**3.2 Vitiligo**

Vitiligo is an acute skin disease characterized by unilaterally distributed depigmented areas in the skin due to the systematic degradation of melanocytes [56]. The mechanism triggering this disease has not completely elucidated yet; however, there are several theories proposed to explain it including genetics (mutations of certain genes cause autoimmunity) [57], autoimmunity (instable melanocytes induce immune system activation), oxidative stress (endogenous and exogenous stress-induced reactive oxygen species that cause internal damage of melanocytes)


*\* IC50, half maximal inhibitory concentration; ERK1/ERK2, extracellularly regulated kinase 1 and 2; CREB, cyclic adenosine monophosphate (cAMP) response element-binding protein. \*\*HEMn: Primary skin melanocyte cells from neonatal foreskin.*

#### **Table 1.**

*Chalcone derivatives activities in inhibiting cellular melanogenesis.*


#### **Table 2.**

*Chalcone derivatives' activities in activating cellular melanogenesis.*

[58], melanocyte growth and defective melanocyte adhesion (repeated pressure and friction cause detachment of melanocytes to surrounding structures) [59], viral infections (certain viruses cause vitiligo) [60], and neural mechanism (neuropeptides elevate in vitiligo lesions) [61].

Improvement of skin appearance in vitiligo can be approached either by pigmentation or depigmentation. Chalcone derivatives are able to act as hypopigmenting (as described in Section 4.1) and hyperpigmenting agents. Several chalcone derivatives acted as hyperpigmenting agent by activating tyrosinase enzyme and elevating melanin production (**Table 2**). The presence of certain electron-withdrawing substituents such as halogen and trifluoromethyl substituents on the chalcone structure exhibited a significant effect in activating tyrosinase [62]. Chalcones also showed strong absorption in UV regions with low toxicity and have been formulated as broad-spectrum sunscreen protecting the affected skin from UV radiations and photofilter used in narrow-band UVB (NB-UVB) phototherapy [63].

#### **4. Cutaneous leishmaniasis**

Leishmaniasis is one of the vector-borne diseases generated by *Leishmania* spp*.* protozoans and transmitted to mammals through infected female sandflies (*Phlebotomus* and *Lutzomyia*) [66]. In general, certain *Leishmania* species can cause different clinical features with different degree of severity as the result of the interplay between *Leishmani*a species characteristics, biological vector, and the responses of host immune system [67]. In this section, the explanation is focused on the cutaneous leishmaniasis as the most well-known form [68].

Cutaneous leishmaniasis is identified by the presence of skin lesions (ulcers) in the biting spot of *Leishmania* spp.-infected sandfly. Almost all pathogenic *Leishmania* spp. could cause cutaneous leishmaniasis (18 from 20 species) [69] with 24 species of *Phlebotomus* spp. and 40 species of *Lutzomyia* spp*.* acting as a vector or potential vector [70]. At first, after biting by the infected female sandfly, the spot will form small erythema developing into a papule and then a nodule and ulcerate to become skin lesion. In the human body, promastigotes of *Leishmania* parasites injected by sandfly will be phagocytosed by macrophages [71]. Promastigotes manipulate macrophages to develop and multiply promastigote into amastigotes that infect another sandfly by biting infected human [72]. These processes cause

#### *Chalcones in Dermatology DOI: http://dx.doi.org/10.5772/intechopen.91145*


*\*\*Been reviewed by de Mello and coworkers [88].*

#### **Table 3.**

*Several chalcone derivatives with high activity and selectivity against* Leishmania *spp*.

the complex inflammatory responses that mediate and determine the appearance of clinical features and the severity degree.

Various investigations have been conducted and showed that several chalcone (natural and synthetic) derivatives have high activity (IC50 < 10 μg/mL or IC50 < 5 μM) and selectivity against *Leishmania* parasites in vitro and in vivo. However, the mode of action and molecular target of these chalcone derivatives have not been well elucidated yet. Licochalcone A showed strong activity against *L. major* (IC50 = 2.4 μg/mL) by damaging ultrastructure of promastigote and amastigote mitochondria of the parasite selectively and disturbing its function as respiration organelle [73]. Several studies also showed that fumarate reductase [74], nucleoside hydrolase, dihydroorotate dehydrogenase, oligopeptidase B and methionyl-*t*RNA synthetase in *L. major* [75], cysteine proteases in *L. infantum* [76], and glycerol 3-phosphate dehydrogenase (G3PDH) of *L. mexicana* [75, 77] can be targeted to kill the parasite. Chalcone derivatives strongly inhibiting these enzymes showed high activity in killing the parasite (**Table 3**). When the sunscreen activity of chalcones is generated by their conjugated electronic system, the antimicrobial activity of chalcones is caused by the presence of halogen, methoxy, hydroxy, and other functional groups.

