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1.
Chemistry ; 30(7): e202302996, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37721804

RESUMEN

α-Sulfinyl esters can be readily prepared through thiol substitution of α-bromo esters followed by oxidation to the sulfoxide. Enzymatic resolution with lipoprotein lipase provides both the unreacted esters and corresponding α-sulfinyl carboxylic acids in high yields and enantiomeric ratios. Subsequent decarboxylative halogenation, dihalogenation, trihalogenation and cross-coupling gives rise to functionalized sulfoxides. The method has been applied to the asymmetric synthesis of a potent inhibitor of 15-prostaglandin dehydrogenase.


Asunto(s)
Ácidos Carboxílicos , Ésteres , Estereoisomerismo , Sulfóxidos , Halogenación
2.
Org Biomol Chem ; 14(39): 9287-9293, 2016 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-27722737

RESUMEN

A stereoselective approach for the synthesis of haliclamide 1, a marine natural product, has been developed. The notable features of our synthesis include MacMillan cross aldol, Mitsunobu inversion, Yamaguchi-Hirao alkylation, Steglich esterification and macrolactamization reactions and the Corey-Fuchs protocol as the key steps.


Asunto(s)
Depsipéptidos/síntesis química , Estereoisomerismo
3.
Cell Chem Biol ; 31(8): 1503-1517.e19, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39084225

RESUMEN

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome ß5 active-site (Pfß5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto ß7. Inhibition of Pfß5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the ß5/ß6/ß3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.


Asunto(s)
Antimaláricos , Piperidinas , Plasmodium falciparum , Inhibidores de Proteasoma , Piperidinas/química , Piperidinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Animales , Antimaláricos/farmacología , Antimaláricos/química , Humanos , Ratones , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/síntesis química , Administración Oral , Complejo de la Endopetidasa Proteasomal/metabolismo , Malaria/tratamiento farmacológico , Malaria/parasitología , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Malaria Falciparum/tratamiento farmacológico , Femenino , Estructura Molecular
4.
ACS Infect Dis ; 9(3): 527-539, 2023 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-36763526

RESUMEN

Current malaria treatments are threatened by drug resistance, and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their targets are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for the activity of (S)-SW703, suggesting differences in the mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity for multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.


Asunto(s)
Antimaláricos , Malaria Falciparum , Malaria , Humanos , Antimaláricos/farmacología , Antimaláricos/química , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Malaria Falciparum/tratamiento farmacológico , Malaria/tratamiento farmacológico , Hígado , Aminas/metabolismo
5.
J Med Chem ; 64(5): 2739-2761, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33620219

RESUMEN

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.


Asunto(s)
Amidas/farmacología , Antimaláricos/farmacología , Hemoglobinas/metabolismo , Plasmodium falciparum/efectos de los fármacos , Tetrazoles/farmacología , Amidas/síntesis química , Amidas/farmacocinética , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Farmacorresistencia Microbiana/efectos de los fármacos , Hemoproteínas/antagonistas & inhibidores , Células Hep G2 , Humanos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/farmacocinética
6.
ACS Infect Dis ; 6(8): 2057-2072, 2020 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-32686409

RESUMEN

The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against Leishmania amazonensis axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC50 values from 50 to 480 nM. Concentration-response assays demonstrated that the best hit, MMV676477, had mid-nanomolar cytocidal potency against intracellular Leishmania amastigotes, Trypanosoma brucei, and Plasmodium falciparum, suggesting broad antiparasitic activity. We explored structure-activity relationships (SAR) within a small group of MMV676477 analogs and observed a wide potency range (20-5000 nM) against axenic Leishmania amastigotes. Compared to MMV676477, our most potent analog, SW41, had ∼5-fold improved antileishmanial potency. Multiple lines of evidence suggest that MMV676477 selectively disrupts Leishmania tubulin dynamics. Morphological studies indicated that MMV676477 and analogs affected L. amazonensis during cell division. Differential centrifugation showed that MMV676477 promoted partitioning of cellular tubulin toward the polymeric form in parasites. Turbidity assays with purified Leishmania and porcine tubulin demonstrated that MMV676477 promoted leishmanial tubulin polymerization in a concentration-dependent manner. Analogs' antiparasitic activity correlated with their ability to facilitate purified Leishmania tubulin polymerization. Chemical cross-linking demonstrated binding of the MMV676477 scaffold to purified Leishmania tubulin, and competition studies established a correlation between binding and antileishmanial activity. Our studies demonstrate that MMV676477 is a potent antiparasitic compound that preferentially promotes Leishmania microtubule polymerization. Due to its selectivity for and broad-spectrum activity against multiple parasites, this scaffold shows promise for antiparasitic drug development.


Asunto(s)
Leishmania , Malaria , Animales , Antiparasitarios/farmacología , Polimerizacion , Porcinos , Tubulina (Proteína)
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