Press Release | Targeting kinetoplastid and apicomplexan thymidylate biosynthesis as antiprotozoal strategy


Kinetoplastid and apicomplexan parasites include protozoans which are responsible for human diseases, and cause a serious impact on human health and the socioeconomic growth of developing countries. Chemotherapy is the main option to control these pathogenic organisms. The organisms’ nuclear metabolism is considered a promising area for the provision of antimicrobial therapeutic targets.

The viability of parasitic protozoa is severely diminished by imparing thymidylate (dTMP) biosynthesis. The absence of enzymatic activities which are specifically involved in the formation of dTMP (e.g. dUTPase, thymidylate synthase, dihydrofolate reductase or thymidine kinase) results in decreased de-oxythymidine triphosphate (dTTP) levels and the so-called thymineless death.

In this process, the ratio of deoxyuridine triphosphate (dUTP) as compared to dTTP in the cellular nucleotide pool has a crucial role. A high dUTP/dTTP ratio leads to uracil misincorporation into DNA, which then leads to the activation of DNA repair pathways, DNA fragmentation and eventually cell death.

For the identification and development of drugs, the essential character of dTMP synthesis has stimulated interest. These agents specifically block the biochemical steps involved in thymine nucleotide formation.

The review covers available literature related to drug discovery of agents targeting thymidylate biosynthesis in kinetoplastid (genera Trypanosoma and Leishmania) and apicomplexan (Plasmodium spp and Toxoplasma gondii) protozoans.The most relevant findings concerning novel inhibitory molecules with anti-parasitic activity against these human pathogens are presented in the review. Read full press release to find out more at:




This article by Dr. Dolores Gonzalez Pacanowska et al. is published in Current Medicinal Chemistry, 2018. The article is available from the following link:


Most Accessed Articles | Synthesis and Biological Evaluation of PF-543 Derivative


Journal Name: Letters in Organic Chemistry

Author(s): Seon Woong Kim, Taeho Lee, Joo-Youn Lee, Sanghee Kim, Hee-Sook Jun, Eun-Young Park*, Dong Jae Baek*.



PF-543 has been known as a substance that strongly inhibits SK1. However, it also exhibits antineoplastic activity that is lower than other inhibitors of SK1. In this study, we compared PF-543 and synthesized a newly designed derivative of PF-543 (compound 2) in which two aromatic structures were connected in para-form. The synthesized derivative showed inhibitory effect on SK1, similar to that of PF-543. However, it was more cytotoxic to HT29, AGS, and PC3 cells than PF-543. We also carried out a docking study for SK1 and demonstrated that the synthesized derivative showed interaction with SK1 similar to PF-543. Results obtained from this study suggest that the structure of compound 2 may be well substituted for the structure of PF-543 in terms of biological activity, providing us important structural information for the design of new derivatives of PF-543. Read out full article here:


EDITOR’S CHOICE – Inhibitory Effects of 1,4-disubstituted Thiosemicarbazide Derivatives on Streptococcus mutans and Streptococcus sanguinis Mono-species Biofilms

Journal: Letters in Drug Design & Discovery

Author(s): Malgorzata Miazga-Karska, Maciej Wos, Agnieszka A. Kaczor, Anna Pachuta-Stec, Grazyna Ginalska, Monika Pitucha*

Graphical Abstract:



Background: Bacterial biofilms are a cause of a number of infections and are associated with specific drug resistance. In particular, dental biofilm can consist of up to 100 bacterial species and may result in the diseases in the teeth and the surrounding tissues, including dental caries and periodontal diseases. Moreover, pathogens from the dental biofilm can migrate to other organs and lead to systemic diseases. Thus, it is important to search for inhibitors of dental biofilm formation. The series of 1,4-disubstitued thiosemicarbazide derivatives were evaluated for their ability to inhibit mono-species Streptococcus mutans or Streptococcus sanguinis biofilm formation.

Methods: The Minimum Biofilm Inhibitory Concentration (MBIC) is defined as the lowest concentration of an antimicrobial agent required to inhibit the formation of biofilm. MBIC was determined spectrophotometrically. Molecular docking was performed using Glide from the Schrödinger suite of software. The grid file was generated indicating acarbose as a reference ligand. The compounds were modeled using LigPrep protocol from the Schrödinger suite of software. Molecular docking was performed using the SP (standard precision) protocol of Glide. Molecular dynamics studies of ligand-receptor complexes was performed using Desmond v.

Results: The series of 1,4-disubstituted thiosemicarbazide derivatives were synthesized and investigated for their ability to inhibit S. mutans or S. sanguinis biofilm. The most active compounds caused inhibition of S. sanguinis and S. mutans biofilm formation in the concentration of 7.81 µg/ml- 62.5 µg/ml. We showed, that growth of S. mutans and S. sanguinis biofilm was faster and higher in presence of sucrose. Additionally it was harder to inhibit the growth of biofilm in BHIbroth with the presence of sucrose, than the biofilm growing in BHI without sucrose. It seems that colonization by tested caries bacteria depends on sucrose content in medium. Based on above in vitro anti-biofilm data, we postulated that the mechanism of antibacterial activity of the investigated compounds might be connected with the inhibition of mono-species bacteria biofilm formation. In order to demonstrate that the investigated compounds may inhibit the enzyme glucansucrase and thus, biofilm formation, we performed molecular docking and molecular dynamics of the studied compounds to glucansucrase crystal structure. The obtained results reveal that the thiosemicarbazide derivatives can be used as potential inhibitors of dental biofilm formation, acting possibly through inhibition of glucansucrase.

Conclusion: In this study we showed that some of tested thiosemicarbazide derivatives can be used as potential inhibitors for mono-species cultures of S. mutans or S. sanguinis biofilm. The possible blocking mechanism of mono-species biofilm formation was proposed via molecular modelling technique. The data suggested that this mechanism may involve the glucansucrase inhibition as it was demonstrated that tested derivatives occupy the same binding pocket in this enzyme as acarbose, commonly known inhibitor of glucosylotransferases. Therefore, it is possible that tested derivatives could be used in prevention of dental caries.

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Podcast: Tip60: Main functions and its inhibitors

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