Guanidine-Containing Antifungal Agents against Human-Relevant Fungal Pathogens (2004-2022)-A Review

Abstract

The guanidine moiety is typically a highly basic group, and can be found in a wide variety of drugs, such as zanamivir (Relenza) and metformin (Fortamet), as well as in biologically active compounds for numerous disease areas, including central nervous system (CNS) diseases and chemotherapeutics. This review will focus on antifungal agents which contain at least one guanidine group, for the treatment of human-related fungal pathogens, described in the literature between 2004 and 2022. These compounds include small molecules, steroids, polymers, metal complexes, sesquiterpenes, natural products, and polypeptides. It shall be made clear that a diverse range of guanidine-containing derivatives have been published in the literature and have antifungal activity, including efficacy in in vivo experiments.

Keywords: antifungal agent; guanidine; metal complex; natural product; polymer; polypeptide; sesquiterpene; small molecule; steroid.

Figure 1

Structures of representative guanidine-containing approved drugs. zanamivir (Relenza) (1), famotidine (Pepcid), (2), and tizanidine (Zanaflex) (3).

Figure 2

Structure of mirabilin B (4).

Figure 3

Phenyl guanidinium salt antifungal agents (5) and (6).

Figure 4

Pyrrole-diguanide antifungal derivative (7).

Figure 5

Guanidine-containing small molecules (8) and (9) separated from guazatine.

Figure 6

Cyclized derivatives (10) and (11) related to guazatine.

Figure 7

Fluorescent probe derivative (12) based on a cyclized analog of guazatine.

Figure 8

Cyclic guazatine-related analogs (13), (14), and (15).

Figure 9

Arylated derivatives (16), (17), and (18) of cyclized guazatine-derived analog (13).

Figure 10

Drimenol-derived antifungal compound (19).

Figure 11

Structure of abafungin (20).

Figure 12

Fungistatic and fungicidal piperazine-1-carboxamidines (21) and (22).

Figure 13

Structure of polyhexamethylene-guanidine hydrochloride (PHMGH) (23).

Figure 14

Fungicidal benzylsulfanyl-phenylguanidines (24) and (25).

Figure 15

Mannich base antifungal derivative (26).

Figure 16

Copper (II) complex antifungal agent (27).

Figure 17

Antifungal derivatives (28) and (29) of batzelladine K.

Figure 18

Structure of cabanillasin (30).

Figure 19

Ferrocene-based guanidine-containing antifungal agents (31), (32), and (33).

Figure 20

Short cationic antimicrobial peptide (LTX-109, AMC-109) (34).

Figure 21

Lead thiophene-based bis-guanylhydrazone antifungal compound (35).

Figure 22

Furan-based bis-guanylhydrazone antifungal derivative (36).

Figure 23

Lead guanidine-containing benzothiazole derivatives (37) and (38).

Figure 24

α-Mangostin derived antifungal analog (39).

Figure 25

Structure of alexidine dihydrochloride (40).

Figure 26

Structure of metformin (41).

Figure 27

Bis-guanidine containing oxadiazole analog (42).

Figure 28

1,2,4-triazole bis-guanidine-containing antifungal derivatives (43) and (44).

Figure 29

Lead thiazole-aminoguanidine analog (45).

Figure 30

Aminoguanidine-containing antifungal compounds (46) and (47).

Figure 31

Guanidine-containing GlcN-6-P synthase inhibitor (48).

Figure 32

Guanidine-containing betulinic acid derived antifungal analogs (49) and (50).

Figure 33

Surfactants (51) and (52) containing guanidine groups as antifungal agents.

Figure 34

Guanidine-containing bis-thiazole analog antifungal agent (53).

Figure 35

Optimized antifungal polypeptide K-oLBF127 (54).

Figure 36

Peptide-heterocycle conjugate antifungal derivative (55).

Figure 37

28-Mer antifungal polymer (56).

Figure 38

Antifungal cyclic pentapeptide (57).

Figure 39

Structure of crambescidic acid-671 (58).

Figure 40

General structure of guanylated lysine-based polymer (59).