### **5. Rashes**

#### **5.1 Acne vulgaris**

Acne vulgaris, one of multifactorial acute inflammatory diseases, affects the pilosebaceous unit (hair follicles) in the skin. This disease is commonly found in the area with high-density pilosebaceous units (face, neck, upper chest, shoulders, and back) and characterized by the presence of seborrhea (excessive grease production), noninflammatory lesions (open comedones/blackhead and closed comedones/whitehead), inflammatory lesions (papules and pustules), and various degrees of scarring [89].

Pathogenesis of acne involves the interplay between four main factors including hyperseborrhoea (excessive sebum production) mediated by certain androgens and alterations in sebum fatty acid composition, hyperkeratinization within the follicle that lead to the formation keratin plug (microcomedone), pilosebaceous unit colonization by *Cutibacterium acnes* (aerotolerant anaerobic bacterium) colony, and the release of inflammatory mediators in response to the presence of *Cutibacterium acnes* [90]. It was shown that *Staphylococcus epidermidis* (facultative anaerobic bacterium) also had a beneficial role by limiting the colonialization of *Cutibacterium acnes* and inflammation [91].

Several chalcone derivatives exhibited anti-acne activity with mainly as antibacterial and anti-inflammatory agents. Licochalcone A as a potent anti-inflammatory agent [31] has been studied and combined with other active compounds in several anti-acne formulations. Skin care formulation containing licochalcone A, L-carnitine, and 1,2-decanediol can reduce pustule lesions, popular lesions, total lesions, and sebum levels [92]. A combination of 0.1% adapalene gel and moisturizer containing licochalcone A, L-carnitine, and 1,2-decanediol also showed synergistic effect in reducing inflammatory lesions without interfering the efficacy of each active ingredient [93]. Another combination between 0.1% adapalene gel and moisturizer containing licochalcone A, glycolic acid, salicylic acid, and gluconolactone even showed better results than monotherapy using only adapalene [94]. Licochalcone A, in another report, had antibacterial activity against *Cutibacterium acnes* and inhibited *Cutibacterium acnes*-mediated NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome activation in the skin [95].

#### *Chalcones in Dermatology DOI: http://dx.doi.org/10.5772/intechopen.91145*

Antibacterial effects against *Cutibacterium acnes* have been shown by phloretin, xanthohumol, panduratin A, isopanduratin A, and some chalcone derivatives. Phloretin, a natural dihydrochalcone derivative, showed both antibacterial effects by inhibiting the growth of *Cutibacterium acnes* (MIC = 0.5 mg mL<sup>−</sup><sup>1</sup> ) by blocking the activity of KAS III [beta-ketoacyl-(acyl-carrier-protein) synthase III] in *Cutibacterium acnes* and anti-inflammatory effect by attenuating COX-2 and PGE2 expressions and inhibiting c-Jun N-terminal kinases (JNK) via toll-like receptor 2 (TLR2)-mediated inflammatory signaling in *Cutibacterium acnes-*induced inflammation of the skin [96, 97]. Four natural chalcone derivatives, xanthohumol isolated from *Humulus lupulus* L*.* (minimum inhibitory concentration/MIC = 0.003 mg mL<sup>−</sup><sup>1</sup> ) [98], panduratin A and isopanduratin A isolated from *Kaempferia pandurata* Roxb*.* (MICs = 0.002 and 0.004 mg mL<sup>−</sup><sup>1</sup> ) [99], and 2′,6′-dihydroxy-3′-methyl-4′-methoxydihydrochalcone isolated from *Eucalyptus maculata* (MIC = 0.002 mg mL<sup>−</sup><sup>1</sup> ), also exhibited antibacterial activity against *Cutibacterium acnes* [100]. Different mode of action was shown by two synthetic chalcone derivatives, 2,2′-dihydroxychalcone and 2′-hydroxy-2,3,5′ trimethoxychalcone, to reduce sebum secretion and pore size on the skin [101].

### **5.2 Seborrheic dermatitis and dandruff**

Seborrheic dermatitis is a skin illness mainly influencing skin area with high amounts of sebaceous glands (such as the face, scalp, central chest, and anogenital) and characterized with the presence of erythematous patches with superficial scaling. The mildest form of seborrheic dermatitis that only affects the scalp area with no overt inflammation is usually considered as dandruff or pityriasis capitis. In general, seborrheic dermatitis affects adolescents during puberty to adulthood; however, another form of this disease is considered as infantile seborrheic dermatitis affecting babies and young children [102].

