22 and J23 demonstrated significant antimycobacterial activity. These compounds exhibited low MIC values ranging from 6.24 to 6.64 µg mL-1, highlighting their promising potential as lead compounds for further developing novel tuberculosis therapeutics. In addition to the promising in vitro activity, structure-activity relationship (SAR) analysis revealed that electron-withdrawing groups on the aryl-substituted ring of the dihydropyridines (J10-J24), a triazole with an unsubstituted aryl ring or with electron-donating groups (methyl or methoxy), and a geminal dimethyl group are essential structural features for the observed antitubercular activity. Furthermore, in silico ADME (absorption, distribution, metabolism, and excretion) parameters and pharmacokinetic studies supported the potential of these conjugates for oral bioavailability. These findings collectively highlight the 1,4-dihydropyridine-1,2,3-triazole scaffold as a promising platform for developing novel orally active anti-tuberculosis drugs.
RESUMO
In the quest for the discovery of antidiabetic compounds, a series of 27 1,4-dihydropyridine-indole derivatives were synthesized using a diversity approach. These compounds were systematically evaluated for their antidiabetic activity, starting with an in vitro assessment for GLUT4 translocation stimulation in L6-GLUT4myc myotubes, followed by in vivo antihyperglycemic activity evaluation in a streptozotocin (STZ)-induced diabetic rat model. Among the synthesized compounds, 12, 14, 15, 16, 19, 27, and 35 demonstrated significant potential to stimulate GLUT4 translocation in skeletal muscle cells. Compound 19 exhibited the highest potency and was selected for in vivo evaluation. A notable reduction of 21.6% (p < 0.01) in blood glucose levels was observed after 5 h of treatment with compound 19 in STZ-induced diabetic rats. Furthermore, pharmacokinetic studies affirmed that compound 19 was favorable to oral exposure with suitable pharmacological parameters. Overall, compound 19 emerged as a promising lead compound for further structural modification and optimization.
Assuntos
Diabetes Mellitus Experimental , Di-Hidropiridinas , Desenho de Fármacos , Transportador de Glucose Tipo 4 , Hipoglicemiantes , Indóis , Animais , Transportador de Glucose Tipo 4/metabolismo , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Indóis/farmacocinética , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , Di-Hidropiridinas/farmacologia , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Di-Hidropiridinas/uso terapêutico , Di-Hidropiridinas/farmacocinética , Ratos , Masculino , Relação Estrutura-Atividade , Glicemia/análise , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Linhagem Celular , Ratos Sprague-DawleyRESUMO
In pursuance of our efforts to expand the scope of novel antileishmanial entities, a series of thirty-five quinoline-piperazine/pyrrolidine, and other heterocyclic amine derivatives were synthesized via a molecular hybridization approach and examined against intracellular amastigotes of luciferase-expressing Leishmania donovani. The preliminary in vitro screening suggests that twelve compounds in the series exhibited better inhibition against amastigote form with good IC50 values ranging from 2.09 to 8.89 µM and lesser cytotoxicity in contrast to the standard drug miltefosine (IC50 9.25 ± 0.17 µM). Based on the satisfactory selectivity index (SI), two compounds were tested for in vivo leishmanicidal efficacy against Leishmania donovani/golden hamster model. Compounds 33 and 46 have shown significant inhibition of 56.32%, and 49.29%, respectively, in vivo screening at a daily dose of 50 mg/kg for 5 days. The pharmacokinetic results confirmed that 33 and 46 have satisfactory IP exposure with adequate parameters. Collectively, Compound 33 was identified as the most significant potential lead that could be employed as a prototype for future optimizations.
Assuntos
Antiprotozoários , Leishmania donovani , Quinolinas , Piperazina , Quinolinas/farmacologiaRESUMO
Towards identification of novel therapeutic candidates, a series of quinazolinone-based acetamide derivatives were synthesized and assessed for their anti-leishmanial efficacy. Amongst synthesized derivatives, compounds F12, F27 and F30 demonstrated remarkable activity towards intracellular L. donovani amastigotes in vitro, with IC50 values of 5.76 ± 0.84 µM, 3.39 ± 0.85 µM and 8.26 ± 1.23 µM against promastigotes, and 6.02 µM ± 0.52, 3.55 ± 0.22 µM and 6.23 ± 0.13 µM against amastigotes, respectively. Oral administration of compounds F12 and F27 entailed >85% reduction in organ parasite burden in L. donovani-infected BALB/c mice and hamsters, by promoting host-protective Th1 cytokine response. In host J774 macrophages, mechanistic studies revealed inhibition of PI3K/Akt/CREB axis, resulting in a decrease of IL-10 versus IL-12 release upon F27 treatment. In silico docking studies conducted with lead compound, F27 demonstrated plausible inhibition of Leishmania prolyl-tRNA synthetase, which was validated via detection of decreased proline levels in parasites and induction of amino acid starvation, leading to G1 cell cycle arrest and autophagy-mediated programmed cell death of L. donovani promastigotes. Structure-activity analysis and study of pharmacokinetic and physicochemical parameters suggest oral availability and underscore F27 as a promising lead for anti-leishmanial drug development.
Assuntos
Antiprotozoários , Leishmania donovani , Leishmaniose Visceral , Cricetinae , Animais , Camundongos , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/metabolismo , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Quinazolinonas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Acetamidas/metabolismo , Camundongos Endogâmicos BALB CRESUMO
A silver-catalyzed decarboxylative cyclization process has been developed for the synthesis of substituted pyrazoles from the readily available 1,2-diaza-1,3-dienes and α-keto acids. Under the optimized conditions, a series of multisubstituted pyrazoles were well prepared in moderate to good yields. In addition, the synthetic utility of this protocol has been demonstrated by synthesizing analogs of FDA approved drugs such as anti-inflammatory drug, lonazolac and antiobesity drug, rimonabant.