Medicinal Chemistry - Volume 19, Issue 1, 2023

Leishmaniasis is a neglected tropical disease widely distributed worldwide, caused by parasitic protozoa of the genus Leishmania. Despite representing a significant public health problem, the therapeutic options are old, with several reported adverse effects, have high costs, with administration mainly by parenteral route, which makes treatment difficult, increasing dropout and, consequently, the emergence of resistant strains. Thus, the research and development of new antileishmanial therapies become necessary. In this field, inhibiting essential targets that affect the parasite’s growth, survival, and infectivity represents an attractive therapeutic strategy. With this in mind, this review addresses the main structural, functional characteristics and recent reports of the discovery of promising inhibitors of the enzymes Arginase (ARG) and trypanothione synthase (TryS), which are involved in the biosynthesis of polyamines and trypanothione and Trypanothione Reductase (TR), responsible for the reduction of trypanothione thiol.

Background: Heterocycles play a major role in many fields of biochemical and physiological such as amino acids, DNA bases, vitamins, endogenous neurotransmitters, etc. Nitrogencontaining heterocyclic compounds play a vital role in medicinal chemistry and exhibit notable biological and pharmacological activities. In the past two decades, scientists focused more on the diverse biological activities of pyrimidine derivatives. Pyrimidine is a six-membered heterocyclic compound, and it is present naturally in nucleic acid components (uracil, thymine, and cytosine) and vitamin B1; it is a promising lead molecule for synthesising compounds with various substitutions to treat various diseases. Objective: We focused on the structure-activity relationship of pyrimidine derivatives and its various biological activities reported from 2010 to date. Results: From this review, we concluded that the position of substituents in the pyrimidine nucleus greatly influences biological activities. Thus, the pyrimidine nucleus showed anti-microbial, anticancer, anti-inflammatory, anti-tubercular, anti-convulsant, antihypertensive, anthelmintic, antidepressant, analgesic, anti-hyperglycemic activities, etc. Conclusion: This study provides an overview of the pyrimidine nucleus and its derivatives from 2010 to date. There is a future scope for identifying a lead molecule for the target biological activity.

This review aims to provide a comprehensive report on the quinoline ring with respect to its synthesis, reactivity, and therapeutic values. The reactivity of quinoline for the metal, electrophile, and other reactive counterparts defines the shape of the quinoline pharmacophore, which is an important part of this report; moreover, its spectroscopic characteristics have been included herein with suitable illustration. The quinoline and its derivatives have been presented as well as the general synthetic approaches along with the new developments in the catalytic system; the relevant information is also summarized under the various separate activity classes. The synthesis of heterocyclic scaffolds has been a concern for scientists, so herein we have tried to include the synthetic parameters of quinoline with regard to the important pharmacological aspects.

Aim: The aim of the study was to search for new anticancer agents as TRKA inhibitors. Background: A series of new salicylic acid hydrazide hydrazones were synthesized and evaluated for their in vitro anticancer activities against lung (A549), ovarian (SK-OV-3), skin (SK-MEL-2), and colon (HCT15) cancer cell lines, and tropomyosin receptor kinase A (TRKA) inhibitory activities. Objective: In this study, we focused on the synthesis and anticancer properties evaluation of salicylic acid hydrazide hydrazones as TRKA inhibitors. The in vitro anticancer activities of hydrazone analogs were measured against four cancer cell lines, and the TRKA inhibitory properties were investigated using an enzyme assay to determine their modes of action. In silico molecular docking was conducted using the crystal structure of the TRKA receptor to study the interactions and modes of binding at its active site, and ligand-based target predictions were used to identify putative secondary enzymatic targets of the synthesized compounds. Additionally, pharmacokinetic properties, toxicity effects, and drug scores of the studied molecules were also assessed. Methods: A series of hydrazide hydrazones were prepared by means of a facile and straight-forward two-step reaction under soft reflux conditions from a methyl ester of substituted aromatic acids and hydrazine hydrate followed by the condensation with substituted aldehydes. In vitro cytotoxic properties of the synthesized compounds were screened against four human cancer cells using the SRB (sulforhodamine-B) colorimetric method. The TRKA inhibitory activity was measured by enzymatic assay. In silico ADME, drug score properties, docking studies, and ligand-based target prediction analyses were performed using Osiris Cheminformatics and AutoDock Vina, and SwissTargetPrediction bioinformatics software. Results: In vitro bioassays revealed that compound 6 exhibited the most potent broad-spectrum anticancer activities with IC50 values of 0.144, <0.001, 0.019, and 0.022 μM against A549, SK-OV-3, SK-MEL-2, and HCT15 cancer cells, respectively, followed by compounds 11, 3a, and 9. In TRKA inhibitory assays, compounds 3e and 11 demonstrated the highest potency with IC50 values of 111 and 614 nM, respectively. The results of docking studies on 3e and 11 with the active site of the TRKA receptor revealed that both compounds interacted as previously reported TRKA inhibitors with high docking scores. Conclusion: New salicylic acid hydrazide hydrazones were synthesized, and the most active compounds exhibited significant anticancer properties against A549, SK-OV-3, SK-MEL-2, and HCT15 cancer cells, suggesting to be good candidates for in vivo studies. The results obtained in the present study would help in the design and preparation of new hydrazidehydrazone analogs as potential TRKA inhibitors for cancer treatment.

