Nesteroidni protuupalni lijekovi (NSAID) imaju dugu kliničku primjenu u liječenju mnogih upalnih stanja kao što su različiti oblici artritisa. NSAID-i inhibiraju sintezu prostaglandina inhibirajući enzime ciklooksigenazu-1 (COX-1) i ciklooksigenazu-2 (COX-2). COX-1 je konstitutivno prisutan enzim odgovoran za regulaciju normalnih fizioloških procesa, dok je COX-2 enzim fakultativno prisutan u stanjima upale, uključen u patološkim procesima u organizmu. Međutim, ovi lijekovi pokazuju različite gastrointestinalne i kardiovaskularne nuspojave. Makrolidi su velika skupina različitih spojeva što se tiče njihove kemije i djelovanja, a dolaze kao prirodni bakterijski metaboliti ili kao polusintetski derivati prirodnih spojeva. Pokazalo se da se neki makrolidi, posebno azitromicin, nakupljaju u upalnim stanicama. Danas postoje dokazi da pojedini makrolidi, koji se već niz godina primjenuju u kliničkoj praksi kao antibiotici, pokazuju i protuupalno djelovanje. Cilj ovog istraživanja bio je pripraviti nove konjugate azitromicina i azitromicinu sličnih makrolida s NSAID-ima koji pokazuju protuupalni učinak kako bi se unaprijedilo liječenje različitih upalnih bolesti. Konjugati su pripravljeni koristeći dvostruku aktivaciju u postupku priprave esterske ili amidne veze. Korišteni su neselektivni NSAID-i (klasični) poput indometacina, ibuprofena i flurbiprofena te selektivni COX-2 NSAIDi poput celekoksiba i valdekoksiba. Također su kao makrolide podjedinice korišteni azitromicin, 9-deokso-9aaza- 9a-homoeritromicin A, eritromicin A, klaritromicin i telitromicin. NSAID-i su vezani na položajima 9a, 9 (oksima), 11, 3’-N, 4” i 4“-O- makrocikličkog prstena. Prva tri mjesta vezanja nalaze se na aglikonskom prstenu, a sljedeća tri na šećerima, desozaminu, odnosno kladinozi. Također su pripravljeni i konjugati s dekladinozilnim makrolidima kao i aglikonski konjugati. Sintetizirano je više od 90 konjugata NSAID-a i makrolida. Biološka aktivnost pripravljenih spojeva proučena je na temelju in vitro ispitivanja inhibicije enzima COX-1 i COX-2 te inhibicije produkcije TNF-α (čimbenik nekroze tumora α). Pojedini konjugati pokazuju selektivnu inhibiciju COX-2 enzima uz dodatnu inhibiciju produkcije TNF-α. Većina sintetiziranih konjugata značajno je inhibirala produkciju TNF-α. Značajna inhibicija enzima COX-2 zabilježena je u konjugata u kojima je NSAID vezan preko 9a-dušika na makrolidnu podjedinicu koja ima oba šećera ili na odgovarajući aglikonski analog, te kod konjugata s telitromicinom gdje je NSAID vezan na položaju 11. Konjugati u kojima je NSAID-na podjedinica vezana na položaju 9a pokazuju najbolji biološki učinak. Nonsteroidal anti-inflammatory drugs (NSAIDs) have a long clinical use for the treatment of various inflammatory diseases like different forms of arthritis. NSAIDs inhibit prostaglandin synthesis by inhibition of enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 was described as “constutive” controlling normal homeostasis, and COX-2 as “inflammatory”, involved in pathological prosses in organism. However, these drugs are not devoided of serious side effects affecting gastrointestinal and cardiovascular system. Macrolides form a large group of divergent compounds regarding their chemistry and function, wich occur as natural bacterial metabolites, or as semisyntetic derivatives of natural compounds. Some macrolides, especially azithromycin, have been shown to accumulate within inflammatory cells. Today, there is a clear evidence that some macrolides, used for many years in clinical practice as antibiotics, also show antiinflammatory activity. The aim of this study was to prepare new conjugates of azithromycin and azithromycin-like macrolide scaffolds with NSAIDs that possess anti-inflammatory activity in order to improve the treatment of different inflammatory diseases. Conjugates have been prepared using double activation in the esters or amide coupling procedures. Non-selective NSAIDs (classical) like indomethacine, ibuprofen, flurbiprofen and selective COX-2 NSAIDs like celecoxib and valdecoxib are used. For macrolide subunits, azithromycin, 9-deoxo-9a-aza-9ahomoerythromycin A, erythromycin A, clarithromycin and telithromycin are used. NSAIDs were linked at the positions 9a, 9 (oxime), 11, 3’-N, 4“- and 4”-O- of macrocyclic scaffold. The first three coupling sites are at the aglycon part of the molecule, the later three on the sugar moieties desosamin and cladinose, respectively. Also, conjugates of decladinosyl macrolides have been prepared, as well as macrolide aglycon conjugates. More than 90 conjugates of NSAID and macrolide have been synthesized. Biological activity of the prepared compounds was studied on the basis of in vitro tests of COX-1 and COX-2 inhibition and inhibition of TNF-α (tumor necrosis factor α) production. Some conjugates show selectivity towards COX-2 enzyme and they additionally inbibit TNF-α production. Most of the synthesized conjugates significantly inhibited TNF-α production. Significant inhibition of COX-2 was observed for conjugates with NSAID linked through 9a-nitrogen of macrolide subunit having both sugars or for corresponding aglycon analogues, as well as with telithromycin conjugate where NSAID is linked through position 11. Conjugates having NSAID subunit linked at 9a position showed the highest biological activity.