Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential beta-lactamase stable beta-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.Peer reviewe

Synthesis, Antibacterial and Antiribosomal Activity of the 3C-Aminoalkyl Modification in the Ribofuranosyl Ring of Apralogs (5-O-Ribofuranosyl Apramycins)

The synthesis and antiribosomal and antibacterial activity of both anomers of a novel apralog, 5-O-(5-amino-3-C-dimethylaminopropyl-D-ribofuranosyl)apramycin, are reported. Both anomers show excellent activity for the inhibition of bacterial ribosomes and that of MRSA and various wild-type Gram negative pathogens. The new compounds retain activity in the presence of the aminoglycoside phosphoryltransferase aminoglycoside modifying enzymes that act on the primary hydroxy group of typical 4,5-(2-deoxystreptamine)-type aminoglycoside and related apramycin derivatives. Unexpectedly, the two anomers have comparable activity both for the inhibition of bacterial ribosomes and of the various bacterial strains tested

mPGES-1 Inhibitoru dizains. Heteroaromātisko C–H saišu aminēšanas un oksidēšanas metožu izstrāde

Promocijas darbu veido pielietojamo pētījumu kopums, un darbs veltīts medicīnas ķīmijas problēmu risināšanai. Viens no promocijas darbā iekļautajiem pētījumiem vērsts uz jauna darbības mehānisma nesteroidālo pretiekaisuma līdzekļu izstrādi, par farmakoloģisko mērķi izmantojot mikrosomālo prostaglandīna sintāzi 1 (mPGES-1). mPGES-1 sintāzes inhibitoru dizainā līdztekus tradicionālajiem struktūras-aktivitātes likumsakarību pētījumiem izmantota arī datormodelēšana. Farmakoforā datormodeļa izstrāde paātrināja potenciālo pretiekaisuma līdzekļu izstrādi, un darbs ir vainagojies ar vairākiem augsti efektīviem līdersavienojumiem tālākai virzībai in vivo pētījumos. Intelektuālais ieguldījums mPGES-1 inhibitoru izstrādē aizsargāts ar 4 starptautiskajiem patentiem. Otrs promocijas darbā iekļautais pētījums vērsts uz jaunu organiskās sintēzes metožu izstrādi, kuras būtu piemērotas potenciālo zāļvielu struktūras modifikācijai sintēzes shēmas pēdējās stadijās. Promocijas darbs sagatavots kā tematiski vienotu zinātnisko publikāciju un patentu kopums, un kopsavilkums sniedz paveiktā darba kopskatu

Indirect C—H Azidation of Heterocycles via Copper-Catalyzed Regioselective Fragmentation of Unsymmetrical λ3-Iodanes

A convenient approach to the synthesis of heteroaryl-substituted azides via C—H activation is followed by direct 1,3-dipolar Cu-catalyzed cycloaddition with terminal alkynes or by direct Cu-catalyzed reductive fragmentation to amino compounds

Iodonium Salts Are Key Intermediates in Pd-Catalyzed Acetoxylation of Pyrroles

The reaction of pyrroles and indoles with Ph-I(O-Ac)2 proceeds via initial regioselective formation of iodonium acetate intermediates which are converted into acetoxy derivatives

Copper-Catalyzed Intermolecular C–H Amination of (Hetero)arenes via Transient Unsymmetrical λ3-Iodanes

A one-pot two-step method for intermolecular C–H amination of electron-rich heteroarenes and arenes has been developed. The approach is based on a room-temperature copper-catalyzed regioselective reaction of the in situ formed unsymmetrical (hetero)aryl-λ3-iodanes with a wide range of primary and secondary aliphatic amines and anilines

Copper-Catalyzed Intermolecular C—H Amination of (Hetero)arenes via Transient Unsymmetrical λ3-Iodanes

A one-pot two-step method for intermolecular C–H amination of electron-rich heteroarenes and arenes has been developed. The approach is based on a room-temperature copper-catalyzed regioselective reaction of the in situ formed unsymmetrical (hetero)aryl-λ3-iodanes with a wide range of primary and secondary aliphatic amines and anilines

Indirect C–H Azidation of Heterocycles via Copper-Catalyzed Regioselective Fragmentation of Unsymmetrical λ3-Iodanes

A C–H bond of electron-rich heterocycles is transformed into a C–N bond in a reaction sequence comprising the formation of heteroaryl(phenyl)iodonium azides and their in situ regioselective fragmentation to heteroaryl azides. A Cu(I) catalyst ensures complete regiocontrol in the fragmentation step and catalyzes the subsequent 1,3-dipolar cycloaddition of the formed azido heterocycles with acetylenes. The heteroaryl azides can also be conveniently reduced to heteroarylamines by aqueous ammonium sulfide. The overall C–H to C–N transformation is a mild and operationally simple one-pot sequential multistep process