Design, synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues

Abstract

The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50=20μM-visual CPE score; EC50=18μM-MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50=9 and 12μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50=2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50=4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4-50μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4-7μM range).

Synthesis, antiviral, cytotoxic and cytostatic evaluation of N 1-(phosphonoalkyl)uracil derivatives

“…After entering into the cell debenzoylation would provide nucleoside analogues capable of Watson-Crick bas pairing. Our previous results [44] support this conclusion.…”

“…Moreover, based on the literature report [43] and on our previous observations regarding the effect of the benzoyl substituent at N-3 of a nucleobase on the antiviral activity [29,44], the N 3 -benzoyluracil analogues 10a-10d were synthesized from phosphonates 5a-5d as shown on Scheme 4.…”

Synthesis of Novel Chiral Sulfonamide‐Bearing 1,2,4‐Triazole‐3‐thione Analogs Derived fromD‐andL‐Phenylalanine Esters as Potential Anti‐Influenza Agents

“…Viral cytopathicity or plaque formation was recorded as soon as it reached completion in the control virus‐infected cell cultures that were not treated with the test compounds. Antiviral activity was expressed as the EC 50 or compound concentration required to reduce virus‐induced cytopathogenicity or viral plaque formation by 50% …”

“…The cytotoxicity of the tested compounds toward the uninfected host cells was defined as the minimum cytotoxic concentration (MCC) that causes a microscopically detectable alteration of normal cell morphology. The 50% cytotoxic concentration (CC 50 ), causing a 50% decrease in cell viability, was determined using a colorimetric 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2 H ‐tetrazolium (MTS) assay system …”

Keto‐Enol Tautomerism in Nucleobase‐Substituted Aldols

“…The first known member of this family, acyclovir, displays extremely low toxicity for normal cells and a strong inhibitory activity against herpes simplex virus (HSV) being today the main drug for the treatment of this infection . The subsequent development of a series of ANs with diverse side chains resulted in analogues such as ganciclovir, penciclovir, famciclovir, and adefovir that showed improved solubility and oral bioavailability.…”