Anti-trypanosomal activity of doubly modified salinomycin derivatives

Abstract: As a group of biologically active compounds, polyether antibiotics (ionophores) show a broad spectrum of interesting pharmacological properties, ranging from anti-bacterial to anti-cancer activities. There is increasing evidence that ionophores, including salinomycin (SAL), and their semi-synthetic analogues are promising candidates for the development of drugs against parasitic diseases. Our previous studies have shown that esterification and amidation of the C1 carboxylate moiety of SAL provides compounds with potent activity against Trypanosoma brucei, protozoan parasites responsible for African trypanosomiasis. In this paper, we present the synthetic pathways, crystal structures and anti-trypanosomal activity of C1 esters, amides and hydroxamic acid conjugates of SAL, its C20-oxo and propargylamine analogues as well novel C1/C20 doubly modified derivatives. Evaluation of the trypanocidal and cytotoxic activity using bloodstream forms of Trypanosoma brucei and human myeloid HL-60 cells revealed that the single-modified C20-oxo and propargylamine precursor molecules 10 and 16 were the most anti-trypanosomal and selective compounds with 50% growth inhibition (GI50) values of 0.037 and 0.0035 µM, and selectivity indices of 252 and 300, respectively. Also the salicylhydroxamic acid conjugate of SAL (compound 9) as well as benzhydroxamic acid and salicylhydroxamic acid conjugates of 10 (compounds 11 and 12) showed promising trypanocidal activities with GI50 values between 0.032 to 0.035 µM but less favorable selectivities. The findings confirm that modification of SAL can result in derivatives with improved trypanocidal activity that might be interesting lead compounds for further anti-trypanosomal drug development

Antiparasitic activity of ivermectin: Four decades of research into a “wonder drug”

Parasitic diseases still pose a serious threat to human and animal health, particularly for millions of people and their livelihoods in low-income countries. Therefore, research into the development of effective antiparasitic drugs remains a priority. Ivermectin, a sixteen-membered macrocyclic lactone, exhibits a broad spectrum of antiparasitic activities, which, combined with its low toxicity, has allowed the drug to be widely used in the treatment of parasitic diseases affecting humans and animals. In addition to its licensed use against river blindness and strongyloidiasis in humans, and against roundworm and arthropod infestations in animals, ivermectin is also used “off-label” to treat many other worm-related parasitic diseases, particularly in domestic animals. In addition, several experimental studies indicate that ivermectin displays also potent activity against viruses, bacteria, protozoans, trematodes, and insects. This review article summarizes the last 40 years of research on the antiparasitic effects of ivermectin, and the use of the drug in the treatment of parasitic diseases in humans and animals

Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities

Ivermectin is a sixteen-membered macrolactone “wonder drug” of Nobel prize-honored distinction that exhibits a wide range of antiparasitic activities. It has been used for almost four decades in the treatment of various parasitic diseases in humans and animals. In this paper, we describe the synthesis of the first-in-class ivermectin derivatives obtained via derivatization of the C13 position, along with the unexpected rearrangement of the oxahydrindene (hexahydrobenzofuran) unit of the macrolide ring. The structural investigation of the rearrangement has been performed using the single-crystal X-ray diffraction method. The antiparasitic and cytotoxic activities of the newly synthesized derivatives were determined in vitro with the bloodstream form of Trypanosoma brucei brucei, the hepatic stage of Plasmodium berghei, and human leukemia HL-60 cells. The compounds with the highest trypanocidal activity were the C13-epi-2-chloroacetamide analogs of native (6h) or rearranged (7h) ivermectin. Both 6h and 7h displayed trypanocidal activities within a similar mid-nanomolar concentration range as the commercially used trypanocides suramin and ethidium bromide. Furthermore, 6h and 7h exhibited a comparable cytotoxic to trypanocidal ratio as the reference drug ethidium bromide. The double-modified compound 7a (C13-epi-acetamide of rearranged ivermectin) exhibited the highest activity against P. berghei grown in human hepatoma cells, which was 2.5 times higher than that of ivermectin. The findings of this study suggest that C13-epi-amide derivatives of ivermectin are suitable leads in the rational development of new antiparasitic agents

Application of the click chemistry for the synthesis of salinomycin bioconjugates

