In
Table 2, antibacterial and antifungal diarylureas are described. The work by Pujol et al. [
55] was devoted to diarylureas designed to overcome the toxicological effect of TCC due to the three chlorine atoms. One or more chlorine atoms of TCC were reduced and/or replaced by pentafluorosulfanyl groups, bioisosteres of the trifluoromethyl groups. Some of the newly synthesized compounds exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacteria, and high selectivity index, while displaying a lower spontaneous mutation frequency than TCC. Preliminary experiments suggested a bactericidal mode of action for this family of ureas. Moreover, some of the new molecules removed preexisting
S. aureus biofilms, which is important in food industry as well as in hospital settings and displayed a lower spontaneous mutation frequency in
S. aureus than TCC. Compound
8 emerged as the most promising compound showing the highest potency against both
S. aureus ATCC 12600 and methicillin-resistant
S. aureus MRSA (MIC
50 = 0.05 µg/mL versus MIC
50 = 0.5 µg/mL of TCC), a broader spectrum of activity, and a higher selectivity index [
55]. Le et al. (2020) has recently studied 72 compounds deriving from sorafenib as antibacterials. Compound PK150 showed anti-bacterial activity against several pathogenic strains of
S. aureus at sub-micromolar concentrations. MIC value against methicillin sensitive (MSSA)
S. aureus NCTC 8325 was 0.3 µM for PK150 and 3 µM for both sorafenib and regorafenib (MIC = 1 and 3 µM for vancomycin and linezolid, respectively). It exhibited a 10-fold enhanced anti-MRSA activity, lack of resistance development under laboratory conditions, killing of persisters, elimination of established biofilms, and in vivo efficacy in a mouse model. Chemical proteomic studies did not reveal a known kinase as target, but interference with menaquinone biosynthesis and dysregulation of protein secretion as putative target mechanisms [
56]. Macsics et al. (2020) studied the mechanism of PK150. As TCC, it is an inhibitor of MenG biosynthesis, but unlike TCC, it is not affected by environmentally acquired TCC resistance as it causes over-activation of SpsB, the bacterial signal peptidase I enzyme from
S. aureus [
39]. The two anticancer agents sorafenib and regorafenib were also investigated as antibacterials and proposed for further studies in this field [
57]. Chang et al. (2016) studied antibacterial and antiproliferative activity of sorafenib. The authors compared anti-
Staphylococcus activity (MIC, Minimum Inhibitory Concentration) versus antiproliferative activity (IC
50) of test agents against HEK-293 human embryonic kidney, K-562 human erythromyeloblastoid leukaemia, HT-29 human colon adenocarcinoma cell lines. It showed antibacterial activity against
S. aureus NCTC 8325, with MIC
90 (i.e., concentration that inhibits 90% of bacteria strains tested) = 4 mg/L. However, the authors concluded that it lacked selectivity, having a low selectivity ratio (IC
50 for human cells/MIC for
S. aureus) of 0.7–0.8, thus assessing it is not a feasible candidate for treatment of MRSA infection. Then, the authors studied other diarylureas and found that compounds
6 was highly potent against
S. aureus (NCTC 8325 and ATCC 12598) and
S. epidermidis (ATCC 12228 and ATCC 35984) strains, with MIC = 0.25 mg/L. It was classified as bactericidal. The selectivity ratio for this compound was higher than sorafenib, ranging between 4 and 19 [
58]. In 2004, Francisco et al. [
59] synthesized and studied a series of phenyl thiazolyl urea as new inhibitors of the bacterial cell-wall biosynthesis. Indeed, the peptidoglycan biosynthesis requires 10 synthetic transformations and, correspondingly, 10 specific enzymes, including MurA and MurB. Phenyl thiazolyl urea
9 demonstrated a good activity against MurA and MurB and gram-positive bacteria including MRSA, vancomycin resistant Enterococcus (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP), with MIC values ranging between 0.5 and 8.0 µg/mL. However, when tested in the presence of 4% bovine serum albumin, their MICs increased significantly [
59]. The importance of compound
9 is underlined by its use as a positive control for studies on MurB [
60]. Hassan et al. (2014) reported a study on diarylureas with activity against bacteria and fungi. Compound
10 possessed antimicrobial activity against the tested Gram-positive bacterium
Bacillus subtilis (NCTC-10400) and Gram negative bacteria
Pseudomonas aeruginosa (ATCC 10145) and
Escherichia coli (ATCC 23282) showing mean values of inhibition zones (in mm) of 14.0 versus 34.0, 32.0 and 30.0 of erythromycin, respectively. The compound showed weak antifungal activity [
61]. Diarylurea PQ401 is a small molecule previously described as inhibitor of the insulin like growth factor I receptor (IGF-1R) signaling and then studied in breast cancer and osteosarcoma [
15]. Recently, it has been proposed as a lead candidate for repurposing as a membrane-active antimicrobial agent because it is able to kill both growing and non-growing antibiotic-tolerant MRSA by lipid bilayer disruption. When tested against a panel of antibiotic-resistant
