The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood–brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH’s value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.

Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery

Heterocyclic amino derivatives have been extensively synthesized and validated as potent bioactive compounds, and nowadays, numerous marketed drugs share these scaffolds, from very simple structures (monoamino, monocyclic compounds) to much more complex molecules (polycyclic derivatives with two or more nitrogen atoms within the (fused) rings). In a constant quest for new chemical entities in drug discovery, a few novel heterocycles have emerged in recent years as promising building blocks for the obtainment of bioactive modulators. In this context, pyrrolotriazinones have attracted attention, and some show promising biological activities. Here, we offer an extensive review of pyrrolo[2,1-f][1,2,4]triazin-4(1H)-one and pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one, describing their biological properties en route to drug discovery.

Pharmacological screening of Eryngium foetidum Linn – A Review

Eryngium foetidum L. (Family Apiaceae) is a biennial herb, and it is used as a culinary herb and spice across the different countries of the world, including Sri Lanka, India, Bangladesh, Malaysia, Singapore, etc. due to its high aroma quality. Also, it is used to treat several ailments, such as respiratory diseases, gastrointestinal ailments, and skin diseases among different indigenous populations for its medicinal properties. Based on ethnomedical evidence, many studies have been conducted to identify the phytoconstituents, underlying mechanisms, and related pharmacological effects of different parts of this plant. This study reviewed the current state of findings related to the Pharmacological activities of E. foetidum. Based on this review, this plant is widely used for ethnomedical and culinary purposes. Pharmacological screening of the plant revealed that it had different activities such as anti-inflammatory, antioxidant, antimicrobial, anthelminthic, anticonvulsant, anticancer, antidiabetic, antimalarial, larvicidal, and hepatoprotective activities. This review further promised that potential new chemical entities could be elicited from the phytoconstituents of E. foetidum.

Expanding the scope of prenylated 1,2,3-triazoles as new antiparasitic drug candidates

We have previously shown that prenyl and aliphatic triazoles are interesting motifs to prepare new chemical entities for antiparasitic and antituberculosis drug development. In this opportunity a new series of prenyl-1,2,3-triazoles were prepared from isoprenyl azides and different alkynes looking for new antimalarial drug candidates. The compounds were prepared by copper(I) catalyzed dipolar cycloaddition of the isoprenyl azide equilibrium mixture providing exclusively 1,4-disubstituted 1,2,3-triazols in a regiospecific fashion. The complete collection of 64 compounds was tested on chloroquine -sensitive, Sierra Leone (D6), and the chloroquine-resistant, Indochina (W2), strains of Plasmodium falciparum and those compounds which were not previously reported were also tested against Leishmania donovani , the causative agent for visceral leishmaniasis. Thirteen analogs displayed antimalarial activity with IC50 below 10 uM, while the antileishmanial activity was less potent than the previously reported analogs. The cytotoxicity assay against Vero cells revealed that none of the compounds was cytotoxic up to concentrations of 4.75 ug/mL. Compounds 1o and 1r were identified as the most promising antimalarial drug leads with IC50 below 3.0 uM for both CQ-sensitive and resistant P. falciparum strains. Finally, a chemoinformatic in silico analysis was performed to evaluate physicochemical parameters, cytotoxicity risk and drug score. The validation of a bifunctional farnesyl/geranylgeranyl diphosphate synthase PfFPPS/GGPPS as the potential target of the antimalarial activity of selected analogs should be further investigated.

