Jaime E. Charris

Leishmaniasis is a parasitic human infection that constitutes a major global health challenge due to limited therapeutic options, toxicity, resistance, and high costs of the drugs approved as therapy. In this study, a group of 7‐chloroquinoline derivatives ( 5 – 12 ) was synthesized via an optimized route and evaluated against the human parasite Leishmania mexicana . Compounds were fully characterized and showed favorable in silico ADME/Tox profiles, including high predicted gastrointestinal absorption (>93%), although limited solubility and potential hepatotoxicity were observed for several derivatives. Biological assays demonstrated significant antileishmanial activity. Interestingly, intracellular amastigote assays revealed nanomolar potency and very high selectivity index (SI), with compound 12 exhibiting IC ₅₀ = 2.5 nM (SI = 21.030) and compound 9 IC ₅₀ = 5.2 nM (SI = 7.384). Mechanistic studies demonstrated concentration‐dependent mitochondrial membrane depolarization and acidocalcisome alkalinization. Since these two organelles are both involved in bioenergetics and in parasite intracellular Ca ²⁺ homeostasis, the results support the notion that intracellular Ca ²⁺ disruption is an essential target for different drug actions. Overall, these findings support a multitarget mechanism and position these quinoline derivatives as promising chemical scaffolds for the development of improved antileishmanial strategies.

Two series of 1,2,3‐triazole‐based molecules were synthesized. Their physical properties were documented, and cytotoxicity was evaluated against normal lymphocytes, leukemic, adherent, and nontumor cell lines. Compounds 11 , 15 , and 16 were inactive, while compound 17 affected both normal and cancer cells. Compounds 18 and 20 showed activity against BJ and A549 cell lines, with compound 20 being selective for T‐cell leukemias and compound 18 moderately affecting B‐cell leukemia. Compound 12 specifically affected the HCTp53 KO cell line, while compounds 13 and 14 were selective for U2O2 and HCT116 cell lines, respectively. Compound 14 was highly specific for T‐cell leukemia, whereas compound 19 was specific for A549 and moderately specific for B‐cell lines. Compound 22 affected all tumor cell lines except A549. The active compound induces apoptosis since it activates caspase 3. Spheroid testing revealed that compounds 13 and 22 specifically affected HCT116 spheroids, while compound 19 affected A549 spheroids. Both in vitro and computational analyses demonstrated that compounds 11 , 12 , and 13 exhibit high affinity for the A Cα subunit of protein kinase A. This suggests a kinase‐targeted mechanism of action, providing a structural foundation for future design strategies to optimize the potency of these lead compounds.

We describe a short synthetic route to a new series of 7-chloroquinoline hybrids derived from albendazole-, thioacetazone-, and primaquine-based drugs. The design strategy incorporated a ureido group as a bioisostere of known inhibitors of β-hematin formation (βHF). Compounds 13 – 34 were characterized by infrared (IR), nuclear magnetic resonance (NMR), and elemental analysis. Preliminary in vitro screening identified compounds 13 , 14 , 16 – 18 , and 27 – 29 as inhibitors of βHF. Among these, compound 16 was the most active, exhibiting 90.68% ± 0.043% inhibition of βHF compared with 92.55% ± 0.019% for chloroquine (CQ). In vivo evaluation in Plasmodium berghei ANKA, a CQ-susceptible murine malaria strain, revealed that compound 16 reduced parasitemia to 1.2% ± 0.12% and extended survival to 27.33 ± 0.15 days. This compares favorably with chloroquine (parasitemia: 0.88% ± 0.09%; survival: 29.6 ± 0.13 days). Furthermore, at a tested concentration of 10 mM, compound 16 showed 17.23 ± 0.13 hemolysis, compared to 29.65 ± 0.10% for CQ, indicating no marked lytic action on erythrocytes. This study evaluated the hepatological consequences of malaria infection in mice infected with P . berghei . Based on its potent in vitro and in vivo activity, favorable hemolytic profile, and hepatoprotective effects, compound 16 emerges as a promising new candidate for antimalarial development.

Due to the advantages of drug repurposing, the discovery of new chemotherapeutic agents for the treatment of Chagas disease based on approved drugs has become a strategy for identifying new candidates. In this work, the antidepressant drug sertraline is reported, with an IC ₅₀ of 7.8 ± 1.7 µM against the amastigote forms of Trypanosoma cruzi . The optimization of activity through the formation of tertiary amides results in a small library of compounds, where two compounds, SMBT and SM04 , show increases of 4.3 and 2.7 times in vitro activity against the amastigote form of the parasite, and a safety index of >55.6 and 25.4, respectively, compared to sertraline. Due to hindered rotation around the (O)CN bond, the tertiary amides exist as a mixture of E/Z rotamers, typically inseparable, which display separate signals in their NMR spectra. The differential assignment of the ¹ H resonances of the E/Z rotamers is based on the magnitude of anisotropic solvent‐induced shift effects and confirmed by 2D nuclear Overhauser effect spectroscopy. Computational analysis of the hit compounds reveals that SMBT showed significant affinity for three targets (galactopyranose mutase, dihydrofolate reductase, and squalene synthase), while SM04 displays notable interaction with one (squalene synthase). These results not only suggest a plausible mechanism of action for the studied compounds but also provide valuable insights for the rational design of new derivatives with potentially enhanced trypanocidal activity.