The main mechanism triggering this disease remains unknown; however, it is probably caused by the imbalance of three factors: sebum oversecretion by the sebaceous gland that is affected by certain hormonal [103] and environmental [104] conditions, sebum metabolism by *Malassezia* spp*.* that accumulate linoleic acid, and individual susceptibility to the penetration of the unsaturated fatty acids that mediate pain and itch [105, 106]. The lipid layer of *Malassezia* spp*.* also stimulated keratinocytes to produce anti-inflammatory (IL-4, IL-10) and pro-inflammatory (IL-1α, IL-6, IL-8, IL-12, TNF-α) cytokines [107, 108].

Licochalcone A is an active anti-inflammatory drug used in several formulations in treating seborrheic dermatitis. Tonic containing urea, lactate, polidocanol, and licochalcone A-containing *Glycyrrhiza inflate* root extract improved dry, itchy, and inflamed scalp condition which is often associated with seborrheic dermatitis. A combination of rinse-off shampoo (containing piroctone olamine and climbazole) and leave-on tonic (containing piroctone olamine and licochalcone A) significantly reduced dandruff and relieved its microinflammation. Treatment using this combination also significantly decreased some cytokines including IL-1ra/IL-1α and IL-8, compared to placebo shampoo [109]. In another report, a moisturizer containing licochalcone 0.025% also had a comparable cure rate with hydrocortisone 1% moisturizer in treating infantile seborrheic dermatitis [110].

#### **5.3 Psoriasis**

Psoriasis is a multifactorial skin disease characterized by the presence of red, dry, itchy, and scaly plaques due to chronic hyperproliferative keratinocyte cells and inflammatory cell infiltration [111]. Pathogenesis of this disease includes several steps triggered by environmental [111] and genetic [112] factors: (1) secretion of TNF-α by keratinocyte cells triggered by certain environmental and genetic factors, (2) TNF-α-induced dendritic cell activation and production of IL-23, (3) IL-23 induced T-helper 17 (Th17) cell differentiation, and secretion of IL-17A that cause hyperproliferation of keratinocyte cells [113]. Moreover, IL-17A also synergizes with IL-36 secreted by keratinocytes to amplify and support chronic characteristic of this disease [114]. Several molecular targets have been identified with drug candidates being tested in clinical stages such as cytokines (TNF-α, IL-17A, IL-17E, IL-17F, and IL-23 p19 subunit), phosphodiesterase 4, A3 adenosine receptor, and Janus kinases (JAK1-JAK3) signaling pathways [115].

Recent studies report that chalcones are efficient in improving some psoriasis models. Intraperitoneal injection of isoliquiritigenin compound remedied mouse with psoriasis-like skin predisposition and decreased several pro-inflammatory cytokines (IL-6 and IL-8) as well by inhibition of NF-κB on in vitro and in vivo assays [116]. The isolated licochalcone B and echinatin compounds from *Glycyrrhiza glabra* also exhibited higher activity than isoliquiritigenin compound in relieving psoriasis-like inflammation induced by several pro-inflammatory agents such as 12-*O*-tetradecanoylphorbal-13-acetate (TPA), adenosine diphosphate (ADP), and UVB radiation [117]. In other targets, several α-bromo- and α-tetrafluoromethyl-2′,3,4,4′-tetramethoxychalcones showed anti-inflammatory and immunomodulatory activities through inhibition on IL-3 and interferon-α (IFNα)-induced JAK2/ STAT5 (signal transducer and activator of transcription 5) [118] and STAT1 and STAT2 [119] signaling pathways. Furthermore, both compounds were also able to inhibit NF-κB and to activate Nrf2 transcriptional activity [120].

#### **5.4 Atopic dermatitis**

Atopic dermatitis (atopic eczema) is a complex inflammatory skin disease characterized by the presence of skin dryness with intense itching sensation, younger/ early-onset, and atopy [121]. There are three main factors that contribute to pathogenesis of atopic dermatitis, i.e*.*, (1) genetic and immune factors on the defect of physical and chemical barrier in the skin [122], (2) hyperactive immune cells due to a biological response (mutation on caspase recruitment domain family member 11/CARD11 gene) because of the incoming pollutants and pathogens [123], and (3) environmental factors that contribute in triggering and enhancing severities of atopic dermatitis process [124].

