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1.
Bioorg Med Chem ; 63: 116738, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35421710

RESUMEN

Chiral alkylidene-ß-lactams and alkylidene-γ-lactams were synthesized and screened for their in vitro activity against four human cancer cell lines (melanoma, esophageal, lung and fibrosarcoma carcinoma). Alkylidene-ß-lactams were synthesized via Wittig reaction of diverse phosphorus ylides with benzhydryl 6-oxopenicillanate, derived from 6-aminopenicillanic acid. Moreover, novel chiral alkylidene-γ-lactams were synthesized through a multistep strategy starting from a chiral substrate (d-penicillamine). The in vitro assays allowed the identification of four compounds with IC50 values < 10 µM for A375 cell line, and three compounds with IC50 values < 10 µM for OE19 cell line. The effect of the most promising compounds on cell death mechanism, reactive oxygen species generation as well as the evaluation of their ability to act as MMP-9 inhibitors were studied. The reported results unveil the potential of alkylidene-ß-lactams as anticancer agents.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/química , Línea Celular , Humanos , Lactamas , beta-Lactamas
2.
Int J Mol Sci ; 23(22)2022 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-36430777

RESUMEN

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-ß-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Humanos , VIH-2/genética , Raltegravir Potásico/farmacología , Raltegravir Potásico/uso terapéutico , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , Farmacorresistencia Viral/genética , beta-Lactamas/uso terapéutico , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico
3.
RSC Adv ; 12(48): 30879-30891, 2022 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-36349033

RESUMEN

The first examples of the diastereoselective 1,3-dipolar cycloaddition reaction of nitrile oxides and 6-alkylidene penicillanates leading to chiral spiroisoxazoline-penicillanates are reported. The synthesis of this new type of penicillanate involved the selective generation of two consecutive stereogenic centers, including a quaternary chiral center. Furthermore, the present work also describes the outcomes of these 1,3-dipolar cycloaddition reactions under three distinct reaction conditions (conventional heating, microwave irradiation and continuous flow). The successful use of the continuous flow technique as well as the proper selection of the reaction media allowed the development of a sustainable route to chiral spiroisoxazoline-penicillanates.

4.
Front Chem ; 10: 1017250, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36277353

RESUMEN

The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-ß-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule's bioactivity profile. The spirocyclopentene-ß-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure-activity relationship open avenues for further development of spirocyclopentene-ß-lactams as multivalent, highly active broad spectrum antimicrobial agents.

5.
Eur J Med Chem ; 219: 113439, 2021 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-33887681

RESUMEN

The synthesis and antimicrobial activity of new spiro-ß-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-ß-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information. Among the tested compounds, two spirocyclopentenyl-ß-lactams were identified as having remarkable nanomolar activity against HIV-1. Additionally, the same molecules showed promising antiplasmodial activity, inhibiting both the hepatic and blood stages of Plasmodium infection.


Asunto(s)
Fármacos Anti-VIH/farmacología , Antimaláricos/farmacología , VIH-1/efectos de los fármacos , Plasmodium/efectos de los fármacos , beta-Lactamas/química , Fármacos Anti-VIH/síntesis química , Antimaláricos/síntesis química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , VIH-1/aislamiento & purificación , Humanos , Estadios del Ciclo de Vida/efectos de los fármacos , Conformación Molecular , Plasmodium/crecimiento & desarrollo , Compuestos de Espiro/química , Estereoisomerismo , Relación Estructura-Actividad , beta-Lactamas/síntesis química , beta-Lactamas/farmacología
6.
ACS Infect Dis ; 7(2): 421-434, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33395253

RESUMEN

The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-ß-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 µM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 µM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium.


Asunto(s)
Antimaláricos , Infecciones por VIH , Plasmodium , Antimaláricos/farmacología , Infecciones por VIH/tratamiento farmacológico , Humanos , Plasmodium falciparum , beta-Lactamas
7.
Curr Top Med Chem ; 20(2): 140-152, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31702503

RESUMEN

INTRODUCTION: Structural modulation of previously identified lead spiro-ß-lactams with antimicrobial activity was carried out. OBJECTIVE: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. METHODS: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-ß-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. RESULTS: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied ß- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. CONCLUSION: The designed structural modulation of biologically active spiro-ß-lactams involved the replacement of the four-membered ß-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between ß- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the ß-lactamic core is a requirement for the activity against both HIV and Plasmodium.


Asunto(s)
Fármacos Anti-VIH/farmacología , Antiprotozoarios/farmacología , VIH/efectos de los fármacos , Lactamas/farmacología , Plasmodium/efectos de los fármacos , Compuestos de Espiro/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Lactamas/síntesis química , Lactamas/química , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Pruebas de Sensibilidad Parasitaria , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-Actividad
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