Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides

Abstract

A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC50 of ∼10 μM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 μM.

Spectroscopic and theoretical characterization of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide

“…The charge distribution on the molecule has an important influence on the vibrational spectra. In 2-(4-methoxyphenyl)-4,5-dimethy l-1H-imidazole 3-oxide, the Mulliken atomic charge of the carbon atoms in the neighborhood of C 3 , C 6 , C 16 and C 22 become more positive, shows the direction of delocalization and shows that the natural atomic charges are more sensitive to the changes in the molecular structure than Mulliken's net charges. Also we done a comparison of Mulliken charges obtained by different basis sets and tabulated it in Table 6 in order to assess the sensitivity of the calculated charges to changes in (i) the choice of the basis set, (ii) the choice of the quantum mechanical method.…”

“…À0.0 C 1 -C 6 1.424 C 2 -C 1 -H 7 117.9 C 6 -C 1 -C 2 -H 8 179.9 C 1 -H 7 1.0889 C 6 -C 1 -H 7 120.9 H 7 -C 1 -C 2 -C 3 À180.0 C 2 -C 3 1.4127 4 1.4094 C 3 -C 2 -H 8 118.6 C 2 -C 1 -C 6 -C 16 179.9 C 3 -O 11 1.3956 C 2 -C 3 -C 4 119.7 H 7 -C 1 -C 6 -C 5 180.0 C 4 -C 5 1.4049 C 2 -C 3 -O 11 115.5 H 7 -C 1 -C 6 -C 16 À0.0 C 4 -H 9 1.0855 C 4 -C 3 -O 11 124.8 C 1 -C 2 -C 3 -C 4 0.0 C 5 -C 6 1.4186 C 3 -C 4 -C 5 120.1 C 1 -C 2 -C 3 -O 11 À179.9 C 5 -H 10 1.0845 C 3 -C 4 -H 9 121.0 H 8 -C 2 -C 3 -C 4 À179.9 C 6 -C 16 1.4527 C 5 -C 4 -H 9 118.8 H 8 -C 2 -C 3 -O 11 0.0 C 12 -O 11 1.4569 C 4 -C 5 -C 6 120.8 C 2 -C 3 -C 4 -C 5 0.0 C 12 -H 13 1.0918 C 4 -C 5 -H 10 121.1 C 2 -C 3 -C 4 -H 9 À179.9 C 12 -H 14 1.0988 C 6 -C 5 -H 10 118.1 O 11 -C 3 -C 4 -C 5 179.9 C 12 -C 15 1.0988 C 1 -C 6 -C 5 118.1 O 11 -C 3 -C 4 -H 9 0.0 C 16 -N 17 1.3679 C 1 -C 6 -C 16 120.8 C 2 -C 3 -O 11 -C 12 180.0 C 16 -N 18 1.391 20 1.3511 C 3 -O 11 -C 12 118.6 C 3 -C 4 -C 5 -C 6 À0.0 N 17 -C 21 1.4176 O 11 -C 12 -H 13 105.3 C 3 -C 4 -C 5 -H 10 À180.0 N 18 -H 19 1.0085 O 11 -C 12 -H 14 111.2 H 9 -C 4 -C 5 -C 6 179.9 N 18 -C 22 1.4001 O 11 -C 12 -H 15 111.2 H 9 -C 4 -C 5 -H 10 À0.0 C 21 -C 22 1.383 H 13 -C 12 -H 14 109.7 C 4 -C 5 -C 6 -C 1 0.0 C 21 -C 23 1.4923 H 12 -C 12 -H 15 109.7 C 4 -C 5 -C 6 -C 16 À179.9 C 22 -C 24 1.4988 H 14 -C 12 -H 15 109.6 H 10 -C 5 -C 6 -C 1 180.0 C 23 -H 25 1.097 C 6 -C 16 -N 17 127.8 H 10 -C 5 -C 6 -C 16 0.0 C 23 -H 26 1.0951 C 6 -C 16 179.9 C 21 -C 22 -C 24 -H 28 119.4 C 21 -C 22 -C 24 -H 30 À119.5 Table 2 Observed IR, Raman bands and calculated (scaled) wavenumbers of 2-(4-methoxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide and assignments. cCC (54) in Raman spectrum and 924 cm À1 in IR spectrum.…”

“…Imidazole drugs have broadened scope in remedying various dispositions in clinical medicines. Medicinal properties of imidazole include anticancer, b-lactamase inhibitors, carboxypeptidase inhibitors, hemeoxygenase inhibitors, anti-aging agents, anticoagulants, anti-inflammatory, antibacterial, antifungal, antiviral, anti-tubercular, anti-diabetic and anti-malarial [16][17][18][19][20][21]. Imidazole and its derivatives are reported to be physiologically and pharmacologically active and find applications in the treatment of several diseases [22].…”

“…p * (C 3 -C 4 ) which increases ED (0.39338 e) that weakens the respective bonds C 3 -C 4 leading to stabilization of 27.28 kJ/mol. There occurs a strong inter molecular hyper conjugative interaction of C16 -N 17 from N 18 of n 1 (N 18 ) ? p * (C 16 -N 17 ) which increases ED (0.61705 e) that weakens the respective bonds C 16 -N 17 leading to stabilization of 50.66 kJ/mol and also the hyper conjugative interaction of C 16 -N 17 from O 20 of n 3 (O 20 ) ?…”

Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs

“…Among these synthetic strategies, quite recently, Agrofoglio's group has elaborated a novel, efficient and straightforward synthesis of C5-alkenyl substituted ANPs via olefin cross-metathesis. [36][37][38][39][40][41][42] Although structure-activity relationship (SAR) studies on acyclic nucleosides have not clarified their pharmacophore model, the introduction of a rigid structural element such as the double bond has proved to be extremely important for their antiviral activity. 43,44 Precisely, the trans-alkene skeleton is able to mimic the three-dimensional geometry of the ribose ring maintaining also an electronic contribution similar to the one provided by the oxygen.…”