Guanidine based derivatives as potential anti-infective agents: Tackling protozoal diseases and Mycobacterium tuberculosis
Citation:
Rahman, Adeyemi, Guanidine based derivatives as potential anti-infective agents: Tackling protozoal diseases and Mycobacterium tuberculosis, Trinity College Dublin.School of Chemistry, 2022Download Item:
Abstract:
Infectious diseases caused by microorganisms of the genus Trypanosoma (Human African Trypanomiasis-HAT), Leishmania (Leishmaniasis), Plasmodium (Malaria) and Mycobacterium (Tuberculosis) cause some of the deadliest human infections in the world. According to the WHO, in 2019, there were 229 million cases of malaria and 10 million cases of TB with death rates of 409,000 and 1.3 million, respectively. In addition, in sub-Saharan Africa, HAT has an overwhelming risk population of 65 million people with 700,000 - 1 million annual cases of leishmaniasis. Still no definitive cure has been found for these infectious diseases due to factors such as poor patient compliance, severe side effects and multi-drug resistance. Hence, there is a need for the development of new drug therapies.
Compounds that bind into the DNA minor groove have proven to be very promising for the treatment of parasitic diseases. Accordingly, DNA minor groove binders (MGBs) such as pentamidine and distamycin-A have been used to treat malaria and HAT. However, drug resistance and the associated side effects present major drawbacks for the use of these agents. During the last 20 years, Prof. Rozas group has prepared a variety of guanidine-like derivatives that are strong MGBs. More recently, very good antimalarial activity was obtained from a family aminoalkyl derivatives of di-aryl mono guanidines. However, it has been hypothesised that two possible mechanisms of action could be behind this activity (i.e. as MGBs or as inhibitors of the parasite s dihydrofolate reductase DHFR). Hence, we investigated this further and prepared new analogues which displayed improved DNA binding and anti-protozoal activity.
Secondly, based on a series of piperazine and piperidine-linked di-aryl amidines that were recently shown to be active against Mycobacterium tuberculosis, structurally similar MGBs previously synthesised by the Rozas group were tested and showed very good anti-mycobacterial activity. As the DNA binding affinity of the active compounds from this series did not correlate with the anti-mycobacterial activity, various computational and biological studies were performed to identify Enoyl ACP reductase (InhA) as a possible target. Furthermore, using a rational design approach novel guanidine-based derivatives were produced that showed better anti-mycobacterial activity than previous in-house compounds and the known first-line anti-tubercular agent, rifampicin.
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Irish Research Council (IRC)
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:RAHMANADDescription:
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Author: Rahman, Adeyemi
Advisor:
Rozas, IsabelPublisher:
Trinity College Dublin. School of Chemistry. Discipline of ChemistryType of material:
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