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Infections caused by Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp., Entamoeba histolytica, Giardia lamblia, Plasmodium spp., and Trichomonas vaginalis, are part of a large list of human parasitic diseases. Together, they cause more than 500 million infections per year. These protozoa parasites affect both low- and high-income countries and their pharmacological treatments are limited. Therefore, new and more effective drugs in preclinical development could improve overall therapy for parasitic infections even when their mechanisms of action are unknown. In this review, a number of heterocyclic compounds (diamidine, guanidine, quinoline, benzimidazole, thiazole, diazanaphthalene, and their derivatives) reported as antiprotozoal agents are discussed as options for developing new pharmacological treatments for parasitic diseases.

Parasitic diseases, caused by helminths (ascariasis, hookworm, trichinosis, and schistosomiasis) and protozoa (chagas, leishmaniasis, and amebiasis), are considered a serious public health problem in developing countries. Additionally, there is a limited arsenal of anti-parasitic drugs in the current pipeline and growing drug resistance. Therefore, there is a clear need for the discovery and development of new compounds that can compete and replace these drugs that have been controlling parasitic infections over the last decades. However, this approach is highly resource- intensive, expensive and time-consuming. Accordingly, a drug repositioning strategy of the existing drugs or drug-like molecules with known pharmacokinetics and safety profiles is alternatively being used as a fast approach towards the identification of new treatments. The artemisinins, mefloquine, tribendimidine, oxantel pamoate and doxycycline for the treatment of helminths, and posaconazole and hydroxymethylnitrofurazone for the treatment of protozoa are promising candidates. Therefore, traditional antiprotozoal drugs, which were developed in some cases decades ago, are a valid solution. Herein, we review the current status of traditional anti-helminthic and antiprotozoal drugs in terms of drug targets, mode of action, doses, adverse effects, and parasite resistance to define their suitability for repurposing strategies. Current antiparasitic drugs are not only still viable for the treatment of helminth and protozoan infections but are also important candidates for new pharmacological treatments.

Methods: The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure. Results: The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarenedendrimer- flutamide conjugates with a high drug payload improve the activity of the drug. Conclusion: This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens.

Porphyrins meso -substituted with p -phenylene vinylene (OPV) were synthesized. The porphyrin dendrimers obtained showed a strong dependence on the type of connection of the dendritic branches. In the instance of the all trans -conformation linkages, an H-type aggregate is obtained for the linear OPV and strong J-aggregate for the ramified OPV. An adequate intramolecular energy transference stemming from the OPVs (donors) to the respective cores was observed. Furthermore, the number oligo( p -phenylene vinylene) (OPV) groups linked to the porphyrin system increase the energy transfer efficiency. This behavior also was observed in the photovoltaic studies.

p-[bis(chloro-2-ethyl)amino]-L-phenylalanine (melphalan) is an approved anti-cancer agent with a broad spectrum of antitumor activity. However, it has some disadvantages, such as poor water-solubility followed by rapid elimination, which reduce the target specificity. To solve these problems, porphyrin- poly(amidoamine) or PAMAM-conjugates of melphalan were synthesized and characterized. The dendrimeric conjugates showed satisfactory water solubility. It was found that the size of the dendrimer played a crucial role in controlling the drug content and diameter of the melphalan-conjugates. The in vitro studies of cell cytotoxicity revealed that by employing the dendrimeric conjugation strategy and using the PAMAM dendritic arms as spacers, the conjugates had good anti-cancer activity and lower toxicity than free melphalan.

Novel Na+ polymeric complexes, {[Na+(2-ferrocenyl(tetracyano)propenyl)−L]∞ and [Na+(2-amino-3,5-dicyano-4-ferrocenyl-6-pyridyl-dicyanomethyl)−L]∞, where L = methanol, acetonitrile, dimethylformamide, acetone, ethyl acetate} were prepared by reactions of 2-cyano-3-ferrocenylacrylonitrile with malononitrile (∼1:3) in a MeOH/H2O medium in the presence of Na2CO3. The new complexes were characterized by elemental analysis, spectroscopy, and single-crystal X-ray diffraction analysis.

