In the present work, new Co(II) complexes were synthesized from mesogenic aromatic amino acids based Schiff base ligands, HL1 [Methyl 2-((2-hydroxy-4-(tetradecyloxy)benzylidene)amino)-3-phenylpropanoate] and HL2 [Methyl 2-((2-hydroxy-4-(tetradecyloxy)benzylidene)amino)-3-(1H-indol-2-yl)propanoate]. The compounds were thoroughly characterised using different elemental, thermogravimetric and spectroscopic studies. The in-vitro antileishmanial efficacy of the compounds against Leishmania donovani was evaluated by MTT assay and the antioxidant activity was performed by Mensor\'s method. The cell viability percentage and IC50 values for both the antileishmanial and antioxidant studies revealed that the cobalt(II) complexes are comparable to the standard, amphotericin B and ascorbic acid, respectively, signifying the potential applications of the biogenic compounds. The CT-DNA interaction experiments study using photophysical techniques indicated that the cobalt(II) complexes exhibited pronounced interactions as compared to the parent ligand. The parent ligands were found to possess mesogenicity as evidenced from the polarizing optical microscope (POM) and differential scanning calorimetry (DSC). The optical band gap of the compounds, as estimated from the Tauc plot of the UV-Vis spectra, lies within the domain of optoelectronic material properties, which was further supported through Density Functional Theory (DFT) study. Moreover, DFT methods have been used to explore the ground state geometry and DFT based reactivity descriptors of the two synthesised ligands, HL1 and HL2 along with their corresponding Co(II) complexes, Co(L1)2 and Co(L2)2. Reactivity descriptors obtained from Conceptual Density Functional Theory (CDFT) analysis reveal that Co(L1)2 is the most stable and Co(L2)2 is the most electrophilic.

Cryptosporidium parvum (C. parvum) is one of the most prevalent species infecting humans and animals. Currently, the only FDA-licensed drug to treat cryptosporidiosis is nitazoxanide (NTZ), with no efficacy in immunocompromised hosts. Citrus paradisi (C. paradisi) has demonstrated anti-protozoal activities. This study aimed to investigate the anti-cryptosporidiosis effect of C. paradisi peel extract, either alone or in mediating the green synthesis of chitosan silver nanoparticles (Cs/Ag NPs), compared to NTZ. Mice were sorted into nine different groups. The effectiveness of the treatments was evaluated using parasitology, histopathology, immunohistochemistry, and immunology. C. paradisi outperformed nitazoxanide regarding oocyst shedding (79% vs. 61%). The effectiveness of NTZ Cs/Ag NPs and Citrus Cs/Ag NPs was enhanced to 78% and 91%, respectively. The highest oocyst inhibition was obtained by combining NTZ and Citrus Cs/Ag NPs (96%). NF-κB, TNF-α, and Il-10 levels increased in response to infection and decreased in response to various treatments, with the highest reduction in the group treated with combined NTZ citrus Cs/Ag NPs. Combining C. paradisi with NTZ could have a synergistic effect, making it a potentially effective anti-cryptosporidiosis agent. Utilizing C. paradisi in the green synthesis of Cs/Ag NPs improves the therapeutic response and can be used to produce novel therapeutic antiparasitic drugs.

Secondary metabolites produced by the fermentation of Streptomyces avermitilis bacterium are powerful antiparasitic agents used in animal health, agriculture and human infection treatments. Avermectin is a macrocyclic lactone with four structural components (A1, A2, B1, B2), each of them containing a major and a minor subcomponent, out of which avermectin B1a is the most effective parasitic control compound. Avermectin B1a produces two homologue avermectins (B1 and B2) that have been used in agriculture as pesticides and antiparasitic agents, since 1985. It has a great affinity with the Cl-channels of the glutamate receptor, allowing the constant flow of Cl- ions into the nerve cells, causing a phenomenon of hyperpolarization causing death by flaccid paralysis. The purpose of this work was to gather information on the production of avermectins and their biocidal effects, with special emphasis on their role in the control of pests and phytopathogenic diseases. The literature showed that S. avermitilis is an important producer of macrocyclic lactones with biocidal properties. In addition, avermectin contributes to the control of ectoparasites and endoparasites in human health care, veterinary medicine and agriculture. Importantly, avermectin is a compound that is harmless to the host (no side effects), non-target organisms and the environment.

Fluazuron is a novel veterinary pour-on antitick formulation which can be applied simultaneously with bovine reproduction management strategies. Considering the economic importance of the livestock industry in many countries, it is important to know whether antiparasitics such as fluazuron may cause embryonic loss. The aim of this study was to evaluate the toxicological effect of fluazuron on bovine oocytes during in vitro maturation. The best fluazuron concentrations were determined in a preliminary experiment on Chinese hamster ovary (CHO)-K1 cells and further used to compare fluazuron toxicity in both study models. Results of the annexin V and alkaline single cell gel electrophoresis assays demonstrated that fluazuron caused cytotoxicity and genotoxicity in bovine cumulus cells at all the concentrations tested (50, 75 and 100 μg fluazuron/mL). The evaluation of cortical granules and mitochondria distribution showed that cytoplasmic maturation was not affected by fluazuron treatment. However, a decrease in metaphase II + polar body, degenerate oocytes as well as disorganized chromatin in polar body were observed at all concentrations tested. Whereas the fertilization process was not altered by 50 μg/mL fluazuron, the embryo development rate decreased significantly. No significant differences were observed in any of the oxidative stress parameters assessed. This study contributes to a better understanding of fluazuron in bovines, suggesting that the antiparasitic may affect bovine reproduction and might cause embryo loss.