The aim of this work was to obtain and evaluate, as antiprotozoals, new derivatives of benzoate imidazo-1,3,4-thiadiazole 18–23 based on the concepts of molecular repositioning and hybridization. In the design of these compounds, two important pharmacophoric subunits of the fexnidazole prototype were used: metronidazole was used as a repositioning molecule, p-aminobenzoic acid was incorporated as a bridge group, and 1,3,4-thiadiazole group was incorporated as a second pharmacophore, which at position 5 has an aromatic group with different substituents incorporated. The final six compounds were obtained through a five-step linear route with moderate to good yields. The biological results demonstrated the potential of this new class of compounds, since three of them 19–21 showed inhibitory activity on proliferation, in the order of 50%, in the in vitro assay against epimastigotes of T. cruzi (Strain Y sensitive to nifurtimox and benznidazole) and promastigotes of L. donovani, at a single concentration of 50 μM.

Después de las enfermedades cardiovasculares, el cáncer una patología no transmisible ha sido considerada como la segunda causa de muertes cada año a nivel global y como la barrera más importante para aumentar la esperanza de vida en el siglo 21. Se han alcanzado avances de gran relevancia en su prevención y tratamiento, sin embargo, existe aún un largo camino por recorrer para alcanzar un tratamiento efectivo para cada tipo de cáncer. En este trabajo se describen enfoques de reposicionamiento y síntesis de moléculas hibridas con potencial actividad antineoplásica. Para obtener el aldehído intermediario clave, se empleó la metodología de oxidación de Dess-Martin, que fue acoplado con las cetonas correspondientes usando LDA. Los compuestos híbridos finales fueron obtenidos como una mezcla racémica. La actividad antiproliferativa in vitro de los compuestos finales se evaluó frente a ocho líneas celulares derivadas de tumores sólidos humanos, y cuatro líneas celulares no cancerosas. El compuesto 11d resulto ser el más efectivo y con mayor índice de seguridad. Los resultados sugirieron que estos compuestos podrían bloquear el ciclo celular e inducir la apoptosis y la muerte en las células CCRF-CEM de forma dependiente de la dosis in vitro.

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of β-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC₅₀ values < 10 µM. The values were comparable to chloroquine’s, with an IC₅₀ of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC₅₀ < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber’s rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

A series of benzocycloalkanone derivatives have been prepared and evaluated as antimalarial and antitrypanosomal agents. The compounds were obtained by direct coupling of preformed 4-substituted benzaldehyde and indanone or tetralone substitutes through aldol condensation of Claisen-Schmidt using sodium hydroxide as a catalyst in ethanol at room temperature. Although designed to inhibit the formation of β-hematin in vitro, only three compounds, 10, 11, and 12, showed activities greater than 50% (75.16%, 63.02%, and 56.17%, respectively). The results of the in vivo antimalarial evaluation show that 10, 11, and 12 reduced parasitemia marginally, and an insignificant increase in the days of survival of the mice was observed. As trypanocidals, all compounds showed marginal activity as inhibitors of the proliferation of T. cruzi epimastigotes, except compound 33, with an activity of 51.08 ± 3.4% compared to the activity shown by the reference compound benznidazole 59.99 ± 2.9%. The compounds appear to have little cytotoxic effect against VERO cells in vitro; this new class of Michael acceptor agents clearly warrants further investigation.

Tumour relapse, chemotherapy resistance, and metastasis continue to be unsolved issues in cancer therapy. A recent approach has been to scrutinise drugs used in the clinic for other illnesses and modify their structure to increase selectivity to cancer cells. Chloroquine (CQ) and hydroxychloroquine (HCQ), known antimalarials, have successfully treated autoimmune and neoplastic diseases. CQ and HCQ, well-known lysosomotropic agents, induce apoptosis, downregulate autophagy, and modify the tumour microenvironment. Moreover, they affect the Toll 9/NF-κB receptor pathway, activate stress response pathways, enhance p53 activity and CXCR4-CXCL12 expression in cancer cells, which would help explain their effects in cancer treatment. These compounds can normalise the tumourassociated vasculature, promote the activation of the immune system, change the phenotype of tumour-associated macrophages (from M2 to M1), and stimulate cancer-associated fibroblasts. We aim to review the historical aspects of CQ and its derivatives and the most relevant mechanisms that support the therapeutic use of CQ and HCQ for the treatment of cancer.