A number of 2-aminobenzophenones have been synthesized by acylation of para-chloroaniline with different 2-, 3-, 4-chloro- or fluorobenzoyl chloride in solid state via the Friedel–Crafts reaction. Synthesized compounds were characterized by 1H and 13C NMR, Fourier transform–infrared, ultraviolet–visible spectroscopy, mass spectrometry, and elemental analysis. Evaluation of biological activity in vitro showed that the selected compounds 9, 10, and 13 have potential anticancer activity. The presence of one chlorine atom in the second aromatic ring of the benzophenone molecule makes it more active.

C60 pyrene anthrylvinylene triads were synthesized with good yields by an O-alkylation reaction of pyrene an- thracene chloride derivatives and functionalized fullerene C60. The presence of lateral butoxy chains imparts good solubil- ity. The NMR data indicate the formation of only the trans isomers. After C60 cyclopropanation, the UV-Vis spectra show the pyrene electronic transition with an absorption band extending from 400 to 800 nm due to the combination of the  electronic transition of the antrylvinylene moiety and the C60 band, regardless the extension of the anthrylvinylene moiety. However, the emission is almost mirror-like with respect to the absorption bands of pyrene, suggesting that the HOMO and LUMO are more localized on this substituent. All the obtained compounds were characterized by 1 H and 13 C NMR

Ibuprofen has been reported to possess anticancer activity. In the present work, four ibuprofen conjugates of resorcinarene-Polyamidoamine PAMAM-dendrimers were synthesized with eight or 16 ibuprofen moieties. The ibuprofen was released from the dendrimers in a dependent manner. The drug-conjugated nanoresorcinarene-dendrimers showed higher cellular uptake than free ibuprofen. In vitro cytotoxicity studies were performed with free ibuprofen and with the synthesized conjugates in U251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and MDA U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma), and MDA-MB-231 (human mammary adenocarcinoma) cancer cell lines by different cytotoxicity assays. Ibuprofen conjugates of the first and second generations showed significant cytotoxic effects towards the human glioblastoma (U251) and human mammary adenocarcinoma (MCF-7, MDA) cell lines. Moreover, the ibuprofen conjugates improved cytotoxicity compared to free ibuprofen. Increased therapeutic efficacy was observed with specific ibuprofen conjugates of the second generation using low doses.

Acetamidine hydrochloride and p-aminobenzamidine dihydrochloride interact with 3-ferrocenylmethylidene-2,4-pentanedione at 80–82 °C in the presence of K2CO3 in the water–alcohol medium in two tautomeric forms (the amidoimine and enediamine ones) with formation of mixtures of pyrimidine and piperidone derivatives and polymeric coordination complexes of potassium ferrocenyl(hexahydro)pyrimidoxides. The structure of the resultant compounds is elucidated on the basis of IR, 1H- and 13C-NMR spectroscopy, mass spectrometry and elemental analysis data. The crystal structures of 6-ferrocenyl-4-hydroxy-4-methyl-2-piperidone, potassium 6-ferrocenyl-4-methyl-2-methylidene(hexahydro)pyrimidin-4-oxide and 2-(4-aminophenyl)-4-ferrocenyl-6-methyl-pyrimidine were determined by X-ray analysis of suitable single crystals.

2-Aminobenzophenone derivatives (IIIa)—(IIIc) show potential anticancer activities, with compound (IIIb), bearing a chlorine atom in the second ring of the benzophenone, being the most potent one.

A series of resorcinaren-PAMAM dendrimers with benzodiazepines in the periphery were synthesized and their anticancer properties studied. The synthesized dendrimers showed potential anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4-benzodiazepine. The dendrimers were characterized by IR, (1)H and (13)C NMR, UV-vis absorption, electrospray (ES) and/or MALDI-TOF mass spectrometries.