Unit:
Κατεύθυνση Φαρμακευτική ΧημείαLibrary of the School of Science
Author:
Kousioris Christoforos
Supervisors info:
Κολοκούρης Αντώνιος, Καθηγητής, Τμήμα Φαρμακευτικής, Ε.Κ.Π.Α.
Original Title:
Σύνθεση νέων αναλόγων του φαρμακομορίου SQ109 κατά παθογόνων μικροοργανισμών
Translated title:
Synthesis of new analogs of SQ109 against different pathogens
Summary:
Despite the introduction of effective treatment 40 years ago, tuberculosis remains high on the list of diseases causing death. In recent years, various research teams from around the world have focused on the development of drugs against Mycobacterium Tuberculosis (Mtb). A derivative of ethambutol, the SQ109 (N-geranyl-N'-(2-adamantyl) ethylene-1,2-diamine), has been shown to be more potent against Mtb in both in vitro and in vivo studies. Additionally, it has been found that the pharmacokinetic properties of SQ109 are superior compared to ethambutol. Studies have also shown that SQ109 is concentrated in high concentrations in the lungs, an organ of the human body where infection by Mycobacterium tuberculosis occurs. SQ109 has been found to be effective against both Mtb drug-sensitive strains (MIC=0.2-0.39μg/ml) and drug-resistant strains (MIC=0.2-0.78μg/ml) of Mtb in in vitro testing using clinically isolated bacteria. It is also noteworthy that SQ109 exhibited a distinct pharmacological profile in mice, while showing low bioavailability when administered orally to dogs and rodents. Phase I & II clinical trials of single and multiple doses have shown that SQ109 is safe and well-tolerated. Additionally, studies on hepatic cells have not shown toxicity.
Following the recent determination of the crystal structure of the transporter MmpL3 bound to SQ109, various research groups have proceeded to design molecules according to the experimental structure of MmpL3-SQ109 complex. Pharmacological data have also shown that benzyl and phenyl substitution at 2-position of adamantyl group led to potency of the SQ109 analogs against Mycobacterium Abscessus (Mab), malaria parasites, respectively, as well as against other pathogens. Interestingly, malaria and other pathogens which are inhibited by these SQ109 analogs do not bear the MmpL3 transporter. Based on these findings, we have designed and synthesized the 16 new analogs of SQ109, AK172-AK187 with substituted benzyl and phenyl groups at 2-position of adamantyl group, as part of an ongoing project for the development of SQ109 analogs as new anti-tubercular compounds or/and inhibirors of MAbs.
For the synthesis of these analogues, we used the low-cost geraniol as starting material to synthesize geranylamine, and then the necessary adamantyl amine derivatives that were converted to the aminoamide precursors. The latter compounds were reduced to the target diamines (SQ109 analogs) through LiAlH4/Me3SiCl under mild conditions. The molecules will be screened for their biological activity, against Mtb, M. Abs, malaria pathogens and other microorganisms that do not bear the MmpL3 transporter.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
Tuberculosis, Mycobacterium tuberculosis, Abscessus, Mycobacterium abscessus, MmpL3, TMM transporter, SQ109, Malaria, Antimalarial drugs, SQ109 analogos
File:
File access is restricted until 2027-05-21.
C.Kousioris_thesis.pdf
9 MB
File access is restricted until 2027-05-21.
