Antiviral pyrimidines

Several synthetic pyrimidines and purines are useful drugs Acyclovir was the first effective antiviral compound and is used to treat herpes infections 6 Mercaptopunne is one of the drugs used to treat childhood leukemia which has become a very treatable form of cancer with a cure rate approaching 80%... 

Although the term nucleoside was once limited to the compounds in Table 28.2 and a few others, cunent use is more permissive. Pyrimidine derivatives of D-arabinose, for exfflnple, occur in the free state in certain sponges and are called spongonticleosides. The powerful antiviral drug ribavirin, used to treat hepatitis C and Lassa fever, is a synthetic nucleoside analog in which the base, rather than being a pyrimidine or purine, is a triazole. 

Prusoff WH, Chen MS, Fischer PH, Lin TS, Shiau GT, Schinazi RF, Walker J (1979) Antiviral iodinated pyrimidine deoxyribonucleosides 5-iodo-2 -deoxyuridine 5-iodo-2 -deoxycytidine 5-iodo-5 -amino-2, 5 -dideoxyuridine, Pharmacol Ther 7 1-34... 

Balzarini J, Schols D, Van Laethem K, De Clercq E, Hockovd D, Masojidkova M, Holy A (2007) Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines, J Antimicrob Chemother 59 80-86 Beadle JR, Wan WB, Ciesla SL, Keith KA, Hartline C, Kern ER, Hostetler KY (2006) Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses, J Med Chem 49 2010-2015... 

De Clercq E, Eield H J (2006) Antiviral prodrugs - the development of successful prodrug strategies for antiviral chemotherapy. Brit J Pharmacol 147 1-11 De Clercq E, Hol A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC (1986) A novel selective broad-spectrum anti-DNA virus agent. Nature 323 464 67 De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Hol A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8 261-272... 

Zhou S, Breitenbach JM, Borysko KZ, Drach JC, Kern ER, GuUen E, Cheng YC, Zemhcka J (2004) Synthesis and antiviral activity of (Z)- and (E)-2,2-[bis(hydroxymethyl) cyclopropylidene]methylpurines and -pyrimidines second-generation methylenecyclopropane analogues of nucleosides. J Med Chem 47 566-575... 

Extensive investigations have been performed related to the synthesis of new adamantane derivatives with better therapeutic actions and less adverse effects. For example, it has been proved that adamantylamino-pyrimidines and -pyridines are strong stimulants of mmor necrosis factor-a (TNF-a) [132]. TNF is a substance that can improve the body s namral response to cancer by killing cancer cells. Another example is 1,6-diaminodiamantane [87], which possesses an antitumor and antibacterial activity. Also, many derivatives of aminoadamantanes have antiviral activity like 3-(2-adamantyl) pyrolidines with two pharmacophoric amine groups, which have antiviral activity against influenza-A virus [133]. 

The renaissance of the Biginelli MCR can be attributed to the obtained pyrimidine derivatives, which show remarkable pharmacological activity. A broad range of effects, including antiviral, antitumor, antibacterial, anti-inflammatory as well as antihypertensive activities has been ascribed to these partly reduced pyrimidine derivatives [96], such as 9-117 and 9-118 (antihypertensive agents) [97] and 9-119 (ala-adrenoceptor-selective antagonist) [98] (Scheme 9.24). Recently, the scope of this pharmacophore has been further increased by the identification of the 4-(3-hydroxyphenyl)-pyrimidin-2-thione derivative 9-120 known as monastrol [98], a novel cell-permeable lead molecule for the development of new anticancer drugs. Monastrol appears specifically to affect cell division (mitosis) by a new mechanism,... 

Ar-(4-ChIorobenzyI)-7-substituted-4-oxo-4//-pyrazino[l,2-tf]pyrimidine-3-carboxarnidcs have been claimed as compounds to treat atherosclerosis and restenosis <2004W02004/019933> and as antiviral agents, particularly against herpes viruses <2002W02002/004444>. The mesoionic pyrazino[l,2-tf]pyrimidine 95 exhibited platelet aggregation inhibitory activity <2000BMC1917>. 

The condensation of various heterocycles (pyrimidine or purine) with allyl bromide has been effected in the presence of KI. This selectively afforded N-1 isomers with pyrimidines, but N-9, N-3 or N-9, N-7 isomer mixtures with purines (88MIP1 89MI12 91 Mil). Alkyl esters of 3-adenin-9-yl-2-hydroxypropanoic acids were reported as broad-spectrum antiviral agents (85JMC282). 

Pharmacology A fluorinated pyrimidine nucleoside with in vitro and in vivo activity against herpes simplex virus types 1 and 2, and vaccinia virus. Some strains of adenovirus are also inhibited in vitro. Its antiviral mechanism of action is not completely known. 

Pyrazolo[3,4-, pyrimidines 427 and 428 were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It is very interesting that this class of compounds provide remarkable evidence that they are very specific for human enteroviruses, in particular coxsackie viruses <2004BML2519>. 

Although any of these seven steps could be a druggable target, most of the antiviral agents clinically employed for non-AIDS infections act on the synthesis or assembly of either purines or pyrimidines (steps 3 and 4). For AIDS, reverse transcriptase inhibitors block transcription of the HIV RNA genome into DNA, thereby preventing synthesis of viral mRNA and protein protease inhibitors act on the synthesis of late proteins (steps 5 and 6). 

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