Investigation of novel malaria parasite enzyme (DHODH) inhibitors based on 4-amino-3-benzylcoumarin and 4-amino-8-azacoumarin scaffolds

Popular summery Malaria is a parasitic disease caused by five species of the genus Plasmodium (P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi) that affect humans. The most deadly form of Malaria is due to Plasmodium Falciparum and it is mostly spread in African areas. Almost half of the world population is at risk to contract the infection and every year malaria causes around half million deaths. Since an effective vaccine is still not available, malaria treatment relies on chemotherapeutics. It is important to find new targets and new drugs to fight the parasite because it has an inherent ability to develop resistance. Biological background and discussion Dihydroorotate dehydrogenase (DHODH) is the enzyme which catalyzes the fourth and rate limiting step of de novo pyrimidine biosynthesis. It is an interesting target because the parasites rely on this pathway to get pyrimidines, while mammalian cells can also get them from salvage of “used pyrimidines”; if DHODH is inhibited in the parasite (PfDHODH), it will not be able to synthesize DNA so its growth will be impeded. Furthermore, dissimilarities between the human and the parasite enzyme in the primary structure allow the design of species-specific inhibitors. Some 4-aminocoumarin derivatives earlier showed micro molar IC50. In this study we have synthesized new 4-amino-3-benzylcoumarin and 4-amino-8-azacoumarin derivatives, after calculations with molecular modeling, trying to optimize the interactions with the protein. Conclusion In the end we got nine derivatives which will be tested on the purified recombinant pfDHODH. These results will aid us towards further optimization of the coumarin scaffold.Abstract Plasmodium falciparum is the causative agent of the most serious and fatal malarial infections, and it has developed resistance to commonly employed chemotherapeutics. The de novo pyrimidine biosynthesis enzymes offer potential as targets for drug design, because, unlike the host, the parasite lacks pyrimidine salvage pathway.In search for new Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH) inhibitors as antimalarials, modifications of original 4-aminocoumarin scaffold were synthesized. 4-Amino-3-benzylcoumarin derivatives are inactive against the recombinant enzyme, while results for the 4-Amino-8-azacoumarin derivatives are still not available. These results demonstrate that position-3 in the coumarin scaffold cannot be expanse most likely due to the steric hindrance in the hydrophobic subsite of the binding site

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice