Enrique Luis Michelotti

Synthesis and SAR of cis-1-Benzoyl-1,2,3,4-tetrahydroquinoline ligands for control of gene expression in ecdysone responsive systems

A library of 35 cis-1-benzoyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolines was prepared. The compounds bore various substitutuents on the benzoyl ring, at the 4-position of the phenylamino ring and at the 6-position of the tetrahydroquinoline ring. The compounds were assayed for their ability to cause expression of a reporter gene downstream of an ecdysone response element in a mammalian cell line engineered to express the ecdysone receptor from Aedes aegypti. In general, compounds with small lipophilic substituents at the meta and para-positions of the benzoyl ring and hydrogen or fluorine at the 4-position of the phenylamino ring and the 6-position of the tetrahydroquinoline ring were the most potent.

Solid-supported synthetic equivalents of 3-formylchromone and chromone

Abstract Treatment of bound o -hydroxyacetophenone 10 under Vilsmeier–Haack reaction conditions yields 11a or 12b , synthetic equivalents of 3-formylchromone ( 1 ) and chromone ( 13 ) respectively, depending on the resin used as solid support (Merrifield or Wang chloro resin respectively).

Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).

Discovery of a new class of DFG-out p38α kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the αC-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38α IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.

Solid phase synthesis of sulfahydantoins

A five step solid phase synthesis of 2-unsubstituted 1,2,5-thiadiazolidin-3-one 1,1-dioxides (sulfahydantoins) from Nα-FMOC-amino acids and aromatic aldehydes is described. The key step is the base mediated cyclitive cleavage of a resin bound Nα-(aminosulfonyl)-Nα-benzyl-amino acid to afford the desired product. This synthesis allows the preparation of a diverse library of compounds based on this heterocycle.

Discovery and SAR of a series of 4,6-diamino-1,3,5-triazin-2-ol as novel non-nucleoside reverse transcriptase inhibitors of HIV-1.

The discovery and SAR study of a series of 4,6-diamino-1,3,5-triazin-2-ol compounds as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are reported. The lead compounds in this series showed excellent activity against wild-type and drug-resistant RT enzymes and viral strains. In addition, compounds from this series demonstrated favorable pharmacokinetic profile in rat. A preliminary modeling study was conducted to understand the binding mode of this series of compounds.

Combined solid phase and solution synthesis of a library of α,α-disubstituted-α-acylaminoketones

Abstract Preparation of a demonstration library of α,α-disubstituted-α-acylaminoketones, of interest as ecdysone agonists, is described. The five-step synthetic sequence employed α,α-disubstituted amino acids, Grignard reagents and carboxylic acids as building blocks in a strategic combination of solid phase and solution steps.

Solid-phase synthesis of 1-substituted 4,5-dihydro-1,2,4-triazin-6-ones

Abstract The solid-phase synthesis of 1-substituted 4,5-dihydro-1,2,4-triazin-6-ones from imidate esters and substituted hydrazines is reported. The synthesis starts with the reaction of imidic esters with polymer-bound glycine to form the imidate esters. A rehearsal library of 59 compounds was synthesized.

Solid phase synthesis of α-acylamino-α,α-disubstituted ketones

α-Acylamino-α,α-disubstituted ketones are of interest as ecdysone agonists. Solid phase synthesis of prototypical α-acylamino-α,α-disubstituted ketones on two different solid supports is described. In both cases the ketone was formed by reaction of a Grignard reagent with an N-acyl-α,α-disubstituted amino acid immobilized through its carboxylate as a Weinreb amide derivative.

Design and synthesis of two pyrazole libraries based on o-hydroxyacetophenones.

Two new solid-phase syntheses of substituted pyrazoles are described. The first includes supporting an o-hydroxyacetophenone on Merrifield resin, Vilsmeier-Haack formylation on the methyl group and cyclization with a substituted hydrazine to afford a pyrazole ring with two diversity centers. The second starts from o-hydroxyacetophenone supported on Wang resin, which undergoes a Claisen condensation with a carboxylic acid ester to yield a 1,3-dicarbonyl compound that cyclizes to a pyrazole using a hydrazine. Both methods have been used to synthesize two small pyrazole libraries.

Solid phase vs. solution phase differential behavior: Formation of a salicylate structure from a malondialdehyde moiety

Treatment of 2, solid supported synthetic equivalent of 3-formylchromone (4), and ethyl acetoacetate affords the salicylate structure 8 instead of the previously reported isophtalate 7. This is the first formation of a salicylate by a double carbonyl condensation of a malondialdehyde moiety ever reported.