A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.

Herein we describe the synthesis and in vitro and in vivo activity of thiazolo[5,4-d]pyrimidines as a novel class of immunosuppressive agents, useful for preventing graft rejection after organ transplantation. This research resulted in the discovery of a series of compounds with potent activity in the mixed lymphocyte reaction (MLR) assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. The most potent congeners displayed IC(50) values of less than 50 nM in this MLR assay and hence are equipotent to cyclosporin A, a clinically used immunosuppressive drug. One representative of this series was further evaluated in a preclinical animal model of organ transplantation and showed excellent in vivo efficacy. It validates these compounds as new promising immunosuppressive drugs.

The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.

According to the WHO, 1 1.7 million people died from tuberculosis (TB) in 2009 and more than 2 billion people (constituting one-third of the world's population) are infected with TB. Among the 9.4 million new TB cases reported in 2009, an estimated 1.1À1.2 million (11À13%) suffer from HIV coinfection. Hence, TB, a contagious infectious disease, is regarded as the leading cause of death due to an infectious agent among adults worldwide and a major threat to global health. 2 The disease establishes mainly in the pulmonary system and is caused by some mycobacteria of the Mycobacterium tuberculosis complex, predominantly Mycobacterium tuberculosis. 3 Active TB is treated by chemotherapy with so-called first-line drugs. 4À6 From the many trials conducted in the past 50À 60 years, two standard regimens emerged which are recommended by the WHO and consist of a two-month daily treatment of either isoniazid, rifampin, pyrazinamide, and streptomycin or isoniazid, rifampin, pyrazinamide, and ethambutol, followed by further four months daily or intermittent doses of isoniazid and rifampin. Unfortunately, the long treatment times and the side effects 7 of the drugs (especially hepatotoxicity) lead to a high proportion of noncompliance patients. This and the rise of the HIV pandemic 8 in the early 1980s led to the emergence of multidrug resistant 9 (MDR) and, more recently, even extensively drug resistant 10 (XDR) strains. MDR-TB is defined as resistance to the action of at least isoniazid and rifampin, and its treatment requires the inclusion of so-called second-line drugs such as aminoglycosides,

The halogen atom transfer radical cyclization (HATRC) has been evaluated on N-(indolylmethyl)trichloroacetamides under Cu(I)Cl catalysis using nitrogen containing ligands. The ring closure leads to the formation of 3,3-spiro-3H-indoles in moderate to good yields by a 5-exo-mechanism. Derivatives with an N-electron withdrawing substituent also lead to a 5-exo-trig and not to a 6-endo-trig cyclization.