Marco Radi

Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: Part 2. Synthesis of rigid pyrazolones

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC=4 microg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity.

Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 microg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure-activity relationship analysis.

ATP-Competitive Inhibitors of mTOR: An Update

mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives. mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signaling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents. This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD-8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.

Vascular Endothelial Growth Factor (VEGF) Receptors: Drugs and New Inhibitors

The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this Perspective we briefly report the inhibitors that are in clinical use, while we dedicate two wider sections to the compounds that are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic and report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past 5 years.

Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation.

A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD‐box RNA helicase DDX3 led to the design and synthesis of second‐generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV‐1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure–activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti‐HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV‐1 host cofactors.

Discovery of the first small molecule inhibitor of human DDX3 specifically designed to target the RNA binding site: Towards the next generation HIV-1 inhibitors

Efficacy of currently approved anti-HIV drugs is hampered by mutations of the viral enzymes, leading invariably to drug resistance and chemotherapy failure. Recent data suggest that cellular co-factors also represent useful targets for anti-HIV therapy. Here we describe the identification of the first small molecules specifically designed to inhibit the HIV-1 replication by targeting the RNA binding site of the human DEAD-Box RNA helicase DDX3. Optimization of a easily synthetically accessible hit (1) identified by application of a high-throughput docking approach afforded the promising compounds 6 and 8 which proved to inhibit both the helicase and ATPase activity of DDX3 and to reduce the viral load of peripheral blood mononuclear cells (PBMC) infected with HIV-1.

Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study.

A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported by us and proved to be active against several tumor cell lines. Among these compounds, a promising antileukemia lead (1) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead 1 is described in the present work. A series of more soluble pyrazolo[3,4-d]pyrimidine derivatives were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compounds showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water solubility, microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogues of lead 1 as promising antileukemia agents.

Synthesis and biological evaluation of new enantiomerically pure azole derivatives as inhibitors of Mycobacterium tuberculosis

A series of novel enantiomerically pure azole derivatives was synthesized. The new compounds, bearing both an imidazole as well as a triazole moiety, were evaluated as antimycobacterial agents. One of them proved to have activity against Mycobaterium tuberculosis comparable to those of the classical antibacterial/antifungal drugs Econazole and Clotrimazole.

New insights into small-molecule inhibitors of Bcr-Abl

Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr‐Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr‐Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr‐Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP‐competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second‐generation ATP‐competitive inhibitors endowed with increased potency against imatinib‐resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US‐FDA for the treatment of imatinib‐resistant CML, and many other compounds are currently in clinical trial. Although second‐generation TK inhibitors have shown to be clinically effective against most of the imatinib‐resistant mutants, to date poor results have been obtained in the treatment of the Bcr‐Abl T315I mutant. In this review we will report the most interesting second‐generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP‐competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure–activity relationship.  © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 1, 1–41, 2010

Biologically Driven Synthesis of Pyrazolo[3,4-d]pyrimidines As Protein Kinase Inhibitors: An Old Scaffold As a New Tool for Medicinal Chemistry and Chemical Biology Studies

Protein Kinase Inhibitors: An Old Scaffold As a New Tool for Medicinal Chemistry and Chemical Biology Studies Silvia Schenone,*,† Marco Radi,‡ Francesca Musumeci,† Chiara Brullo,† and Maurizio Botta †Dipartimento di Farmacia, Universita ̀ degli Studi di Genova Viale Benedetto XV, 3, 16132 Genova, Italy ‡Dipartimento di Farmacia, Universita ̀ degli Studi di Parma Viale delle Scienze, 27/A, 43124 Parma, Italy Dipartimento di Biotecnologie, Chimica e Farmacia, Universita ̀ degli Studi di Siena Via Aldo Moro, 2, 53100 Siena, Italy Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States