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Cooperability
| Project leader |
MAKSIĆ MIRJANA |
| Project co-leader: |
Tomislav Friščić |
| Administering organization: |
Ruđer Bošković Institute
Bijenička cesta 54
HR-10002 Zagreb
Croatia |
| Partner Institution/Company: |
Department of Chemistry, University of Cambridge |
| Grant type: |
1B |
| Project title: |
Mechanochemistry for the clean and efficient metal-catalysed synthesis of pharmaceutical targets and the study of their molecular recognition |
| Project summary: |
The proposed research intends to develop a catalytic and environmentally-friendly approach for the rapid and simple construction of guanidine derivatives. Guanidines are of considerable pharmaceutical importance and some of their pharmaceutically interesting derivatives are generally difficult to construct using conventional synthetic methods. Application of mechanochemical methodologies allows the development of rapid and inherently low-solvent or even solvent-free synthetic methods, as previously demonstrated for pharmaceutical cocrystals and functional metal-organic materials. The recent discovery of catalytic effects in organic mechanosynthesis offers a suitable means to extend this efficiency, speed and versatility of mechanosynthesis into the broad field of organic synthesis. The proposed collaboration will take advantage of this opportunity and develop an environmentally-friendly synthetic approach of guanidine derivatives using Lewis acid catalysis. In order to achieve an efficient and green synthesis of guanidines, we will combine the research expertise of the Croatian group in guanidine chemistry with the expertise of the Cambridge team in the development of new approaches to conduct environmentally-friendly synthesis. In particular, mechanochemical methods, or reactions induced by mechanical force, that are already being developed in Cambridge, will be used to synthesise guanidines via Lewis acid-based synthetic pathways and screen for their molecular recognition (already being investigated in Zagreb, Croatia). Additionally, mechanochemistry will be used to screen for the binding of small molecules to guanidine derivatives. This will allow the study of their molecular recognition, important for understanding biological activity, in the absence of solvent and solubility effects that are inherent to all methodologies for studying molecular recognition to date. Besides the benefit of contributing to the understanding of the mechanism of interaction of guanidine-based drugs with other molecules, the proposed research will also generate a variety of new solid-state forms of these pharmaceutical compounds in the form of pharmaceutical cocrystals. The ability to conduct mechanochemical processes in a high-throughput fashion will be an additional benefit that will enable the rapid optimisation of mechanochemical reaction conditions, screening for different types of Lewis acid catalysts, and construction of cocrystals. As Lewis acid catalysis is broadly applied across organic synthesis, we envisage that the realisation of this collaboration will open a vast number of new research directions in environmentally-friendly synthesis. |
| Hrvatski sažetak: |
U okviru predloženog projekta razvit će se katalitička i ekološki prihvatljiva metoda priprave novih derivata gvanidina i ispitati mehanizam njihovog međudjelovanja s malim molekulama. Gvanidinski spojevi imaju široku primjenu u farmaceutskoj industriji, no njihova priprava primjenom konvencionalnih sintetskih metoda je u pravilu energetski zahtjevna i ekološki neučinkovita. Te probleme pokušat ćemo riješiti primjenom nedavno razvijenih mehanokemijskih metoda koje omogućuju pripravu kompleksnih spojeva uz male količine ili u odsustvu otapala. Vrijednost navedenih pristupa potvrđena je novijim istraživanjima i posebno dolazi do izražaja u sintezi farmaceutskih kokristala i organometalnih materijala. Posebno učinkovitom pokazala se je primjena katalizatora u mehanokemijskoj sintezi, čime je otvoren put daljnjem razvoju ove ekološki prihvatljive metode u sintezi širokog dijapazona organskih spojeva. Polazeći od te činjenice, u okviru ovog projekta istražit ćemo mogućnost primjene mehanokemijskog pristupa u razvoju ekološki prihvatljive metode sinteze odabranih gvanidinskih spojeva. U tu svrhu kombinirat ćemo dosadašnje iskustvo i ekspertizu domaćeg istraživačkog tima u gvanidinskoj kemiji i ekspertizu suradne grupe sa Sveučilišta u Cambridgeu u razvoju mehanokemijskih metoda. Osnovni cilj istraživanja je sinteza novih gvanidinskih spojeva. Pored toga, primjenjujući mehanokemijsku metodu ispitat će se vezanje malih organskih molekula na derivate gvanidina što će omogućiti studij molekulskog prepoznavanja, važnog za razumijevanje njihove biološke učinkovitosti u odsustvu otapala. Osim doprinosa razumijevanju mehanizama međudjelovanja gvanidinskih lijekova s drugim molekulama, predloženi projekt će rezultirati novim formama farmaceutskih pripravaka u čvrstom stanju u obliku kokristala. Dodatna vrijednost postići će se provedbom mehanokemijskih reakcija u uvjetima visoke propusnosti (high throughput), što će omogućiti brzo i učinkovito optimiranje reakcijskih uvjeta, pouzdanu i učinkovitu procjenu katalitičke učinkovitosti Lewisovih kiselina, kao i pripravu molekulskih kokristala. S obzirom da je kataliza Lewisovim kiselinama vrlo raširena u organskoj sintezi, planirana suradnja dviju iskusnih istraživačkih grupa na problematici predloženog projekta otvorit će nove pravce istraživanja u ekološki prihvatljivoj sintezi kemijskih spojeva, što je jedan od temeljnih ciljeva "zelene kemije". |
| Amount requested from UKF: |
819.914,43 HRK |
| Amount of matching funding: |
248.740,00 HRK |
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