Optimized synthesis of indole carboxylate metallo-beta-lactamase inhibitor EBL-3183

A new synthetic route for the preparation of the metallo-β-lactamase inhibitor pre-candidate EBL-3183 was developed and carried out on a kilogram scale. The described process starts from a commercially available indole-2-carboxylate and employs an Ellman auxiliary approach coupled with ruthenium-catalyzed stereoselective reduction for the introduction of chirality. The key spirocyclic cyclobutane motif was assembled utilizing an epoxide building block, which was conveniently obtained in diastereomerically pure form. The amount and quality of the prepared final target EBL-3183 were sufficient for the preclinical studies

Synthesis of cyclic boronates as potential b-lactamase inhibitors

Potenciālu β-laktamāžu inhibitoru sintēze ciklisko borskābju esteru klasē. Parkova A., zinātniskais vadītājs Dr. chem. Trapencieris P. Promocijas darbs, 156 lappuses, 63 attēli, 6 tabulas, 94 literatūras avoti, 3 pielikumi. Latviešu valodā. Darbā apkopota literatūra par β-laktamāžu lomu antibiotiku rezistences veicināšanā, par pašlaik zināmiem β-laktamāžu inhibitoriem un par ciklisku borskābju pusesteru iegūšanas metodēm. Pētījuma ietvaros izstrādātas metodes ciklisko boronātu iegūšanai un sintezēti viens biciklisks un seši tricikliski borskābju pusesteri. Veikta sintezēto savienojumu β-laktamāžu inhibēšanas aktivitātes datu analīze un kristalogrāfijas datu analīze, nosakot to saistīšanās veidu enzīmu aktīvajā centrā. Sintezētie savienojumi uzrādīja inhibitoro aktivitāti gan pret serīna β-laktamāžu, gan pret metāl-β-laktamāžu enzīmiem. Atslēgvārdi: ANTIBIOTIKU REZISTENCE, SERĪNA β-LAKTAMĀZES, METĀL-β-LAKTAMĀZES, CIKLISKI BORSKĀBJU PUSESTERI.Synthesis of cyclic boronates as potential β-lactamase inhibitors. Parkova A., supervisor Dr. chem. Trapencieris P. Doctoral thesis, 156 pages, 63 figures, 6 tables, 94 literature references, 3 appendices. In Latvian. Doctoral thesis summarizes the literature review about the role of β-lactamases in rise of antibiotic resistance, known-to-date β-lactamase inhibitors and about synthesis of cyclic boronates. Procedures for the synthesis of cyclic boronates have been developed. One bicyclic and six tricyclic boronates were synthesized. The inhibititory activity against β-lactamases of synthesized compounds was analyzed. Analysis of crystallographic data of compounds was made, allowing to identify their binding modes in the active site of an enzyme. Synthesized compounds have shown inhibitory activity against serine β-lactamase and metallo-β-lactamase enzymes. Keywords: ANTIBIOTIC RESISTANCE, SERINE β-LACTAMASES, METALLO-β-LACTAMASES, CYCLIC BORONATE

Cleavage of coumarins with oxygen and nitrogen nucleophiles

Kumarīnu šķelšanas reakcijas ar skābekļa un slāpekļa nuklofiliem. Parkova A., zinātniskie vadītāji Dr.chem. Trapencieris P., Mg.sc.ing. Vendiņa I. Bakalaura darbs, 42 lappuses, 18 attēli, 7 tabulas, 32 literatūras avoti. Latviešu valodā. KUMARĪNI, KANĒĻSKĀBES ATVASINĀJUMI, SULFAMĀTI, SULFAMĪDI Darbā tika veiktas kumarīnu cikla šķelšanas reakcijas ar skābekļa un slāpekļa nukleofiliem, lai iegūtu o-hidroksikanēļskābes esterus un amīdus. Izmantojot von Pehmana reakciju tika sintezēti kumarīnu atvasinājumi. Savienojumu struktūra tika pierādīta ar 1H-KMR spektroskopiju un LC-MS. Literatūras apskatā apkopota informācija par kumarīna cikla šķelšanas reakcijām.Cleavage of coumarins with oxygen and nitrogen nucleophiles. Parkova A., Supervisors Dr.chem., Trapencieris P., Mg.sc.ing. Vendiņa I. Bachelor’s thesis, 42 pages, 18 figures, 7 tables, 32 literature references. In Latvian. COUMARINS, CINNAMIC ADIC DERIVATIVES, SUFAMATES, SULFAMIDES Coumarin ring cleavage reactions with oxygen and nitrogen nucleophiles were performed to obtain o-cinnamic acid esters and amides. Synthesis of coumarin derivatives were performed by von Pechmann reaction. Structures are confirmed by 1H-NMR and LC-MS. Literature review summarizes information on coumarin ring cleavage reactions