Fungi are ubiquitous in nature, and typically cause little or no environmental or pathogenic damage to their plant, animal, and human hosts. However, a small but growing number of pathogenic fungi are spreading world-wide at an alarming rate threatening global ecosystem health and proliferation. Many of these emerging pathogens have developed multi-drug resistance to front line therapeutics increasing the urgency for the development of new antifungal agents. This review examines the development of thiosemicarbazones, bis(thiosemicarbazones), and their metal complexes as potential antifungal agents against more than 65 different fungal strains. The fungistatic activity of the compounds are quantified based on the zone of inhibition, minimum inhibitory concentration, or growth inhibition percentage. In this review, reported activities were standardized based on molar concentrations to simplify comparisons between different compounds. Of all the fungal strains reported in the review, A. niger in particular was very resistant towards a majority of tested compounds. Our analysis of the data shows that metal complexes are typically more active than non-coordinated ligands with copper(II) and zinc(II) complexes generally displaying the highest activity.

This review provides insight into the rapidly expanding field of metal-based antifungal agents. In recent decades, the antibacterial resistance crisis has caused reflection on many aspects of public health where weaknesses in our medicinal arsenal may potentially be present - including in the treatment of fungal infections, particularly in the immunocompromised and those with underlying health conditions where mortality rates can exceed 50%. Combination of organic moieties with known antifungal properties and metal ions can lead to increased bioavailability, uptake and efficacy. Development of such organometallic drugs may alleviate pressure on existing antifungal medications. Prodigious antimicrobial moieties such as azoles, Schiff bases, thiosemicarbazones and others reported herein lend themselves easily to the coordination of a host of metal ions, which can vastly improve the biocidal activity of the parent ligand, thereby extending the library of antifungal drugs available to medical professionals for treatment of an increasing incidence of fungal infections. Overall, this review shows the impressive but somewhat unexploited potential of metal-based compounds to treat fungal infections.

Pathogen transfer and infection in the built environment are globally significant events, leading to the spread of disease and an increase in subsequent morbidity and mortality rates. There are numerous strategies followed in healthcare facilities to minimize pathogen transfer, but complete infection control has not, as yet, been achieved. However, based on traditional use in many cultures, the introduction of copper products and surfaces to significantly and positively retard pathogen transmission invites further investigation. For example, many microbes are rendered unviable upon contact exposure to copper or copper alloys, either immediately or within a short time. In addition, many disease-causing bacteria such as E. coli O157:H7, hospital superbugs, and several viruses (including SARS-CoV-2) are also susceptible to exposure to copper surfaces. It is thus suggested that replacing common touch surfaces in healthcare facilities, food industries, and public places (including public transport) with copper or alloys of copper may substantially contribute to limiting transmission. Subsequent hospital admissions and mortality rates will consequently be lowered, with a concomitant saving of lives and considerable levels of resources. This consideration is very significant in times of the COVID-19 pandemic and the upcoming epidemics, as it is becoming clear that all forms of possible infection control measures should be practiced in order to protect community well-being and promote healthy outcomes.

Health care-associated infections (HAIs) are a global problem associated with significant morbidity and mortality. Controlling the spread of antimicrobial-resistant bacteria is a major public health challenge, and antimicrobial resistance has become one of the most important global problems in current times. The antimicrobial effect of copper has been known for centuries, and ongoing research is being conducted on the use of copper-coated hard and soft surfaces for reduction of microbial contamination and, subsequently, reduction of HAIs. This review provides an overview of the historical and current evidence of the antimicrobial and wound-healing properties of copper and explores its possible utility in obstetrics and gynecology.

Although copper-ligand complexes appear to be promising as a new class of therapeutics, other than the family of copper(ii) coordination compounds referred to as casiopeínas these compounds have yet to reach the clinic for human use. The pharmaceutical challenges associated with developing copper-based therapeutics will be presented in this article along with a discussion of the potential for high-throughput chemistry, computer-aided drug design, and nanotechnology to address the development of this important class of drug candidates.

Designing a multitarget anticancer drug with improved delivery and therapeutic efficiency in vivo presents a great challenge. Thus, we proposed to design an anticancer multitarget metal pro-drug derived from thiosemicarbazone based on the His146 residue in the IB subdomain of palmitic acid (PA)-modified human serum albumin (HSA-PA). The structure-activity relationship of six Cu(II) compounds with 6-methyl-2-formylpyridine-⁴N-substituted thiosemicarbazones were investigated, and then the multitarget capability of 4b was confirmed in cancer cell DNA and proteins. The structure of the HSA-PA-4b complex (HSA-PA-4b) revealed that 4b is bound to the IB subdomain of modified HSA, and that His146 replaces the nitrate ligand in 4b, coordinating with Cu²⁺, whereas PA is complexed with the IIA subdomain by its carboxyl forming hydrogen bonds with Lys199 and His242. In vivo data showed that 4b and the HSA-PA-4b complex inhibit lung tumor growth, and the targeting ability and therapeutic efficacy of the PA-modified HSA complex was stronger than 4b alone.

In the present paper we report the synthesis and characterization by 1H 13C NMR and heteronuclear 2D NMR spectroscopies of two new metallic complexes derived from phenylacetaldehyde thiosemincarbazone: Pt(C9H11N3S)Cl2, compound 2, and Pd(C9H11N3S)Cl2, compound 3. The testing of the cytotoxic activity of these compounds against several human and murine cell lines sensitive and resistant to cis-DDP suggests that compounds 2 and 3 may be considered potential anticancer agents since they exhibit 1C50 values in a microM range similar to cisplatin (cis-DDP). The cytotoxic activity of these compounds is higher in cis-DDP-resistant tumor cells than that of other antitumor drugs such as etoposide and adriamycin. On the other hand, the analysis of the interaction of compounds 2 and 3 with linear plasmid DNA indicate that both compounds, particularly compound 3, have an enhanced capacity to form DNA interstrand cross-links in comparison with cis-DDP.

The mechanisms of toxicity to isolated rat hepatocytes of Fe(II) and Fe(III) complexes of two structurally related naphthoquinones have been studied. All complexes were found to show a dose-dependent toxicity which precedes cell death. Within the naphthoquinone series the order of toxicity is Fe(II) > parent naphthoquinone > Fe(III). The iron complexes of 5-OH-1,4 naphthoquinone (5-OH-1,4 NQ; Juglone) are more toxic than the iron complexes of 2-OH-1,4 naphthoquinone (2-OH-1,4 NQ; Lawsone) indicating that the mechanisms of toxicity are different. Electrochemical studies on these complexes shows that 5-OH-1,4 NQ facilitates formation of stable semiquinone species while 2-OH-1,4 NQ does not. The low redox potential of 2-OH-1,4 NQ makes it a poor substrate for metabolism by reductases.

Coordinately unsaturated Cu(II) and Fe(III) complexes of the stoichiometry [Cu(L)Cl] and [Fe(L)Cl2], where L = tridentate anion of 2-hydroxy-1,4-naphthoquinone 1-thiosemicarbazone (2HNQTSC) and its 3-methyl derivative (3M2HNQTSC), were screened in vitro against P388 lymphocytic leukemia cells. Copper complexes were found to be more effective inhibitors of DNA synthesis than analogous Fe(III) compounds. The inhibitory activities are suggested to be related to Cu(II)-Cu(I) redox couple or nitrogen adduct formation.