Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy

Abstract

Acyclic nucleoside phosphonates (ANPs) are nowadays one of the key drugs in the treatment of DNA virus and retrovirus infections. In this work, we report the synthesis and antiviral evaluation of phosphonoamidate and diamidates prodrugs of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain. In the phosphonoamidate series, the most active compound 15, showed sub-micromolar activity against varicella zoster virus (VZV) (EC = 0.09-0.5 μM) and μM activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). Separation of single diastereoisomers for compound 14, showed that 14b had better anti-herpesvirus activity and no cytotoxicity compared to the diastereoisomeric mixture 14. Very interestingly, phosphonodiamidate 21 showed anti-herpesvirus activity with excellent activity against wild type and thymidine kinase-deficient (TK) VZV strains (EC = 0.47 and 0.2 μM, respectively) and HCMV (EC = 3.5-7.2 μM) without any cytotoxicity (CC > 100).

Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs

“…However, during the preparation of this manuscript, a paper reporting the use of the cross metathesis for the synthesis of ProTide derivatives of linear (E)-but-2enyl nucleoside scaffold, was published. 49 The prodrugs described in this work belong to the same family of compounds previously reported by us, 48 and indeed their antiviral profile was in agreement with our published results. In the present article, we would like to report an effective and improved methodology for the synthesis of allyl phosphonoamidate and their further application in olefin cross-metathesis for the synthesis of ANP ProTides.…”

“…36,[38][39][40][41]46,47 Although adopting a different procedure, our group extended the range of prodrugs of (E)-but-2-enylpyrimidine, by synthesising their ProTide and bisamidate derivatives. 48 In this study we showed that the ProTide technology was able to broaden the spectrum of antiviral activity when compared to other phosphate prodrug approaches. However, we discovered that this methodology suffers from the limitation that only linear olefin must be employed, as with trisubstituted alkenyl derivatives we observed only formation of traces of the desired ProTides.…”

“…3a was isolated by flash chromatography in excellent yield (79%) ( Table 1, Entry 1). Quite surprisingly, no evidence of side reactions 48 (bromination of the double bond and formation of the phosphonodiamidate) have been observed.…”

“…This methodology was already adapted in our laboratory for the synthesis of adefovir and tenofovir phosphonoamidate prodrugs 53 and more recently for the preparation of (E)-but-2-enyl pyrimidine ProTides. 48 Briefly, commercial dimethyl allylphosphonate 1 was converted into the corresponding silyl ester 2, by reaction with an excess of bromotrimethylsilane (5.0 equivalents). Due to the hydrolytically instability of this ester, 2 was not isolated but immediately dissolved in a mixture of pyridine/Et 3 N and treated with the L-alanine isopropyl ester hydrochloride (1.0 equivalents), an excess of 1-naphthol (6.0 equivalents), and a premade solution of PPh 3 (6.0 equivalents) and aldrithiol-2 (6.0 equivalents) in pyridine.…”

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“…Pyrimidine derivatives exhibited various biological activities such as anti-proliferative 24 , anticancer 25,26 , antihypertensive 27 , antioxidant 28,29 , antiviral 30 , antiinflammatory and analgesic activities 31,32 . Certain pyrimidine derivatives play a significant role in several biological processes and show, antileishmanial activities 33 and CNS depressant properties 34 .…”