1,2,3-Triazole- and Quinoline-Based Hybrids with Potent Antiplasmodial Activity

Background: Malaria is a disease causing millions of victims every year and requires new drugs, often due to parasitic strain mutations. Thus, the search for new molecules that possess antimalarial activity is constant and extremely important. However, the potential that an antimalarial drug possesses cannot be ignored, and molecular hybridization is a good strategy to design new chemical entities. Objective: This review article aims to emphasize recent advances in the biological activities of new 1,2,3-triazole- and quinoline-based hybrids and their place in the development of new biologically active substances. More specifically, it intends to present the synthetic methods that have been utilized for the syntheses of hybrid 1,2,3-triazoles with quinoline nuclei. Method: We have comprehensively and critically discussed all the information available in the literature regarding 1,2,3-triazole- and quinoline-based hybrids with potent antiplasmodial activity. Results: The quinoline nucleus has already been proven to lead to new chemical entities in the pharmaceutical market, such as drugs for the treatment of malaria and other diseases. The same can be said about the 1,2,3-triazole heterocycle, which has been shown to be a beneficial scaffold for the construction of new drugs with several activities. However, only a few triazoles have entered the pharmaceutical market as drugs. Conclusion: Many studies have been conducted to develop new substances that may circumvent the resistance developed by the parasite that causes malaria, thereby improving the therapy currently used.

Ethnobotanical review of Medicinal Plants Used against Diarrhea and Dysentery in Northeastern India (Assam)

Background: Since primitive times, plants have been extensively utilized in conventional remedies for primary health care. It is observed that medicinal plants have various bioactive components. It becomes an alternative choice for synthetic medications to treat diarrhea and dysentery, which are the primary waterborne diseases with high mortality rates that bring substantial health threats to global populations. Objective: The present review aims to look over the ethnobotanical knowledge for the treatment of diarrhea and dysentery and folklore practices by the people prevailing in Assam. Methods: In this perspective, an extensive literature survey was carried out to understand the mechanism, control, and treatment of diarrhea and dysentery in different online academic databases and books. An advanced search was carried out in 'PubMed' and 'Google Scholar' using the term "Phytoconstituents" and "antidiarrheal" along with "Phytoconstituents" and "anti-amoebic". Results: Data retrieved from databases were analyzed and interpreted to conclude that in Assam, diarrhea and dysentery are the primary leading causes of mortality among children under five years. It is mainly due to the unhygienic livelihood, unavailability of safe drinking water, unhealthy food, seasonal rainfall, flood, and open defecation. The present investigations reveal that the people of Assam use 39 plant species belonging to 36 families to cure diarrhea and dysentery. Conclusion: The present study established the effective use of medicinal plants by various communities in Assam to treat diarrhea and dysentery. Furthermore, it can be used to develop a new therapeutic approach to create new chemical entities (NCE) in drug discovery, which are safe, fruitful, and inexpensive.

Chagas Disease Drug Discovery in Latin America—A Mini Review of Antiparasitic Agents Explored Between 2010 and 2021

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi that endangers almost 70 million people worldwide. The only two drugs that are currently approved for its treatment, benznidazole and nifurtimox, have controversial efficacy in adults and restricting safety issues, leaving thousands of patients without a suitable treatment. The neglect of Chagas disease is further illustrated by the lack of a robust and diverse drug discovery and development portfolio of new chemical entities, and it is of paramount importance to build a strong research and development network for antichagasic drugs. Focusing on drug discovery programs led by scientists based in Latin America, the main endemic region for this disease, we discuss herein what has been published in the last decade in terms of identification of new antiparasitic drugs to treat Chagas disease, shining a spotlight on the origin, chemical diversity, level of characterization of hits, and strategies used for optimization of lead compounds. Finally, we identify strengths and weaknesses in these drug discovery campaigns and highlight the importance of multidisciplinary collaboration and knowledge sharing.

Recent Advances in the Development of Pyrazolopyridines as Anticancer Agents

: Cancer, especially malignant tumor, is a serious threat to people's life and health. It is recognized as an enormous challenge in the 21st century. Continuous efforts are needed to overcome this problem. Pyrazolopyridine nucleus, similar in structure to purine, shows a variety of biological activities, which is mainly attributed to the antagonistic nature towards the natural purines in many biological processes. This has aroused enormous attention for many researchers. At present, a large number of new chemical entities containing pyrazolopyridine nucleus have been found as anticancer agents. In this review we summarize novel pyrazolopyridine-containing derivatives with biological activities. Furthermore, we outline the relationships between the structures of variously modified pyrazolopyridines and their anticancer activity.