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The translocator protein (TSPO) is predominately localized on the outer mitochondrial membrane in steroidogenic cells. In the brain, TSPO expression, low under normal conditions, results upregulated in response to glial cell activation, that occurs in neuroinflammation. As a consequence, TSPO has been extensively studied as a biomarker of such conditions by means of TSPO-targeted radiotracers. Although [11C]-PK11195, the prototypical TSPO radioligand, is still widely used for in vivo studies, it is endowed with severe limitations, mainly low sensitivity and poor amenability to quantification. Consequently, several efforts have been focused on the design of new radiotracers for the in vivo imaging of TSPO. The present review will provide an outlook on the latest advances in TSPO radioligands for neuroinflammation imaging. The final goal is to pave the way for (radio)chemists in the future design and development of novel effective and sensitive radiopharmaceuticals targeting TSPO.

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.

The use of platinum-based anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, is a common frontline option in cancer management, but they have debilitating side effects and can lead to drug resistance. Combination therapy with other chemotherapeutic agents, such as capecitabine and gemcitabine, has been explored. One approach to overcome these limitations is the modification of traditional Pt(II) drugs to obtain new molecules with an improved pharmacological profile, such as Pt(IV) prodrugs. The design, synthesis, and characterization of two novel Pt(IV) prodrugs based on oxaliplatin bearing the anticancer drugs gemcitabine or capecitabine in the axial positions have been reported. These complexes were able to dissociate into their constituents to promote cell death and induce apoptosis and cell cycle blockade in a representative colorectal cancer cell model. Specifically, the complex bearing gemcitabine resulted in being the most active on the HCT116 colorectal cancer cell line with an IC50 value of 0.49 ± 0.04. A pilot study on the encapsulation of these complexes in biocompatible PLGA-PEG nanoparticles is also included to confirm the retention of the pharmacological properties and cellular drug uptake, opening up to the possible delivery of the studied complexes through their nanoformulation.

In recent years, indolylglyoxylamide-based derivatives have received much attention due to their application in drug design and discovery, leading to the development of a wide array of compounds that have shown a variety of pharmacological activities. Combining the indole nucleus, already validated as a “privileged structure,” with the glyoxylamide function allowed for an excellent template to be obtained that is suitable to a great number of structural modifications aimed at permitting interaction with specific molecular targets and producing desirable therapeutic effects. The present review provides insight into how medicinal chemists have elegantly exploited the indolylglyoxylamide moiety to obtain potentially useful drugs, with a particular focus on compounds exhibiting activity in in vivo models or reaching clinical trials. All in all, this information provides exciting new perspectives on existing data that can be useful in further design of indolylglyoxylamide-based molecules with interesting pharmacological profiles. The aim of this report is to present an update of collection data dealing with the employment of this moiety in the rational design of compounds that are able to interact with a specific target, referring to the last 20 years.

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor, with a poor prognosis and the highest mortality rate. Currently, GBM therapy consists of surgical resection of the tumor, radiotherapy, and adjuvant chemotherapy with temozolomide. Consistently, there are poor treatment options and only modest anticancer efficacy is achieved; therefore, there is still a need for the development of new effective therapies for GBM. Indole is considered one of the most privileged scaffolds in heterocyclic chemistry, so it may serve as an effective probe for the development of new drug candidates against challenging diseases, including GBM. This review analyzes the therapeutic benefit and clinical development of novel indole-based derivatives investigated as promising anti-GBM agents. The existing indole-based compounds which are in the pre-clinical and clinical stages of development against GBM are reported, with particular reference to the most recent advances between 2013 and 2022. The main mechanisms of action underlying their anti-GBM efficacy, such as protein kinase, tubulin and p53 pathway inhibition, are also discussed. The final goal is to pave the way for medicinal chemists in the future design and development of novel effective indole-based anti-GBM agents.

Small-molecules acting as positive allosteric modulators (PAMs) of the A2B adenosine receptor (A2B AR) could potentially represent a novel therapeutic strategy for pathological conditions characterised by altered bone homeostasis, including osteoporosis. We investigated a library of compounds (4-13) exhibiting different degrees of chemical similarity with three indole derivatives (1-3), which have been recently identified by us as PAMs of the A2B AR able to promote mesenchymal stem cell differentiation and bone formation. Evaluation of mineralisation activity of 4-13 in the presence and in the absence of the agonist BAY60-6583 allowed the identification of lead compounds with therapeutic potential as anti-osteoporosis agents. Further biological characterisation of one of the most performing compounds, the benzofurane derivative 9, confirmed that such a molecule behaves as PAM of the A2B AR.

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer’s disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure–activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.

Topoisomerase (Topo) inhibitors have long been known as clinically effective drugs, while G-quadruplex (G4)-targeting compounds are emerging as a promising new strategy to target tumor cells and could support personalized treatment approaches in the near future. G-quadruplex (G4) is a secondary four-stranded DNA helical structure constituted of guanine-rich nucleic acids, and its stabilization impairs telomere replication, triggering the activation of several protein factors at telomere levels, including Topos. Thus, the pharmacological intervention through the simultaneous G4 stabilization and Topos inhibition offers a new opportunity to achieve greater antiproliferative activity and circumvent cellular insensitivity and resistance. In this line, dual ligands targeting both Topos and G4 emerge as innovative, efficient agents in cancer therapy. Although the research in this field is still limited, to date, some chemotypes have been identified, showing this dual activity and an interesting pharmacological profile. This paper reviews the available literature on dual Topo inhibitors/G4 stabilizing agents, with particular attention to the structure–activity relationship studies correlating the dual activity with the cytotoxic activity.

Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors.

The development of GPCR (G-coupled protein receptor) allosteric modulators has attracted increasing interest in the last decades. The use of allosteric modulators in therapy offers several advantages with respect to orthosteric ones, as they can fine-tune the tissue responses to the endogenous agonist. Since the discovery of the first A1 adenosine receptor (AR) allosteric modulator in 1990, several efforts have been made to develop more potent molecules as well as allosteric modulators for all adenosine receptor subtypes. There are four subtypes of AR: A1, A2A, A2B, and A3. Positive allosteric modulators of the A1 AR have been proposed for the cure of pain. A3 positive allosteric modulators are thought to be beneficial during inflammatory processes. More recently, A2A and A2B AR allosteric modulators have also been disclosed. The A2B AR displays the lowest affinity for its endogenous ligand adenosine and is mainly activated as a consequence of tissue damage. The A2B AR activation has been found to play a crucial role in chronic obstructive pulmonary disease, in the protection of the heart from ischemic injury, and in the process of bone formation. In this context, allosteric modulators of the A2B AR may represent pharmacological tools useful to develop new therapeutic agents. Herein, we provide an up-to-date highlight of the recent findings and future perspectives in the field of orthosteric and allosteric A2B AR ligands. Furthermore, we compare the use of orthosteric ligands with positive and negative allosteric modulators for the management of different pathological conditions.

Carbonic anhydrases (CAs) are a family of ubiquitous metal enzymes catalyzing the reversible conversion of CO2 and H2O to HCO3− with the release of a proton. They play an important role in pH regulation and in the balance of body fluids and are involved in several functions such as homeostasis regulation and cellular respiration. For these reasons, they have been studied as targets for the development of agents for treating several pathologies. CA inhibitors have been used in therapy for a long time, especially as diuretics and for the treatment of glaucoma, and are being investigated for application in other pathologies including obesity, cancer, and epilepsy. On the contrary, CAs activators are still poorly studied. They are proposed to act as additional (other than histidine) proton shuttles in the rate-limiting step of the CA catalytic cycle, which is the generation of the active hydroxylated enzyme. Recent studies highlight the involvement of CAs activation in brain processes essential for the transmission of neuronal signals, suggesting CAs activation might represent a potential therapeutic approach for the treatment of Alzheimer’s disease and other conditions characterized by memory impairment and cognitive problems. Actually, some compounds able to activate CAs have been identified and proposed to potentially resolve problems related to neurodegeneration. This review reports on the primary literature regarding the potential of CA activators for treating neurodegeneration-related diseases.

Context: The correlation between aggressive prostate cancer and obesity mainly based on body mass index (BMI) and pathology after surgery remains controversial. Aims: The aim of the study was to correlate BMI, visceral adiposity index (VAI), and the plasmatic levels of leptin, adiponectin, and matrix metalloproteinase-3 (MMP-3), and biomarkers of adipose tissue function, with the detection of Gleason patterns 4 and 5 at biopsy. Subjects and Methods: Consecutive patients with prostate cancer at 12-core transrectal biopsy were enrolled. BMI, waist circumference (WC), blood samples to evaluate the plasmatic levels of triglycerides (TG) and high-density lipoproteins (HDL), adiponectin, leptin, and MMP-3 were obtained immediately before biopsy. The VAI was calculated according to the formula: WC/(39.68 + [1.88 × BMI]) × TG/1.03 × 1.31/HDL. Results: One hundred and forty-nine patients were entered. The median PSA, BMI, and VAI were 10.0 ng/ml, 27.6 kg/m2, and 4.6, respectively. Gleason patterns 4 or 5 were detected in 68 (45.6%) patients; in 15 (41.7%), 31 (44.9%), and 22 (50.0%) among normal weight, overweight, and obese patients, respectively (P = 0.55). The statistical analysis did not show any significant correlation between BMI, VAI, the plasmatic levels of leptin, adiponectin, MMP-3, and the detection of Gleason patterns 4 and 5 at biopsy. A statistically significant association emerged with older age (P = 0.017) and higher PSA values (P = 0.02). Conclusion: We did not find any association between BMI, VAI, the plasmatic levels of adiponectin, leptin, and MMP-3 and the detection of Gleason patterns 4 and 5 at prostate biopsy.

Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure–activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.

This article provides an overview of the various research approaches we have explored in recent years to improve metal-based agents for cancer or infection treatments. Although cisplatin, carboplatin, and oxaliplatin remain the cornerstones in tumor chemotherapy, the discovery and approval of novel inorganic anticancer drugs is a very slow process. Analogously, although a few promising inorganic drugs have found clinical application against parasitic or bacterial infections, their use remains relatively limited. Moreover, the discovery process is often affected by small therapeutic enhancements that are not attractive for the pharmaceutical industry. However, the availability of increasing mechanistic information for the modes of action of established inorganic drugs is fueling the exploration of various approaches for developing effective inorganic chemotherapy agents. Through a series of examples, some from our own research experience, we focus our attention on a number of promising strategies, including (1) drug repurposing, (2) the simple modification of the chemical structures of approved metal-based drugs, (3) testing novel drug combinations, and (4) newly synthesized complexes coupling different anticancer drugs. Accordingly, we aim to suggest and summarize a series of reliable approaches that are exploitable for the development of improved and innovative treatments.