Examination of correlation between chemical structure, physicochemical properties and retention parameters and antimicrobial activity of newly synthesized derivatives of propiophenone

Pojava rezistencije mikroorganizama na postojeće antimikrobne lekove predstavlja globalni kliničko-terapijski problem i usmerava interes istraživača ka novim ciljnim mestima delovanja budućih antimikrobnih lekova. Modulatori jonskih kanala poslednjih decenija postaju sve važniji ciljni molekuli u medicinskoj hemiji jer jonski kanali, kao sastavni deo svake žive ćelije, igraju ključnu ulogu u njenoj deobi, proliferaciji, ekscitaciji i apoptozi. Ispitivanja su pokazala da aktivnost modulatora jonskih kanala, između ostalih, imaju i jedinjenja propiofenonske strukture (halkoni i propafenonski derivati). U ovoj doktorskoj disertaciji opisana je sinteza šest halkonskih jedinjenja Claisen-Schmidtovom aldolnom kondenzacijom iz 2-hidroksiacetofenona i mono- ili disupstituisanih benzaldehida. Struktura sintetisanih jedinjenja potvrđena je spektroskopskim metodama, snimanjem IR i NMR spektara. Predmet daljeg istraživanja obuhvata, pored novosintetisanih halkona, 6 propafenonskih derivata, propafenon i 6 halkonskih derivata sintetisanih u okviru ranijih istraživanja. Primenom RP HPLC metode, eksperimentalno su određeni hromatografski parametri tr i t0, faktor kapaciteta k i izračunat parametar lipofilnosti logkw za svih 12 halkonskih derivata. Na osnovu korelacije logkW vrednosti i LogP standardnih supstanci izračunate su vrednosti Log P sintetisanih jedinjenja. Primenom modifikovane metode mućkanja („shake flask“) određen je distribucioni koeficijent propafenona i šest propafenonskih derivata. Eksperimentalno dobijeni podaci Log P i Log D su korelisani sa vrednostima dobijenim korišćenjem različitih programskih paketa. Ispitana je antimikrobna aktivnost derivata halkona i propafenona na: osam standardnih laboratorijskih sojeva mikroorganizama (6 sojeva Gram pozitivnih bakterija i dva soja Gram negativnih bakterija), 7 izolovanih bolničkih i vanbolničkih MRSA sojeva i 11 sojeva kliničkih izolata P. Aeruginosa. Eksperimenti su pokazali da jedinjenja propafenonske grupe pokazuju bolju antimikrobnu aktivnost u odnosu na halkone. Da bi se odredio deo strukture odgovoran za antimikrobno dejstvo halkona i uspostavila korelacija između strukture i antimikrobne aktivnosti izvedena je QSAR analiza. Za izvođenje studije odabrani su deskriptori koji opisuju vodonik donorske osobine funkcionalnih grupa i deskriptori koji definišu kiselost fenolske grupe...Antimicrobial resistance is a global problem in clinical treatment and it directs researchers’ attention to new target activity sites of future antimicrobials. Over the past decades, ion channel modulators have become increasingly important target molecules in medical chemistry since ion channels, being an integral part of every living cell, play a crucial role in cell division, proliferation, excitation and apoptosis. Studies have shown that compounds with propiophenone structure (chalcones and propafenone derivatives), among others, have the activity of ion channel modulators. This doctoral thesis describes the synthesis of six chalcone compounds by Claisen-Schmidt aldol condensation from 2-hydroxyacetophenone and mono- or disubstituted benzaldehydes. The structure of synthetized compounds was confirmed with spectroscopic methods, by recording IR and NMR specters. Subject of further research includes, besides newly synthetized chalcones, 6 propafenone derivatives, propafenone and 6 chalcone derivatives synthetized within earlier research. Application of RP HPLC method enabled the experimental determination of chromatographic parameters tr and t0, capacity factor k and calculation of lipophilicity parameter Log kw for all 12 chalcone derivatives. Log P values for synthetized compounds were calculated on the basis of the correlation between Log kw value and Log P of standard substances. The distribution coefficient of propafenone and six propafenone derivatives was determined by applying the modified shakeflask method. Experimentally obtained Log P and Log D data were correlated with values obtained through using different software packages. The antimicrobial activity of chalcone derivatives and propafenone derivatives was tested on: eight standard laboratory microbial strains (6 strains of Gram positive bacteria and two strains of Gram negative bacteria), 7 isolated hospital and community MRSA strains and 11 strains of clinical isolates of P. aeruginosa. The experiments showed that compounds from propafenone group show better antimicrobial activity in comparison to chalcones. QSAR analysis was performed in order to determine the part of the structure responsible for antimicrobial activity of chalcones and to establish the correlation between the structure and the antimicrobial activity..