RESUMEN
In this study, new series of N'-(2-(substitutedphenoxy)acetyl)-4-(1H-pyrrol-1-yl)benzohydrazides (3a-j) 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N'-(2-(substitutedphenoxy)acetyl)benzohydrazides (5a-j) were synthesized, characterized and assessed as inhibitors of enoyl ACP reductase and DHFR. Most of the compounds exhibited dual inhibition against the enzymes enoyl ACP reductase and DHFR. Several synthesized substances also demonstrated significant antibacterial and antitubercular properties. A molecular docking analysis was conducted in order to determine the potential mechanism of action of the synthesized compounds. The results indicated that there were binding interactions seen with the active sites of dihydrofolate reductase and enoyl ACP reductase. Additionally, important structural details were identified that play a critical role in sustaining the dual inhibitory activity. These findings were useful for the development of future dual inhibitors. Therefore, this study provided strong evidence that several synthesized molecules could exert their antitubercular properties at the cellular level through multi-target inhibition. By shedding light on the mechanisms through which these compounds exert their inhibitory effects, this research opens up promising avenues for the future development of dual inhibitors with enhanced antibacterial and antitubercular properties. The study's findings underscore the importance of multi-target approaches in drug design, providing a strong foundation for the design and optimization of novel compounds that can effectively target bacterial infections at the cellular level.
Asunto(s)
Antituberculosos , Pirroles , Tetrahidrofolato Deshidrogenasa , Humanos , Antituberculosos/farmacología , Antituberculosos/química , Antituberculosos/síntesis química , Dominio Catalítico , Enoil-ACP Reductasa (NADH)/antagonistas & inhibidores , Enoil-ACP Reductasa (NADH)/metabolismo , Enoil-ACP Reductasa (NADH)/química , Antagonistas del Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/química , Antagonistas del Ácido Fólico/síntesis química , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Tetrahidrofolato Deshidrogenasa/metabolismo , Tetrahidrofolato Deshidrogenasa/químicaRESUMEN
Objectives: There is some controversy regarding the clinical significance of cluster of differentiation 38 (CD38) protein in acute myeloid leukemia (AML). We aimed to study the prognostic value of CD38 expression in relation to the standard cytogenetic risk stratification in AML patients. Methods: In this prospective study, adult patients with AML were diagnosed based on the finding of ≥ 20% blasts in the bone marrow and the flow cytometry. The control group was selected from normal bone marrow samples examined at the same period in the lab. The CD38 expression levels were assessed by immunophenotyping the bone marrow samples of the patients prior to therapy, as well as those from the controls. Results: The subjects were N = 52 newly diagnosed adult AML patients, while n = 25 sex-and-age matched normal volunteers served as the control. The CD38 expression among AML patients ranged from 3.6% to 79.9%, significantly higher levels than in the control population (p =0.001). Positive CD38 expression was higher in AML patients with favorable cytogenetics when compared to those with intermediate and poor cytogenetics (75.0%, 57.1%, and 68.2%, respectively) (p =0.007). Median CD38 expression in AML patients was higher in the favorable cytogenetic group and lower in intermediate and poor cytogenetic groups, though lacking in significance (p =0.578). Patients with poor cytogenetic risk were associated with significantly shorter median overall survival when compared to favorable and intermediate cytogenetic risk (p =0.010). Conclusions: The expression of CD38 significantly adds to the prognostic value of cytogenetic risk stratification at diagnosis of AML patients.