Chalcone-containing formulations have been prepared and evaluated in treating atopic dermatitis. These chalcone derivatives were combined with other active ingredients, and it was found that they acted as anti-inflammatory and antioxidative agents. It was also reported that licochalcone A-containing moisturizer showed slightly lower effect than hydrocortisone lotion in treating mildto-moderate atopic dermatitis in children [125]. Another study also found that oil-in-water formulation containing *Glycyrrhiza inflata* root extract (licochalcone A), decanediol, menthoxypropanediol, and ω-6-fatty acids had quite similar efficacy compared to hydrocortisone lotion (standard medication) in a 1-week clinical study with significant improvement in skin conditions, which is remarkable [126]. Using 0.02% triamcinolone acetonide cream as a reference, a combination of 4-*t*-butylcyclohexanol and licochalcone A compounds in moisturizer formulation showed a slower improvement rate, but better result in relieving erythema and increasing skin hydration [127]. Meanwhile, water-in-oil emollient containing licochalcone A, ω-6-fatty acids, ceramide 3, and glycerol formulation could serve a preventing effect on reducing atopic dermatitis flares even after stopping the treatment [128].

#### *Chalcones in Dermatology DOI: http://dx.doi.org/10.5772/intechopen.91145*

Other compounds such as isoliquiritigenin and 3′-isopentenyl-2,2′,4,4′ tetrahydroxy-6′-methoxychalcone (ITC) showed similar effects on atopic dermatitis skin. Evaluation of isoliquiritigenin in relieving atopic dermatitis-like lesion in mice caused a significant improvement in skin condition and attenuated several pro-inflammatory parameters such as Immunoglobulin E (IgE), Th2 cytokine upregulation, TNF-α, IL-6, and IL-4 [129]. ITC isolated from *Sophora flavescens* Aiton also ameliorated atopic dermatitis-like model in mice by inducing HO-1 expression which leads to suppression of Th2 chemokine expressions [130].

#### **6. Rosacea**

Rosacea is a multifactorial chronic inflammatory skin disorder characterized by the presence of persistent or periodical redness and several kinds of changing in phymatous in the central facial skin (cheeks, chin, nose, and central part of forehead) [131]. Based on the appearance of certain major phenotypes, rosacea is divided into erythematotelangiectatic rosacea, papulopustular rosacea, glandular/ hyperplastic rosacea, ocular rosacea, and other special forms such as rosacea conglobata, rosacea fulminans, gram-negative rosacea, steroid-induced rosacea, granulomatous (lupoid) rosacea, Morbihan's disease, and rosacea in children [132]. Pathogenesis of rosacea has not been fully comprehended yet, but there are several factors that involve including (1) genetics, Haber's syndrome with rosacea as one of clinical feature can be inherited; (2) environment, certain environmental factors can trigger rosacea including extreme air temperature, sudden temperature changes, food (caffeine, alcohol, hot and spicy food), sunlight (UV and IR radiation), etc.; (3) overproduction of antimicrobial peptides (AMPs) by congenital immune system such as LL-37; (4) ROS-induced inflammation produced by adaptive immune cells; (5) overexpression of toll-like receptors (TLRs); (6) *Demodex folliculorum*-induced inflammations; and (7) neuroinflammation and vascular hyperactivity [132, 133].

Hesperidin methyl chalcone, licochalcone A, and tetracarboxymethyl naringenin chalcone exhibit significant activity in improving the skin with rosacea. Clinical studies showed that hesperidin methyl chalcone-containing topical formulations could improve infected skin condition by decreasing the proportion of dilated vessels, total vessel area, and IL8 productions. These formulations showed a complementary effect between each active ingredient in relieving inflammation and reducing the redness [134]. Another study reported that hesperidin methyl chalcone had anti-inflammatory and anti-analgesic activities which are two targets in treating rosacea by inhibiting transient receptor potential vanilloid type 1 (TRPV1), oxidative stress, TNF-α, interleukin (IL) production (IL-1β, IL-6, and IL-10), and NF-κB activity [135].

Licochalcone A is a natural product from *Glycyrrhiza inflate* that shows potent activity in treating especially in mild and moderate symptoms. In vivo studies showed that skin care formulations containing licochalcone A provided various activities such as UVA/UVB protecting, moisturizing, and redness concealing abilities that improved skin appearance with rosacea. These formulations exhibited high compatibility with sensitive skin and could be combined with other treatments such as metronidazole treatment [136]. Licochalcone A-containing moisturizer formulation also increased skin hydration and reduced transepidermal water loss [137]. The most recent chalcone derivative used as anti-rosacea is a stabilized form of naringenin chalcone, i.e., tetracarboxymethyl naringenin chalcone (TNC). TNC was obtained from naringenin chalcone by total etherification reaction of methylchloroacetate. In vitro study showed that TNC significantly reduces LL-37, calcitriol, and several LL-37-induced inflammatory mediators in keratinocytes. Clinical test also showed that formulation containing TNC as a single active ingredient reduced the redness of the skin with rosacea compared to untreated skin areas [138].