S. aureus strains (MW2, ATCC 33591, JE2, BF1‒5, BF7,8, BF10,11), including MRSA clinical isolates and a vancomycin-resistant
S. aureus (VRSA; strain VRS1), it showed a MIC value of 4 µg/mL. PQ401 was demonstrated to be active against MRSA (MW2, ATCC 33591, JE2) and VRS1 strains showing a minimum bactericidal concentration (MBC) of 4 g/mL. Unlike other well-studied membrane-disrupting cationic antimicrobial low-molecular-weight antimicrobials, maximum membrane activity was shown by PQ401 in its neutral form rather than its cationic form. PQ401 also showed efficacy in both the
Caenorhabditis elegans and
Galleria mellonella models of MRSA infection [
62]. A series of the diarylureas was synthesized and screened for antimicrobial activity against Gram positive and negative bacteria and fungi. Compounds
11 and
12 showed activity against
Proteus mirabilis ATCC 19181 comparable to that of standard ciprofloxacin (zone of inhibition in 23 and 24 mm, respectively, at a concentration of 200 µg/mL compared to 30 mm of ciprofloxacin) [
63]. In the work by Gezegen et al. (2017), a series of diarylureas was studied as antimicrobial and antiproliferative agents. Antimicrobial activity studies were carried out against Gram-positive and Gram-negative bacteria and yeasts, by using piperacillin/tazobactam (P/T = 8/1) and fluconazole as positive controls. The most interesting compounds were
13 and
14. They were both more active than reference against
Shigella boydii ATCC 9905 and
Enterococcus faecalis ATCC 29212 (MIC = 31.3 µg/mL versus 62.5 µg/mL), a clinically significant pathogen implicated in different types of infections [
64], and against
Bacillus cereus ATCC 10987 (MIC = 31.3 µg/mL versus 125 µg/mL), while they showed the same activity of the reference against
Klebsiella pneumoniae ATCC 10031 (MIC = 31.3 µg/mL) [
65]. Diarylureas
15–17, bearing an aminoguanidine group that is a common moiety in medicinal chemistry [
66], were active against MRSA NRS123 showing MIC values of 10 µg/mL (for compounds
15 and
17) and 8 µg/mL (for compound
16) [
67]. Compound
16 was chosen as the lead compound for further studies on a series of diarylureas bearing an alkoxy side chain in lieu of the
n-butyl moiety. The substitution with an isopentyloxy or cycloheptyloxy group gave compounds
18 and
19, which showed activity in vitro against MRSA (MIC values between 2 and 4 µg/mL versus vancomycin ranging from 0.5 to 1 µg/mL). Compound
19 was chosen for further in vivo studies using a
C. elegans animal model. The antibacterial activity was confirmed as
19, at 10 µg/mL, reduced the burden of MRSA USA400 by more than 50% in infected worms, which is a result better than that observed for vancomycin (at the same concentration it reduces the bacterial burden by 25%). Compound
19 also showed better pharmacokinetics, showing enhanced stability to hepatic metabolism, it was also demonstrated to be suitable for intravenous or topic administration (for treatment MRSA skin infections) [
67]. In a sequent work, the investigation of action mechanism of a series diphenylureas revealed that they exert their antibacterial effect by interfering with bacterial cell wall synthesis. Interestingly, both compounds
18 and
19 are able of re-sensitizing VRSA to the effect of vancomycin. Furthermore, compound
18 can penetrate staphylococcal biofilms (
S. aureus and
S. epidermidis) to reduce the burden of bacteria present within the biofilm, although at high concentrations [
68]. Upadhayaya et al. (2009) studied several quinoline derivatives as antimycobacterials. Tuberculosis (TB) is an old human disease and represent a major threat for mankind especially because of the emergence of resistance strain of
Mycobacterium tuberculosis against antibiotics. Compounds
20 and
21 inhibited
M. tuberculosis H37Rv up to 98% and 94%, respectively, at a concentration of 6.25 µg/mL. They showed MIC values of 6.25 µg/mL and 3.125 µg/mL, respectively [
69]. Compounds
22 and
23 showed MIC values of 6.0 and 5.2 µg/mL, respectively, against
M. tuberculosis pathogenic strain H37Rv and 2.0 and 1.0, respectively, against
M. tuberculosis nonpathogenic strain mc
26030. They also showed selective inhibition of mycolic acid biosynthesis. At the same time, these molecules also executed their potent immunomodulatory activity by up-regulation of the pro-inflammatory cytokines IFN-g and IL-12 and down-regulation of IL-10 [
70]. Compound
24 was studied for antifungal activity, containing 1,2,4-triazole, showed good antifungal activity against
Phomopsis species. These are known as
Phomopsis cane and leaf spot (
P. viticola) causes economic losses to the vine grape production in the USA and Europe, while
P. obscurans is responsible of
Phomopsis leaf blight and fruit rot of strawberry. At 30 μM, compound
24 inhibited the growth of
P. obscurans and
P. viticola by 80% and 100%, respectively, after 120 h exposure, showing an activity similar to that of the positive control Captan, a well-known multisite inhibitor fungicide with no systemic activity, used as a commercial protectant fungicide to prevent anthracnose diseases in fruits and ornamentals [
71].