Design of Annulated Pyrazoles as Inhibitors of HIV-1 Reverse Transcriptase

Sweeney, Zachary K.; Harris, S.F.; Arora, Nidhi; Javanbakht, Hassan; Liu, Yu; Fretland, Jennifer; Davidson, James P.; Billedeau, J. Roland; Gleason, Shelley; Hirschfeld, Donald R.; Kennedy‐Smith, Joshua J.; Mirzadegan, Taraneh; Roetz, Ralf; Smith, Mark A.; Sperry, Sarah L.W.; Suh, Judy M.; Wu, Jiayue; Tsing, Stan; Villaseñor, Armando G.; Paul, Amber M.; Su, Guoping; Heilek, Gabrielle; Hang, Julie Q.; Zhou, Amy S.; Jernelius, Jesper A.; Zhang, Fang‐Jie; Klumpp, Klaus

doi:10.1021/jm800527x

Cited by 70 publications

(45 citation statements)

References 32 publications

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“…Since the discovery that 3-methylpyrazole and 4-ethylpyrazole have potential medicinal value, there has been a rapid growth in synthesizing new derivatives of pyrazole as anticancer (Manfredini et al 1992;Komeda et al 2000;Gamage et al 2002;MoukhaChafiq et al 2002;Rostom et al 2003;Duivenvoorden et al 2005;Park et al 2005;Keter et al 2009a), antibacterial (Jungheim 1989;Aiello et al 2000;Genin et al 2000a;Kucukguzel et al 2000;El-Gaby et al 2000;Farghaly et al 2001;Moukha-Chafiq et al 2002;Haque et al 2002;Kaymakcıoglu and Rollas 2002;Panda et al 2002;Adnan and Abdel-Aziem 2004;Tanitame et al 2004;Akbas and Berber 2005;Bekhit et al 2005;Bildirici et al 2007;Abunada et al 2008;Radi et al 2010), antiparasitic (Garg et al 1973;Rathelot et al 2002), antiviral (Comber et al 1991;Manfredini et al 1992;Storer et al 1999;Johansson et al 2002;Rostom et al 2003;Sweeney et al 2008), analgesics (Menozzi et al 1997;Pinto et al 1999) antiglycemic agents (Bauer et al 1968;Kees et al 1996;Bebernitz et al 2001) and even as anti-inflammatory agents …”

Section: N N Hmentioning

confidence: 99%

Perspective: the potential of pyrazole-based compounds in medicine

2011

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Pyrazoles are widely used as core motifs for a large number of compounds for various applications such as catalysis, agro-chemicals, building blocks of other compounds and in medicine. The attractiveness of pyrazole and its derivatives is their versatility that allows for synthesis of a series of analogues with different moieties in them, thus affecting the electronics and by extension the properties of the resultant compounds. In medicine pyrazole is found as a pharmacophore in some of the active biological molecules. While pyrazole derivatives have been extensively studied for many applications including anticancer, antimicrobial, anti-inflammatory, antiglycemic, anti-allergy and antiviral, much less has been reported on their metal counterparts in spite of the fact that metals have been shown to impart activity to ligands. Thus this perspective is intended to demonstrate the potential of pyrazole and pyrazolyl metal complexes in the areas of drug discovery and development. Several examples, that include palladium, platinum, copper, gold, zinc, cobalt, nickel, iron, copper, silver and gallium complexes, are used to bolster the above point. For the purposes of this review three areas are discussed, that is pyrazole metal complexes as: (i) anticancer, (ii) antibacterial/parasitic and (iii) antiviral agents.

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Section: N N Hmentioning

confidence: 99%

Perspective: the potential of pyrazole-based compounds in medicine

2011

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“…(10), structure-based lead optimization involves the synthesis and biological evaluation of several compounds sharing a high degree of chemical similarity, but still possessing interesting structural diversity. Its success and effectiveness will depend to a large extent on the existence of a well-defined and controlled integration of medicinal chemistry efforts, including molecular modeling, design, synthesis and biological evaluation [10,15,25,39,[89][90][91][92][93][94][95][96][97]]. …”

Section: Structure-based Lead Optimizationmentioning

confidence: 99%

Structure-Based Drug Design Strategies in Medicinal Chemistry

Andricopulo¹,

Salum²,

Abraham

2009

CTMC

138

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A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.Keywords: Structure-based drug design, medicinal chemistry, virtual screening, QSAR, pharmacophores. STRUCTURE-BASED DRUG DESIGNThe performance of biochemical processes and cell mechanisms are dependent upon complex and multiple noncovalent intermolecular interactions between proteins and small-molecule modulators. The understanding of the structural and chemical binding properties of important drug targets in biologically relevant pathways allows the design of small molecules capable of regulating or modulating specific target functions in the body that are closely linked to human diseases and disorders, through multiple intermolecular interactions within a well-defined binding pocket [1][2][3][4]. In general, the identification of promising hits for further optimization is a major challenge faced by the both pharmaceutical and academic laboratories. Although the trial-anderror nature is inherent in drug research, rational concepts and modern computational methods have become widely employed for lead selection and optimization.The use of three-dimensional (3D) protein structure information in the development of new biologically active molecules, which is termed Structure-Based Drug Design (SBDD), is a well-established, successful and highly attarctive strategy used by academic and pharmaceutical research laboratories worldwide [3][4][5][6][7][8]. As a creative and knowledgedriven approach, an essential requirement for structure-based studies is a substantial understanding of the spatial and energetic aspects that affect the binding affinities of proteinligand complexes. Considering that the shape and chemical nature of the binding site of a specific target protein are known, and the possible intermolecular interactions between ligands and the protein within its active site have been identified, this qualified information can be directly employed for the identification of new ligands and the optimization of lead compounds. This opens new possibilities to boost the search for lead molecules and to limit the number of compounds that need to be evaluated experimentally.Hits can be identified through the docking of smallmolecule ligands (selected from databases of chemical structures) into protein active sites or by using receptorbased pharmacophore models. Furthermore, drug candidates can be designed de novo by improving the complementary binding properties of lead compounds and the r...

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“…Heterocyclic compounds have received considerable attention from the last few years due to their variety of biological activities, especially as inhibitors of PDE5 extracted from human platelets [1], HIV-1 reverse transcriptase [2], human EPK2 [3] and cyclin-dependent kinase [4].…”

Section: Introductionmentioning

confidence: 99%

Dibutylamine (DBA): A highly efficient catalyst for the synthesis of pyrano[2,3-d]pyrimidine derivatives in aqueous media

Bhat

Shalla

Dongre

2016

Journal of Taibah University for Science

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Annulated pyrano [2,3-d]pyrimidine derivatives were synthesized via one-pot three component condensation reactions of various aromatic aldehydes, malononitrile and barbituric acid in aqueous ethanol using dibutylamine (DBA) as catalyst. The potential application of DBA in organic synthesis increasing rapidly due to its reaction simplicity, minimum reaction time, high yields of the desired products (83-94%) and low cost chemicals. All the synthesized pyrano[2,3-d] pyrimidine derivatives were characterized by IR, 1 H NMR, 13 C NMR and mass spectra.

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Design of Annulated Pyrazoles as Inhibitors of HIV-1 Reverse Transcriptase

Cited by 70 publications

References 32 publications

Perspective: the potential of pyrazole-based compounds in medicine

Perspective: the potential of pyrazole-based compounds in medicine

Structure-Based Drug Design Strategies in Medicinal Chemistry

Dibutylamine (DBA): A highly efficient catalyst for the synthesis of pyrano[2,3-d]pyrimidine derivatives in aqueous media

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