Jean-Claude Teulade

Synthesis and antiviral activity of imidazo[1,2-a]pyridines

Abstract Imidazo[1,2- a ]pyridines bearing a 3-(dithiolan-, dioxolan- or oxathiolan-2-yl) substituent were synthesized from the corresponding aldehydes. The dithiolanyl derivative 6a proved active against cytomegalovirus at an inhibitory concentration (IC 50 ) of 16 μM, whilethe oxathiolanyl compound 6c inhibited respiratory syncytial virus (IC 50 : 58 μM). The thioacetal 7 was active against cytomegalovirus at an IC 50 of 3.1 μM. None of the compounds had anti-HIV activity and were not inhibitory against other RNA and DNA viruses evaluated. Compounds 6a,c and 7 had in vitro selectivity indexes (ratio cytostatic concentration/antivirally active concentration) ranging between 8 and 10.

Evaluation of Radiolabeled (Hetero)Aromatic Analogues of N-(2-diethylaminoethyl)-4-iodobenzamide for Imaging and Targeted Radionuclide Therapy of Melanoma

Targeted radionuclide therapy using radioiodinated compounds with a specific affinity for melanoma tissue is a promising treatment for disseminated melanoma, but the candidate with the ideal kinetic profile remains to be discovered. Targeted radionuclide therapy concentrates the effects on tumor cells, thereby increasing the efficacy and decreasing the morbidity of radiotherapy. In this context, analogues of N-(2-diethylaminoethyl)-4-iodobenzamide (BZA) are of interest. Various (hetero)aromatic analogues 5 of BZA were synthesized and radioiodinated with (125)I, and their biodistribution in melanoma-bearing mice was studied after i.v. administration. Most [ (125)I] 5-labeled compounds appeared to bind specifically and with moderate-to-high affinity to melanoma tumor. Two compounds, 5h and 5k, stood out with high specific and long-lasting uptake in the tumor, with a 7- and 16-fold higher value than BZA at 72 h, respectively, and kinetic profiles that makes them promising agents for internal targeted radionuclide therapy of melanoma.

Synthesis and antiviral activity of 3-substituted imidazo[1,2-a]pyridines.

A series of 3-substituted imidazo[1,2-a]pyridines wa synthesized as potential antiviral agents. Compound 10b and, to a lesser extent, 10c showed activity against both TK+ and TK− strains of varicella-zoster virus.

The Imidazopyrrolopyridine Analogue AG110 Is a Novel, Highly Selective Inhibitor of Pestiviruses That Targets the Viral RNA-Dependent RNA Polymerase at a Hot Spot for Inhibition of Viral Replication

ABSTRACT Ethyl 2-methylimidazo[1,2-a]pyrrolo[2,3-c]pyridin-8-carboxylate (AG110) was identified as a potent inhibitor of pestivirus replication. The 50% effective concentration values for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect, viral RNA synthesis, and production of infectious virus were 1.2 ± 0.5 μM, 5 ± 1 μM, and 2.3 ± 0.3 μM, respectively. AG110 proved inactive against the hepatitis C virus and a flavivirus. AG110 inhibits BVDV replication at a time point that coincides with the onset of intracellular viral RNA synthesis. Drug-resistant mutants carry the E291G mutation in the viral RNA-dependent RNA polymerase (RdRp). AG110-resistant virus is cross-resistant to the cyclic urea compound 1453 which also selects for the E291G drug resistance mutation. Moreover, BVDV that carries the F224S mutation (because of resistance to the imidazopyridine 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine [BPIP]and VP32947) is also resistant to AG110. AG110 did not inhibit the in vitro activity of recombinant BVDV RdRp but inhibited the activity of BVDV replication complexes (RCs). Molecular modeling revealed that E291 is located in a small cavity near the tip of the finger domain of the RdRp about 7 Å away from F224. Docking of AG110 in the crystal structure of the BVDV RdRp revealed several potential contacts including with Y257. The E291G mutation might enable the free rotation of Y257, which might in turn destabilize the backbone of the loop formed by residues 223 to 226, rendering more mobility to F224 and, hence, reducing the affinity for BPIP and VP32947. It is concluded that a single drug-binding pocket exists within the finger domain region of the BVDV RdRp that consists of two separate but potentially overlapping binding sites rather than two distinct drug-binding pockets.

Synthesis and antiviral activity of an imidazo[1,2-a]pyrrolo[2,3-c]pyridine series against the bovine viral diarrhea virus.

A series of imidazo[1,2-a]pyrrolo[2,3-c]pyridines has been prepared and evaluated for their anti-BVDV activities in MDBK cells. From the synthesized analogues bearing modifications of the substituents at positions 2, 3, 7 and 8, compounds 10a, b, 16, 24, 25 and 26 exhibited significant anti-BVDV activities.

Novel imidazo[1,2-a]naphthyridinic systems (part 1) : Synthesis, antiproliferative and DNA-intercalating activities

Novel imidazo[1,2-a]naphthyridinic systems 6a-15a and 6b-15b were obtained from Friedländers reaction in imidazo[1,2-a]pyridine series. Most of the compounds were evaluated for their antitumor activity in the NCIs in vitro human tumor cell line screening panel. Among them, pentacyclic derivatives 13b and 14a exhibited in vitro activity comparable to anticancer agent such as amsacrine. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against topo1. On the contrary, we highlighted a direct intercalation of the drugs into DNA by electrophoresis on agarose gel.

Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.

Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.

New Opportunities with the Duff Reaction

The Duff reaction (HMTA, AcOH or TFA) was studied on substituted [6 + 5] heterocyclic compounds. This reaction provides a useful route to aldehydes for compounds bearing sensitive amide functions. It gives also access to tricyclic lactams of potential biological interest. The formation of an aminomethyl intermediate in the Duff reaction mechanism is unequivocally demonstrated.

SRN1 reactions in imidazo [1, 2-a] pyridine series

2-Chloromethyl-3-nitroimidazo[1,2-a]pyridine is shown for the first time to react with 2-nitropropane salts by an SRN1 mechanism to give excellent yield of isopropylidene derivative formed from the C-alkylation product by loss of nitrous acid.

Heterocyclic enaminones: Photochemical synthesis of 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-9-ones

Abstract The synthesis of 6,7,8,9-tetrahydro-5 H -pyrido[2,3- b ]indol-9-ones from arylenaminones is described. Two “routes” have been investigated: a radical process through a photochemical reaction, and a catalytic process through an arylpalladium complex.