Mikhail F. Gordeev

Approaches to combinatorial synthesis of heterocycles: Solid phase synthesis of pyridines and pyrido[2,3-d]pyrimidines

An efficient solid phase synthesis of diverse pyridines and pyrido[2,3-d]pyrimidines is described. O-Immobilized keto esters 2 react with aldehydes to afford Knoevenagel derivatives 3. These undergo Hantzsch-condensation with α-oxo enamines to generate 1,4-dihydropyridines 4 that are oxidized with CAN to produce immobilized pyridines 5. The method has been extended to synthesis of fused pyrido[2,3-d]pyrimidines employing 6-aminouracils as the α-oxo enamine component. The course of the reaction on solid phase was studied by gel-phase 13C NMR spectrosopy. The synthesis is designed to be amenable for combinatorial libraries preparation.

A general and efficient solid phase synthesis of quinazoline-2,4-diones

Abstract An efficient solid phase synthesis of chiral quinazolinediones is described. Immobilized amino acid based urea derivatives 3 undergo a racemization-free heterocyclization upon gentle heating in presence of tetramethylguanidine to afford fused pyrimidine-2,4-diones 6 , which are smoothly N 1 -alkylated under mild conditions to produce immobilized quinazolinediones 8 . The method is amenable to combinatorial synthesis and offers broad scope for structural and chemical diversity, as illustrated by preparation of fused thieno[2,3-d]pyrimidine-2,4-dione 10 and hydroxamate pharmacophore bearing quinazolinedione derivative 11 .

N-α-Fmoc-4-phosphono(difluoromethyl)-L-phenylalanine: A new O-phosphotyrosine isosteric building block suitable for direct incorporation into peptides

Abstract An efficient preparation of N-α-Fmoc-4-phosphono(difluoromethyl)-L-phenylalanine 5 is described. The synthesis of this phosphotyrosine isostere involves deprotection of the penultimate diethylphosphonate intermediate 4 with BSTFA/TMSI as the key step. Building block 5 can be utilized directly for incorporation into peptides without protection of the side chain phosphonic acid group, as illustrated by the efficient preparation of model difluorophosphonopeptides Ac-F 2 Pmp-Ile-Asn-Gln-NH 2 and Ac-Glu-F 2 Pmp-Ile-Asn-Gln-NH 2 .

Combinatorial synthesis and screening of a chemical library of 1,4-dihydropyridine calcium channel blockers.

Solid-phase synthesis of a 300-member pharmacophore library of 1,4-dihydropyridines from keto ester, diketone and aldehyde building blocks on a cleavable amine polymeric support is described. Screening and serial deconvolution of the combinatorial library has resulted in identification of known and new potent calcium channel blockers.

New potent antibacterial oxazolidinone (MRX-I) with an improved class safety profile.

Oxazolidinones comprise an important class of antibacterial protein synthesis inhibitors. Myelosuppression and monoamine oxidase inhibition (MAOI) are key independent causes for limiting adverse effects in therapy with the sole approved drug of this class, linezolid. This annotation describes a novel oxazolidinone agent, (S)-5-((isoxazol-3-ylamino)methyl)-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)phenyl)oxazolidin-2-one (MRX-I), distinguished by its high activity against Gram-positive pathogens coupled with markedly reduced potential for myelosuppression and MAOI. The medical need, medicinal chemistry rationale, preclinical data, and phase I clinical trial summary for this new agent are reviewed herein.

Novel antibacterial azetidine lincosamides.

The synthesis and evaluation of novel azetidine lincosamides 1 are described. Eleven new (3-trans-alkyl)azetidine-2-carboxylic acids were synthesized via alkylation of N-TBS-4-oxo-azetidine-2-carboxylic acid and subsequent elaboration then coupled to 7-chloro-1-methylthio-lincosamine. The resulting lincosamides differ from the drug clindamycin in both the size of the ring and the position/structure of the alkyl side-chain. SAR within the series was explored with attention to alkyl variants in positions 1 and 3 of the azetidine ring.

Combinatorial chemistry of natural products: Solid phase synthesis of D- and L-cycloserine derivatives

Abstract An efficient methodology for a solid phase synthesis of D- and L-cycloserine derivatives is described. Fmoc-D-cycloserine 4 and its L-enantiomer 5 prepared by a selective amine acylation of bis-silylated parent compounds are immobilized on Sasrin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The resulting Fmoc-cycloserine resins 7, 10, and 11 are deprotected with piperidine in DMF or DCM to generate immobilized cycloserine reagents with a primary amino group exposed for various synthetic transformations. An example of the parallel D-cycloserine library synthesis on a reaction plate is described.

A GENERAL AND CONVENIENT SYNTHESIS OF NOVEL PHOSPHOTYROSINE MIMETICS

A simple and general procedure for preparation of various phosphotyrosine mimetics from the corresponding phenolic precursors is described. In situ silylation of phenol acids followed by treatment with Et3N/CBr4/HP(O)(OEt)2 provides diethyl phosphate intermediates (36–96%), which can be cleanly deprotected in quantitative yields upon treatment with BSTFA/TMSI to afford novel phosphotyrosine mimetics.

Selection and characterisation of Staphylococcus aureus mutants with reduced susceptibility to the investigational oxazolidinone MRX-I

MRX-I is a new oxazolidinone antimicrobial under development. In this study, the potential for development of resistance to MRX-I in Staphylococcus aureus was investigated and key mutations were characterised. Determination of spontaneous resistance frequency and the mutant selection window (MSW) were performed with meticillin-susceptible S. aureus (MSSA) ATCC 29213, meticillin-resistant S. aureus (MRSA) ATCC 33591 and two clinical MRSA isolates SA 0016 and SA 0017. Selected resistant mutants were sequenced for 23S rRNA as well as genes encoding the ribosomal proteins L3, L4 and L22. Resistance frequencies for the aforementioned strains were <8.25×10(-12), <6.33×10(-12), <2.96×10(-13) and <4.52×10(-13), respectively, and the MSW of MRX-I was 2-4, 1-4, 1-2 and 1-4 mg/L, respectively. After 30 serial passages, MRX-I minimum inhibitory concentrations (MICs) increased up to 8- to 16-fold both against MSSA and MRSA, whilst linezolid MICs increased 128-fold against MSSA and 16- to 32-fold against MRSA. MRX-I resistance mutations were clustered mainly in 23S rRNA and L3 protein regions. The U2504A transversion in 23S rRNA dominated in MRX-I-resistant mutants. No mutations in L4 and L22 proteins were observed. MRX-I exhibits a low potential to develop resistance in S. aureus, with a reduced resistance propensity compared with linezolid.