Bioconjugation is a well-known method of designing new drug candidates for many different diseases, including cancer. The idea of the process is to join two or more bioactive molecules by means of a covalent bond. Thus, obtained hybrids often exhibit higher efficiency compared to that of the starting compounds. Recently, the use of click chemistry, especially Huisgen 1,3-dipolar cycloaddition, has attracted much attention for the synthesis of bioconjugates of natural compounds. The great advantage of this reaction is its high yield and enzymatic stability of the 1,2,3-triazole ring. Mild conditions of this reaction guarantee that it can be used to modify compounds with low stability, such as salinomycin – a representative of ionophore antibiotics. Salinomycin is a naturally occurring lipophilic compound isolated from Streptomyces albus. It is capable of forming complexes with metal cations and transport them across the lipid membranes. This process disturbs the intercellular Na+ /K+ concentration gradient and leads to apoptosis (programmed cell death). Salinomycin exhibits high anticancer activity, including efficiency against multidrug-resistant cancer cells and cancer stem cells of different origin. Chemical modification of the salinomycin skeleton to increase its biological activity is a very interesting research direction. Our review article is focused on the application of click chemistry for the synthesis of salinomycin bioconjugates with many different biologically active compounds (Cinchona alkaloids, nucleosides, triphenylphosphonium cation, betulinic acid and other ionophore antibiotics). Some of the obtained hybrids exhibit higher efficiency compared to that of the starting compounds, e.g., increased anticancer activity, the ability to overcome multi-drug resistance, or improved ionophoretic properties. These results are a good starting point for further research on the use of click chemistry in the synthesis of highly functional hybrids of natural compounds

Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models

Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and their ability to survive such treatment enables tumor reestablishment. Metastasis is the main cause of mortality in women with breast cancer, thus advances in treatment will depend on therapeutic strategies targeting CSCs. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic known for its anticancer activity towards several types of tumor cells. In the present work, a library of 17 C1-single and C1/C20-double modified SAL analogs was screened to identify compounds with improved activity against breast CSCs. Six single- and two double-modified analogs were more potent (IC50 range of 1.1 ± 0.1–1.4 ± 0.2 µM) toward the breast cancer cell line MDA-MB-231 compared to SAL (IC50 of 4.9 ± 1.6 µM). Double-modified compound 17 was found to be more efficacious than SAL against the majority of cancer cell lines in the NCI-60 Human Tumor Cell Line Panel. Compound 17 was more potent than SAL in inhibiting cell migration and cell renewal properties of MDA-MB-231 cells, as well as inducing selective loss of the CD44+/CD24/low stem-cell-like subpopulation in both monolayer (2D) and organoid (3D) culture. The present findings highlight the therapeutic potential of SAL analogs towards breast CSCs and identify select compounds that merit further study and clinical development

Clinical Course and Severity of COVID-19 in 940 Infants with and without Comorbidities Hospitalized in 2020 and 2021: The Results of the National Multicenter Database SARSTer-PED

This study aimed to analyze the differences in severity and clinical characteristics of COVID-19 in infants hospitalized in Poland in 2021, when the dominance of variants of concern (VOCs) alpha and delta was reported, compared to 2020, when original (wild) SARS-CoV-2 was dominant (III–IV vs. I–II waves of the pandemic, respectively). In addition, the influence of the presence of comorbidities on the clinical course of COVID-19 in infants was studied. This multicenter study, based on the pediatric part of the national SARSTer database (SARSTer-PED), included 940 infants with COVID-19 diagnosed between March 1, 2020, and December 31, 2021, from 13 Polish inpatient centers. An electronic questionnaire, which addressed epidemiological and clinical data, was used. The number of hospitalized infants was significantly higher in 2021 than in 2020 (651 vs. 289, respectively). The analysis showed similar lengths of infant hospitalization in 2020 and 2021, but significantly more children were hospitalized for more than 7 days in 2020 (p p < 0.0001). Severe and critical conditions were significantly more common among children with comorbidities. More infants were hospitalized during the period of VOCs dominance, especially the delta variant, compared to the period of wild strain dominance, even though indications for hospitalization did not include asymptomatic patients during that period. The course of COVID-19 was mostly mild, characterized mainly by fever and respiratory symptoms. Comorbidities, particularly from the cardiovascular system and prematurity, were associated with a more severe course of the disease in infants

Effects of the lercanidipine - Enalapril combination vs. The corresponding monotherapies on home blood pressure in hypertension: Evidence from a large database

