Sintesi e meccanismo d'azione dei farmaci antimalarici

Malaria nowadays remains one of the world’s greatest public health problems, especially in the developing countries. Despite numerous efforts expended to reduce its mortalityand morbidity,[1] malaria still threatens approximately 2 billion people worldwide, being responsible for almost two million deaths per year, mostly among young children in sub-Saharan Africa.[2] Among the four malaria species that infect humans, the parasite P. falciparum is universally considered the most aggressive. Particularly impressive is its ability in mutating forms in response to administered antiplasmodial treatment, rapidly giving rise to adaptation and resistance. 4-Aminoquinolines have recently been indicated to be an important class of chemotherapeutic agents for artemisinin based antimalarial combination therapy. A rapid, cheap, possibly clean and scalable route to 4-aminoquinolines endowed with multiple diversity is therefore badly needed. We here report microwave flash-heating chemistry to allow the efficient conversion of the available 4,7-dichloroquinoline into a library of aminoquinolines in high yields and purities, with no need for further purification steps and requiring very short reaction times. Some of the compounds in this library were active against chloroquine-sensitive and chloroquine-resistant parasite strains. [3].The combined use of conventional SNAr reaction and microwave irradiation is another approach developed, proved very valuable in producing derivatized triazines with tunable substituents. A library of 2,4,6-triamino-1,3,5-triazines was synthesized as both cycloguanil and chloroquine analogues, and were assessed in terms of in vitro antimalarial activity and toxicity. [4] [5]Some of the compounds in this library showed higher activity against CQ-resistant parasite strains and some exhibited CQ-sensitive activity in the same order as chloroquine itself. Another important parts of this thesis was study mechanism of action of peroxide compounds. We have demonstrated that a non metallic reagent such a leucomethylene blue is capable of efficiently activating a series of endoperoxides compounds including dioxanes, trioxanes and tetraoxanes. In principle our results suggest that is possible to hypothesize the existence of a unique common activator at the biological level inducing devastating effect toward parasite survival.The present work puts under discussion the assumption of the roles of iron and C center radical in the mechanism of action of antimalarial drugs based on artemisinin derivatives , and paves the way towards a new interpretation of the biological evidences so far.[7,8] We also demonstrated that In line with the enhancement of antimalarial activities of the current clinical artemisinins against parasites cultured under CO, the artemisinins are unaffected in vitro by carboxyhemoglobin (CO–Hb–FeII) or CO–heme–FeII, but are competitively decomposed by Hb–FeII or heme–FeII. In the latter case, the heme studies are greatly facilitated by solubilization of the heme in aqueous medium by use of arginine. None of the Hb species has an appreciable effect on artemisone, or on other aminoartemisinins, and antimalarial activities are either less affected or remain essentially unchanged against parasites cultured under standard microaerophilic conditions or under CO.The findings not only indicate that artemisinins do not require Hb–FeII or heme–FeII for promotion of antimalarial activity, but are also important in relation to the therapy of severe/complicated or cerebral malaria.[6] References [1] World Health Organization 2006: http://www.rollbackmalaria.org/malariaFAQ.html.[2] C. A. Swales, P. L. Chiodini, B. A. J. Bannister, Infect. 2007,54, 107–110; b) D. A. van Schalkwyk, T. J. Egan, Drug Resist.Updates 2006, 9, 211–226.[3] S. Melato, P. Coghi, N. Basilico, D. Prosperi, D. Monti, “Novel 4-Aminoquinolines through Microwave-Assisted SNAr Reactions: a Practical Route Antimalarial Agents”.Eur. J. Org. Chem. 2007, 6118–6123. [4] S.Melato, D.Prosperi, P.Coghi, N.Basilico, and D.Monti. “A Combinatorial Approach to 2,4,6-Trisubstituted Triazines with Potent Antimalarial Activity: Combining Conventional Synthesis and Microwave-Assistance” ChemMedChem,2008, 1 – 4.[5] Expert Meeting COST B22 "DRUG DISCOVERY & DEVELOPMENT FOR PARASITIC DISEASES", Modena, Italy, 19-20 February 2007.[6] Coghi, P. ; Basilico, N. ; Wing-Chi Chan ; Haynes K.R. ; Taramelli ;Monti D. Interaction of Artemisinins with Oxyhemoglobin Hb-FeII, Hb-FeII, CarboxyHb-FeII, Heme-FeII, and Carboxyheme FeII: Significance for Mode of Action and Implications for Therapy of Cerebral Malaria Chemmedchem .2009 [7] Richard K. Haynes, Kwan-Wing Cheu, Maggie Mei-Ki Tang, Min-Jiao Chen, Zu-Feng Guo, Zhi-Hong Guo, Paolo Coghi, Diego Monti Reactions of Antimalarial Peroxides with Each of Leucomethylene Blue and Dihydroflavins: Flavin Reductase and the Cofactor Model Exemplified.. Chemmedchem .2011[8] Richard K. Haynes,Wing-Chi Chan,Ho-Ning Wong, Ka-Yan Li, Wai-Keung Wu, Kit-Man Fan, Herman H. Y. Sung, Ian D. Williams, Davide Prosperi, Sergio Melato,Paolo Coghi, and Diego Monti Facile Oxidation of Leucomethylene Blue and Dihydroflavins by Artemisinins: Relationship with Flavoenzyme Function and Antimalarial Mechanism ofAction,ChemMedChem. 2010, 1-19