Background: Genistein has been limited in clinical application due to its low bioavailability, extremely poor liposolubility, and fast glycosylation rate, though it possesses anti-breast cancer activity. Therefore, the discovery of novel genistein derivatives is an urgency. Objective: To enhance the anti-breast cancer activity of genistein, a series of novel fluorinated genistein derivatives were synthesized. Methods: Their in vitro antitumor activity was investigated by the MTT assay against three cancer cell lines, via, MDA-MB-231, MCF-7, and MDA-MB-435, respectively. Results: Analogs 1d, 2b, and 3b showed remarkable anticancer activities compared to tamoxifen, a clinical anti-breast cancer drug on the market. Conclusion: The activities against breast cancer of genistein were enhanced by introducing the 7- alkoxyl group and fluorine atom into the B-ring. Therefore, these compounds may be potential candidates for treating breast cancer.

Introduction: Multidrug-resistant bacteria are rapidly increasing worldwide, increasing antibiotic resistance. The exploitation, misuse, overuse, and decrease of the therapeutic potential of currently available antibiotics have resulted in the development of resistance against bacteria. As the most common bacterial pathogen in humans, Staphylococcus aureus can cause many adverse health effects. In fighting multidrug-resistant Staphylococcus aureus, scientists have identified an extremely relevant target - SaTMPK. SaTMPK is essential for DNA synthesis, which, in turn, is necessary for the replication and cell division of bacteria. Objective: To perform multi-stage screening using the ZINC database, followed by molecular docking, ADMET profiling, molecular dynamics simulations, and energy calculations. Methods: Based on the similar pharmacophoric characteristics of existing SaTMPK crystal structures, a model of interaction-based pharmacophores was developed. We then performed molecular docking studies on the positive hits obtained from the pharmacophore screening. Compounds that exhibited good molecular interactions within the SaTMPK binding sites were further evaluated using in-silico ADMET profiling. Results: In a multi-stage screening campaign, three compounds were shortlisted that exhibited physicochemical characteristics suitable for human administration. Conclusion: The findings from this study should contribute to in vitro and in vivo studies for clinical applications.

Background: Currently, protozoan infectious diseases affect billions of people every year. Their pharmacological treatments offer few alternatives and are restrictive due to undesirable side effects and parasite drug resistance. Objective: In this work, three ontology-based approaches were used to identify shared potential drug targets in five species of protozoa. Methods: In this study, proteomes of five species of protozoa: Entamoeba histolytica (E. histolytica), Giardia lamblia (G. lamblia), Trichomonas vaginalis (T. vaginalis), Trypanosoma cruzi (T. cruzi), and Leishmania mexicana (L. mexicana), were compared through orthology inference using three different tools to identify potential drug targets. Results: Comparing the proteomes of E. histolytica, G. lamblia, T. vaginalis, T. cruzi, and L. mexicana, twelve targets for developing new drugs with antiprotozoal activity were identified. Conclusion: New drug targets were identified by orthology-based analysis; therefore, they could be considered for the development of new broad-spectrum antiprotozoal drugs. Particularly, triosephosphate isomerase emerges as a common target in trypanosomatids and amitochondriate parasites.

Background: Over the past twenty years, the prevalence of diabetes as one of the most common metabolic diseases has become a public health problem worldwide. Blood glucose control is important in delaying the onset and progression of diabetes-related complications. α-Glycosidase (α- Glu) and α-amylase (α-Amy) are important enzymes in glucose metabolism. Diabetic control through the inhibition of carbohydrate hydrolyzing enzymes is established as an effective strategy. Methods: In this study, curcumin-based benzaldehyde derivatives with high stability, bioavailability, and favorable efficiency were synthesized. Results: The results showed that L13, L8, and L11 derivatives have the highest inhibitory effect on α-Glu with IC50 values of 18.65, 20.6, and 31.7 μM and, also L11, L13, and L8 derivatives have the highest inhibitory effect on α-Amy with IC50 value of 14.8, 21.8, and 44.9 μM respectively. Furthermore, enzyme inhibitory kinetic characterization was also performed to understand the mechanism of enzyme inhibition. Conclusion: L13, compared to the other compounds, exhibited acceptable inhibitory activity against both enzymes. The L13 derivative could be an appropriate candidate for further study through the rational drug design to the exploration of a new class of powerful anti-diabetic drugs considering the antioxidant properties of the synthesized compounds. The derivative helps reduce the glycemic index and limits the activity of the major reactive oxygen species (ROS) producing pathways.