Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics

Abstract

Antimicrobials have allowed medical advancements over several decades. However, the continuous emergence of antimicrobial resistance restricts efficacy in treating infectious diseases. In this context, the drug repositioning of already known biological active compounds to antimicrobials could represent a useful strategy. In 2002 and 2003, the SARS-CoV pandemic immobilized the Far East regions. However, the drug discovery attempts to study the virus have stopped after the crisis declined. Today’s COVID-19 pandemic could probably have been avoided if those efforts against SARS-CoV had continued. Recently, a new coronavirus variant was identified in the UK. Because of this, the search for safe and potent antimicrobials and antivirals is urgent. Apart from antiviral treatment for severe cases of COVID-19, many patients with mild disease without pneumonia or moderate disease with pneumonia have received different classes of antibiotics. Diarylureas are tyrosine kinase inhibitors well known in the art as anticancer agents, which might be useful tools for a reposition as antimicrobials. The first to come onto the market as anticancer was sorafenib, followed by some other active molecules. For this interesting class of organic compounds antimicrobial, antiviral, antithrombotic, antimalarial, and anti-inflammatory properties have been reported in the literature. These numerous properties make these compounds interesting for a new possible pandemic considering that, as well as for other viral infections also for CoVID-19, a multitarget therapeutic strategy could be favorable. This review is meant to be an overview on diarylureas, focusing on their biological activities, not dwelling on the already known antitumor activity. Quite a lot of papers present in the literature underline and highlight the importance of these molecules as versatile scaffolds for the development of new and promising antimicrobials and multitarget agents against new pandemic events.

Searching for Small Molecules as Antibacterials: Non-Cytotoxic Diarylureas Analogues of Triclocarban

“…Triclocarban, N-(4-chlorophenyl)-N'- (3,4-dichlorophenyl)urea, is a highly effective and broad spectrum antimicrobial that has been successfully used in personal care products for over 60 years [3]. It belongs to the privileged class of diarylureas, which have been recently extensively reviewed for their multiple actions, including the anticancer [4], and have also been proposed for a repositioning as antimicrobial agents and/or for the treatment of new pandemics, including COVID-19 [5,6]. It is predominantly found in household necessities and personal care products, especially dermal cleaning products such as antibacterial bar/liquid soap, body lotion, deodorants, aftershave soaps, hand sanitizers, toothpaste, handwash and mouthwash [7].…”

The Different Facets of Triclocarban: A Review

“…Several small molecules analogues of TCC, endowed with different biological activities, have been described in the literature and some of them were recently reviewed in detail by our group [ 13 ]. Several analogues of TCC showed antimicrobial activity ( Table 1 ) and among them, flucofuron, an insecticide [ 108 ], was tested against S. aureus (NCTC 8325 and ATCC 12598) and Staphylococcus epidermidis (ATCC 12228; 35984) exhibiting a MIC value of 0.25 mg/L (versus 1 mg/L of vancomycin) [ 109 ], whereas the compound PK150 was active against S. aureus (NCTC 8325), (MIC = 0.3 μM) [ 110 ].…”

“…The compound 21 was studied for its implications in the neuroinflammation, showing activity against the transient receptor potential vanilloid 1 (TRPV1) ( K i for capsaicin antagonism = 0.56 µM) [ 120 ]. Some other products of molecular complication of TCC with various activities have been described in our previous paper [ 13 ].…”

“…In this review, we will focus our attention on TCC, a small molecule also named 3,4,4′-trichlorocarbanilide that belongs to the class of diarylures or bis-arylureas. This interesting class of compounds has been recently reviewed by our research group as anticancer agents [ 6 ], and then, due to their multiple actions [ 7 , 8 , 9 , 10 , 11 ], they were also suggested for repositioning to antimicrobial agents and/or potential treatment for new pandemics, as COVID-19 [ 12 , 13 ]. TCC is a common ingredient in personal care products, especially dermal cleaning products such as antibacterial bar/Liquid soaps, body lotions, deodorants, detergents, medical disinfectants, aftershave soaps, hand sanitizers, toothpaste, handwash and mouthwash, body washes, cleansing lotions, baby teethers and wipes for its sanitizing properties and detergents [ 14 , 15 , 16 , 17 ].…”

A Review on the Advancements in the Field of Metal Complexes with Schiff Bases as Antiproliferative Agents

“…Complexes containing the transition metals platinum, gold and silver have attracted much attention due to their antitumor effects. Schiff bases, as well as diarylureas [8][9][10], have been defined as "privileged" ligands in organic synthesis, thanks to their affordability, easy synthesis and different biological activities and ability to form complexes with almost all metals [11][12][13]. Actually, they may form complexes with transition metals, platinum group metals (PGM) [14], lanthanides [15,16], and actinides [17,18] and many of them have been extensively described in the literature [19,20].…”