Academic and other non-profit institutions have a long-term vision to improve human health where commercial interests can be limited for profit organizations. Medicinal chemistry to these diseases with no commercial benefit needs is well suited in the academic environment and this chapter outlines some work conducted at Calibr-Skaggs around antibiotic drug development that has led to initiation of multiple clinical trials over the last decade.

The growing global threat of antimicrobial resistance endangers both human and animal life, necessitating the urgent discovery of novel antimicrobial solutions. Medicinal plants hold promise as sources of potential antimicrobial compounds. In this study, we investigated the phytochemical constituents and microbicidal capabilities of the ethanolic extract from Nigella sativa (black seed). Gas chromatography analysis (GC) identified 11 compounds, among them thymoquinone, and thymol, contributing to antimicrobial and antioxidant properties. Antimicrobial assays demonstrated notable inhibition zones against broad spectra of bacteria, including Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi, Staphylococcus aureus, Enterobacter, and Bacillus subtilis, along with potent antifungal activity against Aspergillus niger, Penicillium, and Candida albicans. Notably, when combined with antibiotics, the extract displayed exceptional synergistic antimicrobial efficacy. The black seed extract demonstrated membrane-damaging activity and disrupted virulence factors that protect microbes from antimicrobial agents, including the formation of bacterial biofilm and protease secretion. Thymoquinone, the primary active constituent of the extract, exhibited similar antimicrobial and ant virulence properties. In silico analysis targeting key regulators of quorum sensing and biofilm formation in P. aeruginosa, such as RhlG, LasR, and PqsR, showed a remarkable affinity of thymol and thymoquinone for these targets. Moreover, the N. sativa extract exhibited dose-dependent cytotoxicity against both the promastigote and amastigote forms of Leishmania tropica parasites, hinting at potential antiparasitic activity. In addition to its antimicrobial properties, the extract displayed potential antioxidant activity at a concentration of 400 μg/mL.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.

Malaria represents the greatest global health burden among all parasitic diseases, with drug resistance representing the primary obstacle to control efforts. Sodium metavanadate (NaVO3) exhibits antimalarial activity against the Plasmodium yoelii yoelii (Pyy), yet its precise antimalarial mechanism remains elusive. This study aimed to assess the antimalarial potential of NaVO3, evaluate its genotoxicity, and determine the production of reactive oxygen and nitrogen species (ROS/RNS) in Pyy. CD-1 mice were infected and divided into two groups: one treated orally with NaVO3 (10 mg/kg/day for 4 days) and the other untreated. A 50% decrease in parasitemia was observed in treated mice. All experimental days demonstrated DNA damage in exposed parasites, along with an increase in ROS and RNS on the fifth day, suggesting a possible parasitostatic effect. The results indicate that DNA is a target of NaVO3, but further studies are necessary to fully elucidate the mechanisms underlying its antimalarial activity.

Chalcones are polyphenols that belong to the flavonoids family, known for their broad pharmacological properties. They have thus attracted the attention of chemists for their obtention and potential activities. In our study, a library of compounds from 2\'-hydroxychalcone\'s family was first synthesized. A one-step mechanochemical synthesis via Claisen-Schmidt condensation reaction under ball mill conditions was studied, first in a model reaction between a 5\'-fluoro-2\'-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde. The reaction was optimized in terms of catalysts, ratio of reagents, reaction time, and influence of additives. Among all assays, we retained the best one, which gave the highest yield of 96% when operating in the presence of 1 + 1 eq. of substituted benzaldehyde and 2 eq. of KOH under two grinding cycles of 30 min. Thus, this protocol was adopted for the synthesis of the selected library of 2\'-hydroxychalcones derivatives. The biological activities of 17 compounds were then assessed against Plasmodium falciparum, Leishmania donovani parasite development, as well as IGR-39 melanoma cell lines by inhibiting their viability and proliferation. Compounds 6 and 11 are the most potent against L. donovani, exhibiting IC50 values of 2.33 µM and 2.82 µM, respectively, better than the reference drug Miltefosine (3.66 µM). Compound 15 presented the most interesting antimalarial activity against the 3D7 strain, with IC50 = 3.21 µM. Finally, chalcone 12 gave the best result against IGR-39 melanoma cell lines, with an IC50 value of 12 µM better than the reference drug Dacarbazine (IC50 = 25 µM).

Ferroptosis is an iron-dependent form of regulated cell death characterized by glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation, and the build-up of lipotoxic reactive species. Ferroptosis-targeted induction is a promising therapeutic approach for addressing antimalarial drug resistance. In addition to being the primary source of intracellular energy supply and reactive oxygen species (ROS) generation, mitochondria actively participate in diverse forms of regulated cell death, including ferroptosis. Altered mitochondrial morphology and functionality are attributed to ferroptosis. Diverse mitochondria-related proteins and metabolic activities have been implicated in fine-tuning the action of ferroptosis inducers. Herein, we review recent progress in this evolving field, elucidating the numerous mechanisms by which mitochondria regulate ferroptosis and giving an insight into the role of the organelle in ferroptosis. Additionally, we present an overview of how mitochondria contribute to ferroptosis in malaria. Furthermore, we attempt to shed light on an inclusive perspective on how targeting malaria parasites\' mitochondrion and attacking redox homeostasis is anticipated to induce ferroptosis-mediated antiparasitic effects.