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1.
Molecules ; 26(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500603

RESUMO

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.


Assuntos
Aurora Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
2.
Chem Biol Drug Des ; 98(1): 73-93, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33934503

RESUMO

Aurora kinases (AURKs) are serine/threonine protein kinases that play a critical role during cell proliferation. Three isoforms of AURKs reported in mammals include AURKA, AURKB, AURKC, and all share a similar C-terminal catalytic domain with differences in their subcellular location, substrate specificity, and function. Recent research reports indicate an elevated expression of these kinases in several cancer types highlighting their role as oncogenes in tumorigenesis. Inhibition of AURKs is an attractive strategy to design potent inhibitors modulating this target. The last few years have witnessed immense research in the development of AURK inhibitors with few FDA approvals. The current clinical therapeutic regime in cancer is associated with severe side-effects and emerging resistance to existing drugs. This has been the key driver of research initiatives toward designing more potent drugs that can potentially circumvent the emerging resistance. This review is a comprehensive summary of recent research on AURK inhibitors and presents the development of scaffolds, their synthetic schemes, structure-activity relationships, biological activity, and enzyme inhibition potential. We hope to provide the reader with an array of scaffolds that can be selected for further research work and mechanistic studies in the development of new AURK inhibitors.

3.
Expert Opin Drug Deliv ; 16(5): 525-538, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31007100

RESUMO

INTRODUCTION: The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) is a major health issue and continues to be a global health concern. Despite significant advancements in treatment modalities, ~1.6 million deaths worldwide occur due to TB infection. This is because of tuberculosis reservoirs in the alveoli making it a challenge for the formulation scientist to target this. AREAS COVERED: This review recent investigations on the forefront of pulmonary drug delivery for managing MDR-TB and XDR-TB. Novel delivery systems like liposomes, niosomes, employing carbohydrate, and -coated molecules via conjugation to selectively deliver the drugs to the lung TB reservoir via pulmonary administration are discussed. EXPERT OPINION: Poor patient adherence to treatment due to side effects and extended therapeutic regimen leads to drug-resistant TB. Thus, it is essential to design novel strategies this issue by developing new chemical entities and/or new delivery systems for delivery to the lungs, consequently reducing the side effects, the frequency and the duration of treatment. Delivery of drugs to enhance the efficacy of new/existing anti-TB drugs to overcome the resistance and enhance patient compliance is underway.


Assuntos
Antituberculosos/administração & dosagem , Sistemas de Liberação de Medicamentos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Humanos
4.
Biomed Pharmacother ; 103: 923-938, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29710509

RESUMO

DNA gyrase is classified as topoisomerase II, an ATP-dependent enzyme that is vital in the transcription, replication of DNA and chromosome segregation processes. It plays a crucial role in all bacteria except higher eukaryotes and this makes it a desirable and viable therapeutic target for development of new antibacterial agents. Fluoroquinolones are commonly used effective antibacterial agents that target DNA gyrase, however the spectrum of side-effects and emerging bacterial resistance with no new drugs in the antibacterial pipeline has fuelled intensive research in this area. New chemical entities with varied scaffolds possessing DNA gyrase inhibiting properties have been determined by screening chemical libraries that could serve as good leads for antibacterial drug development. A wide range of natural products and protein-based compounds have been identified and studied as DNA gyrase inhibitors and this adds a huge amount of structural diversity that can be exploited and harnessed in the discovery of new antibacterial agents. The development of new chemical compounds with DNA gyrase inhibitory activity (from natural sources, random screens or rational design) will further validate/corroborate the potential of this enzyme as a useful target. This review presents an overview of the DNA gyrase inhibitors obtained from natural and synthetic sources, their syntheses schemes and spectrum of biological activity of a variety of scaffolds and their analogues. The authors hope to provide focused direction for development of new chemical entities, synthetic routes for analogue synthesis, structure activity relationships and biological activity. The most potent ones can be used as templates to design novel compounds targeting DNA gyrase and are effective against resistant bacterial strains and biofilms.


Assuntos
Antibacterianos/síntese química , DNA Girase/metabolismo , Inibidores da Topoisomerase II/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , DNA Girase/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/enzimologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
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