No abstract

A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC50 values of 7.5 and 2.69 µM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery.

The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.

This study was aimed to develop novel compounds to combat antimicrobial resistance, which is one of the biggest threats to global health. For this purpose, compounds bearing triazolopyrimidinone ring and N-(methylnaphthalene)piperazine (NMP) hybrids were designed and synthesized. Ten new compounds were synthesized and after proving their chemical structures were tested for antimicrobial activity using disk diffusion and microdilution method against Gram-negative bacterial strains (Escherichia coli and Pseudomonas aeruginosa), Gram-positive bacterial strains (Staphylococcus aureus and Enterococcus faecalis) and fungal strains (Candida albicans and Candida parapsilosis). Antibiofilm activity and ethidium bromide accumulation assay results were also determined for the selected compounds. Among the tested compounds, hybrid compound H5 showed promising activity against E. faecalis with 16-fold potency compared to its precursor, TP5. Additionally, it has statistically significant inhibition of biofilm production at 10 µg/ml dose against E. coli and P. aeruginosa and a decreasing effect on the relative accumulation of ethidium bromide in P. aeruginosa at 100 µg/ml dose (85.07%) after 30 min. 2,5-disubstitued[1,2,4]triazolo[1,5-a]pyrimidinone heterocyclic core structure and its antimicrobial activity are reported to the literature for the first time in this study.

Four different Mannich base derivatives containing an aromatic/heteroaromatic propanone structure (C1 (3-(dimethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride); C2 (3-morpholino-1-(pyridin-3-yl)propan-1-one hy-propan-1-one hydrochloride)) were earlier synthesized and characterized with 1 H NMR, 13 C NMR, MS, and elemental analysis. The interaction of these compounds with fish sperm double stranded DNA (fs-dsDNA) was investigated by using differential pulse voltammetry (DPV) in connection with a disposable pencil graphite electrode (PGE). After the interaction procedure, there was a meaningful decrease in the oxidation signal of the electroactive DNA base guanine due to possible intercalation and/or alkylation mechanism between these Mannich base derivatives and DNA. The features of this electrochemical assay were discussed in comparison to previous reports related to DNA targeted agents/drug candidates in the literature.