103siObjective: To compare a combination of a dihydropyridine calcium-channel blocker with an angiotensin converting enzyme inhibitor vs. monotherapy with one or the other drug and placebo for their effects on home blood pressure (HBP). Methods: After a 2-week placebo wash-out, patients with an elevated office blood pressure (BP) (diastolic 100–109 and systolic <180 mmHg) and HBP (diastolic 85 mmHg) were randomized double-blind to a 10-week treatment with placebo, lercanidipine, 10 or 20mg daily, enalapril, 10 or 20mg daily, or the four possible combinations. In addition to office BP, HBP was self-measured via a validated semiautomatic device twice in the morning and twice in the evening during the 7 days before randomization and at the end of treatment. Baseline and treatment HBP values were separately averaged for each day, morning, evening or the whole monitoring period, excluding the first day. Day-by-day HBP variability was defined as the SD or the variation coefficient of the daily BP averages. Results: Eight hundred and fifty-four patients with valid HBP recordings at baseline and at the end of treatment were analyzed (intention-to-treat population). From the baseline value (147.011.6 mmHg) systolic/diastolic HBP showed a small reduction (average baseline-adjusted change: –1.8/–1.6 mmHg) with placebo, a more marked significant fall with monotherapies (8.8/5.9 mmHg, P<0.001/<0.001 vs. placebo) and even more with combination treatment (11.6/7.6 mmHg, P<0.001/ <0.001 vs. placebo and P<0.01/<0.05 vs. monotherapy). A similar pattern was observed for each of the days of the BP self-monitoring period as well as for either morning or evening values, although the difference between mono and combination treatment appeared to be consistently significant for the morning values only. Dayby- day systolic BP-SD was unaffected by placebo and slightly reduced by drug treatments, with no, however, significant changes in SBP-variation coefficient. Baseline and end of treatment HBP values showed a limited correlation with office BP values, this being particularly the case for treatment-induced changes (correlation coefficients: 0.37 for systolic and 0.45 for diastolic BP). Conclusion: This large HBP database shows that the lercanidipine–enalapril combination lowers HBP more effectively than the corresponding monotherapies and placebo, and that this greater effect is consistent between days.reservedmixedMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek-Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza-Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka-Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk-Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, ValeriiMancia, Giuseppe; Omboni, Stefano; Chazova, Irina; Coca, Antonio; Girerd, Xavier; Haller, Hermann; Parati, Gianfranco; Pauletto, Paolo; Pupek Musialik, Danuta; Svyshchenko, Yevgeniya; Boye, Alain; Charrier, Bruno; Couffin, Yvon; Marmor, Philippe; Marty, Jacques; Navarre, Jean Louis; Ansari, Anwar; Büttner, Claudia; Kropp, Maximilian; Mehling, Heidrun; Paschen, Christine; Schenkenberger, Isabelle; Schneider, Helmut; Sperling, Karsten; Stübler, Petra; Von Behren, Volker; Lembo, Giuseppe; Scanferla, Flavio; Sechi, Leonardo Alberto; Gębala, Andrzej; Hoffmann, Andrzej; Janik, Krzysztof; Klimza Masłowska, Anna; Kaczmarek, Barbara; Koźminski, Piotr; Makowiecka Cies̈la, Magdalena; Mordaka, Robert; Nowakowski, Tomasz; Pasternak, Dariusz; Skibińska, Elzbieta; Sulik, Piotr; Szpajer, Michał; Walczewska, Jolanta; Zaczek, Marcin; Zienciuk Krajka, Agnieszka; Alexeeva, Nadezhda; Bokarev, Igor; Chazova, Iina; Conrady, Alexandra; Emelyanov, Alexander; Galustyan, Anna; Idrisova, Elena; Khasanov, Niyaz; Khokhlov, Alexander; Libov, Igor; Reshetko, Olga; Sokurenko, German; Stryuk, Raisa; Tereshchenko, Sergey; Trofimov, Vasily; Zrazhevsky, Konstantin; Carlos Calvo, S.; De Teresa, Luis; Ferre, Raimon; García, Juan; Gil, Apolonia; Gil, Blas; Montenegro, Jesús; Oliván, Josefina; Ortiz, Jacinto; Pascual, José María; Rivera, Antonio; De Quevedo, José Antonio Sainz; Zúñiga, Manuel; Martinez, Valentin; Pujol, Montserrat; Bazylevych, Andriy; Gyrina, Olga; Ignatenko, Grygoriy; Kazymyrko, Vitaly; Khomazyuk, Tetyana; Kononenko, Lyudmyla; Korzh, Oleksii; Kovalenko, Volodymyr; Kuryata, Oleksander; Kushnir, Mykola; Lishnevska, Viktoriia; Lymar, Iurii; Ostrovska, Lidiia; Popik, Galyna; Rudyk, Yuriy; Shershnyova, Oxana; Sierkova, Valentyna; Storozhuk, Borys; Tseluyko, Vira; Vatutin, Mykola; Vayda, Myroslava; Vizir, Vadym; Volkov, Volodymyr; Voloshyna, Olena; Yagensky, Andriy; Zhurba, Svitlana; Zorin, Valeri