Kombinirani in silico i in vitro pristup pronalaženju spojeva s mogućim ljekovitim djelovanjem

The purpose of High Throughput Screening (HTS) in pharmaceutical industry is to identify, as soon as possible, compounds that are good starting points for successful new drug development process. Experts from this area study the chemical structures of so called »hit« compounds that have been found to interact with the target protein, interfere with proliferation of different types of cells or stop bacterial or fungal growth. Hypotheses to design related structures with improved biological properties are than builded. Each idea is then tested by the iterative synthesis and testing of novel compounds in various biological assays, searching for hits with better properties and defining useful and promising »lead« molecules. In parallel, molecular modeling and chemoinformatics experts can increase efficiency and decrease experimental costs by using different database filtering methods. In such a way, hits from HTS may be assessed before committing significant resource for chemical optimization. Joint efforts of these HTS experimental and modeling groups are the best way to speed up the process of finding a new useful hits and promising leads.Svrha HTS-a u farmaceutskoj industriji je identifikacija spojeva koji mogu poslužiti kao dobre polazne molekule u procesa razvoja lijeka iz novih kemijskih entiteta. Proučavanjem kemijske strukture takvih »hit« spojeva koji interagiraju s proteinom – metom, stručnjaci iz tog područja tragaju za strukturama poboljšanih bioloških svojstava. Svaka se ideja kasnije provjerava iterativnim postupkom sinteze i testiranja novih spojeva uporabom različitih metoda bioloških probira, kako bi se došlo do hitova s boljim svojstvima i do uporabivih i obećavajućih »lead« molekula. Istovremeno, molekularno modeliranje i kemoinformatika mogu povećati učinkovitosti i smanjenja troškova eksperimenata uporabom različitih metoda filtriranja baza spojeva. Na taj način, »hitovi« iz HTS-a mogu virtualno biti procijenjeni prije značajnog ulaganja resursa u kemijsku optimizaciju. Udruženi napori eksperimentalnih HTS grupa i grupa koje se bave molekularnim modeliranjem najbolji su način ubrzavanja procesa pronalaženja novih, uporabivih »hitova« i obećavajućih »leadova«

Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis