Synthesis and evaluation of 5-substituted-2'-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in Mycobacterium tuberculosis

Abstract

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,

ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents

“…10 The chemical class of C5-alkynyl substituted 2'-deoxyuridine-5'-monophosphate (dUMP) has been reported as selective inhibitor of ThyX in M. tuberculosis. 11 In this study, among several compounds, N- (3-(5-(2'-deoxyuridine-5'monophosphate))prop-2-ynyl)octanamide 1 (figure 1) was identified as the most potent and selective analogue with an IC 50 value of 0.91 M versus recombinant ThyX from M. tuberculosis. However, the polarity of this compound constitutes a major obstacle for its penetration through the complex mycobacterial cell wall.…”

“…Our synthetic efforts started with the synthesis of the propargyloctylamide 4 from propargylamine 3 and octanoyl chloride. 11 Then, Sonogashira cross coupling 24 of the commercially available 5-iodo-2'-deoxyuridine 5 with alkyne 4 afforded the desired nucleoside 2, isolated in excellent yield (91%) without column chromatography purification. It is noteworthy to mention that our synthetic procedure to the preparation of 2 was made less time-consuming than the previously reported procedure, with great improvement in terms of yield achieved.…”

“…It is noteworthy to mention that our synthetic procedure to the preparation of 2 was made less time-consuming than the previously reported procedure, with great improvement in terms of yield achieved. 11 Following the general synthetic procedure for compounds 7a-l, nucleoside 2 was reacted with the appropriate phosphorochloridate 6a-l using N-methylimidazole as activator, according to a previously described method. 25 The desired phosphoroamidates 7a-l were obtained from 5 to 39% yield.…”

Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

“…The first selective ThyX inhibitors were synthesized by Herdewijn et al who identified N-(3-(5-(2′deoxyuridine-5′-phosphate))prop-2-ynyl)octanamide (29, Figure 8A) as the most active candidate in a series of differently C-5 alkynyl-substituted 2′-deoxyuridine-5′-monophosphate analogs, with an IC 50 value of 0.91 μM against ThyX [99]. This compound was also found to be selective for ThyX, showing 92.8% inhibition at 50 μM compared with only 15.6% inhibition for ThyA at the same concentration.…”

Investigating an unusual flavin-dependent mechanism of thymidylate biosynthesis

“…R=2'-deoxyribose-5'-phosphate; R'=(p-aminobenzoyl)-glutamate; R"=adenosine-5'-pyrophosphate-ribityl. A few moderate inhibitors of FDTS enzymes have been developed, none of which are mechanism-based nor have shown highly specific inhibition of FDTS over classical TSase (41,51). Potent inhibitors of classical TSase, such as 5F-dUMP, produce moderate reversible inhibition of FDTS, and crystal structures of FDTS with 5F-dUMP (e.g.…”