Valérie Collot

Suzuki-type cross-coupling reaction of 3-iodoindazoles with aryl boronic acids: A general and flexible route to 3-arylindazoles

Abstract This paper describes a Suzuki Type cross coupling reaction of 3-iodoindazoles with aryl and heteroaryl boronic acids as a general route to 3-arylindazoles. The coupling reaction is illustrated by the preparation of new aryl- or heteroarylindazoles 7. Scope and limitation of the method are outlined. The coupling reaction works best on a 1-substituted indazole nucleus. The usefulness of the reaction is illustrated by a short practical synthesis of YC-1, a pharmacological agent potentialy useful for the treatment of cardiovascular diseases or erectile dysfunction.

Synthesis and biological evaluation of five-membered heterocycles fused to cyclopenta[c]thiophene as new antitumor agents

A series of 10 derivatives 2-6 issued from the fusion of various five-membered heterocycles to cyclopenta[c]thiophene were evaluated for potential anticancer activity in the NCIs in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Among these tested compounds, four were found to be cytotoxic allowing us to point out some structure-activity relationships. The oxazolidinone derivatives 2a-c displayed further in vivo antitumor activity in the hollow fiber assay and standard xenograft testing developed at the NCI.

Synthesis and biological evaluation of cyclopenta[c]thiophene related compounds as new antitumor agents

A series of 22 cyclopenta[c]thiophene related compounds was obtained by the pharmacomodulation of 6-amino-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ones 1a-g. All compounds were evaluated for potential anticancer activity in the NCIs in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Among these tested compounds, seven were found to be cytotoxic, especially against leukemia cell lines, allowing us to point out some structure-activity relationships. These derivatives were further evaluated for potential in vivo anticancer activity in the hollow fiber assay developed at the NCI, which selected two compounds, 1f and 3a for standard xenograft testing.

7‐Methoxy‐1H‐indazole, a new inhibitor of neuronal nitric oxide synthase

The crystal structure of 7-methoxy-1H-indazole, C(8)H(8)N(2)O, an inhibitor of nitric oxide synthase, shows that the methoxy group lies in the plane of the indazole system with its methyl group located trans to the indazole N-H group. The crystal packing consists principally of hydrogen-bonded trimers. Intermolecular hydrogen-bonding interactions are formed between the indazole N atoms, with the N-H group as a hydrogen-bond donor and the remaining N atom as an acceptor.

New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase.

Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N(1)- and N(2)-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.

7-Nitro-1H-indazole, an inhibitor of nitric oxide synthase.

The crystal structure of 7-nitro-1H-indazole, C(7)H(5)N(3)O(2), an inhibitor of nitric oxide synthase, shows the existence of an intramolecular hydrogen bond between an O atom of the nitro group and the NH group of the indazole ring. The crystal packing consists of intermolecular hydrogen bonding and indazole.indazole interactions.

YC-1, an activation inductor of soluble guanylyl cyclase

The crystal structure of 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole, C(19)H(16)N(2)O(2), showed that the furan O and indazole N atoms lie on the same face of the molecule. The crystal packing consists of intermolecular hydrogen bonding, and indazole-indazole and indazole-phenyl interactions.

Iodoindazoles with Selective Magnesiation at Position 3: A Route to Highly Functionalized Indazoles

A unique route to highly functionalized indazoles is described. A regioselective magnesiation at position 3 of 4-, 5-, 6- and 7-iodo-2-THP-indazoles (THP=tetrahydropyranyl) has been developed using TMPMgCl⋅LiCl (TMP=2,2,6,6-tetramethylpiperidyl). The obtained magnesiate can be trapped by different electrophiles to introduce a wide range of functional groups including halogens, thioalkyls, alcohols, aldehydes, ketones, amides, or esters at position 3. Once this position is functionalized, the iodine atoms can be further reacted through metal-halogen exchange or cross-coupling strategies. Finally, N-substitution reactions allow the synthesis of a variety of highly functionalized indazoles giving access to these valuable scaffolds through a simple and unique route.

Substituted flavones: a promising scaffold in the fight against malaria

Background Ever since 2008, when evidence of artemisinin resistant malaria was highlighted in Western Cambodia [1], the need for new drugs with an original structure and novel mechanisms of action is even more pressing. The study of traditional remedies such as Cinchona bark or Artemisia aerial parts led to the discovery of the most potent antimalarials, bearing out that nature is still an incredible source of inspiration. Based on this approach, we are developing new synthetic antimalarial agents with an original structure inspired by nature.