Terconazole targets fungal cytochrome P450 14α-demethylase (lanosterol 14α-demethylase, CYP51), an enzyme essential for ergosterol biosynthesis. By inhibiting this enzyme, terconazole blocks the conversion of lanosterol to ergosterol, leading to the accumulation of methylated sterols and depletion of ergosterol. This disruption compromises fungal cell membrane integrity, alters membrane permeability, and promotes the loss of essential intracellular elements, ultimately resulting in fungal cell death.

The growth of Candida albicans ATCC 44859 was decreased by terconazole in a concentration-dependent manner. However, the effect was minimal at 0.1 to 10 μM when the yeast was cultured on medium that supported cell morphology. Terconazole's capacity to reduce yeast cell viability differs according on the type and strain of the parasite being examined. Candida albicans ATCC 44859's sensitivity to terconazole was greatly increased when it was cultivated on Eagle's minimal essential medium, which aided in the mycelium's development. The alterations occur in a sequence, starting at 0.1 μM terconazole and ending with total necrosis at 100 μM [1]. At doses of 0.008 to 0.05 μg/mL, terconazole inhibits the morphogenetic transition of yeast to filamentous forms [2].
In vitro, terconazole exhibits potent activity against a broad spectrum of Candida species, including Candida albicans. The compound's antifungal activity is assessed by determining minimum inhibitory concentrations (MIC) against various fungal strains. It shows relatively broad-spectrum activity compared to other azole compounds. In vitro studies demonstrate its efficacy against both azole-susceptible and some azole-resistant Candida isolates. The compound also shows activity against other fungal pathogens.

A 3-day, once-daily intravaginal administration of terconazole 0.8% is typically sufficient to produce a 7-day functional therapeutic period due to the vagina's long-lasting high bioactive antifungal levels. At whatever terconazole concentration, no negative effects were noted [2].
In vivo, terconazole is effective in animal models of vaginal candidiasis. In a rat model, administration of terconazole as a 1% topical ointment eliminated vaginal C. albicans infection in 97% of animals. Oral administration at a dose of 10 mg/kg was effective in 50% of rats. These in vivo efficacy data support the clinical use of terconazole for vulvovaginal candidiasis. The compound is also studied for its pharmacokinetics and resistance patterns.

In vitro enzyme assays for terconazole measure its inhibition of fungal cytochrome P450 14α-demethylase activity. The enzyme is typically obtained from Candida microsomal preparations. The assay involves incubating the enzyme with its substrate (lanosterol) and NADPH in the presence of varying concentrations of terconazole. The production of ergosterol or the accumulation of 14α-methylated sterols is quantified by HPLC or GC-MS. The IC50 for enzyme inhibition is calculated from dose-response curves, providing a measure of the compound's potency against the target enzyme.

In vitro cell-based assays for terconazole use fungal cell cultures, primarily Candida albicans and other Candida species. Cells are cultured in liquid or solid media and exposed to serial dilutions of the compound. Antifungal susceptibility testing is performed using broth microdilution or agar dilution methods according to CLSI (formerly NCCLS) guidelines. The minimum inhibitory concentration (MIC) is determined after 24-48 hours of incubation. Fungicidal activity is assessed by subculturing onto drug-free media to determine the minimum fungicidal concentration (MFC).

In vivo animal models for terconazole include rat and mouse models of vaginal candidiasis. Female animals are rendered pseudopregnant and infected intravaginally with Candida albicans. Terconazole is administered topically as a cream or suppository, or orally at various doses. Efficacy is evaluated by quantitative vaginal cultures to determine fungal burden reduction. Clinical signs of infection are also monitored. Pharmacodynamic parameters such as the effective dose for 50% cure (ED50) are calculated from dose-response studies.

Absorption, Distribution and Excretion
Following intravaginal administration of terconazole, the absorption rate was 5-8% in 3 subjects who had undergone hysterectomy and 12-16% in 2 subjects who had not undergone hysterectomy but had tubal ligation. Following oral administration of 30 mg of 14C-labeled terconazole, the radioactive material was primarily excreted via the kidneys (32-56%) and feces (47-52%). Metabolism/Metabolites Systemically absorbed drugs appear to be metabolized rapidly and extensively. Terconazole primarily undergoes oxidative N- and O-dealkylation, dioxolane cleavage, and conjugation reactions. Biological Half-Life 6.9 hours (range 4.0-11.3 hours)
Terconazole is administered topically for the treatment of vulvovaginal candidiasis, with minimal systemic absorption following vaginal application. The compound is highly lipophilic and partitions into vaginal tissues, achieving therapeutic concentrations locally. Systemic exposure is low, which contributes to its favorable safety profile. When absorbed, terconazole is metabolized in the liver and excreted via the bile and urine. The pharmacokinetics of oral terconazole have been studied in preclinical models.

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation: The use of terconazole vaginal preparations during lactation has not been studied. Other antifungal medications may be more appropriate, especially for breastfed newborns or premature infants. ◉ Effects on Breastfed Infants: No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk: No published information found as of the revision date.

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Protein Binding Rate
94.9%
Terconazole has a favorable safety profile with minimal systemic adverse effects due to its topical administration. Local irritation, burning, or itching may occur at the application site. Systemic toxicity is rare because of low systemic absorption. The compound is generally well-tolerated in clinical use for vulvovaginal candidiasis. Drug interactions are minimal due to limited systemic exposure. As with other azole antifungals, caution is advised in patients with hepatic impairment.

[1]. Anticandidal activities of terconazole, a broad-spectrum antimycotic. Antimicrob Agents Chemother. 1986 Jun;29(6):986-91.

[2]. The in vitro activity of terconazole against yeasts: its topical long-acting therapeutic efficacy in experimental vaginal candidiasis in rats. Am J Obstet Gynecol. 1991 Oct;165(4 Pt 2):1200-6.

(2R,4S)-Ticonazole is a 1-(4-{[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy}phenyl)-4-isopropylpiperazine, wherein the 1,3-dioxolane moiety has R and S configurations at positions 2 and 4, respectively. It is the enantiomer of (2S,4R)-Ticonazole. Ticonazole is a prescription antifungal drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of vulvovaginal candidiasis. Vulvovaginal candidiasis may be an opportunistic infection (OI) of HIV. Ticonazole is an antifungal drug primarily used to treat vaginal yeast infections (or vaginal candidiasis). It is classified as a triazolone derivative. Ticonazole was initially approved by the U.S. Food and Drug Administration (FDA) in 1987. This drug is available in both cream and suppository formulations, and clinical trials have shown that both formulations have high safety, efficacy, and tolerability. Due to the presence of two stereocenters, teconazole has four possible stereoisomers. Teconazole is a synthetic triazole derivative whose structure is related to the antifungal drug fluconazole. Teconazole appears to disrupt cell wall synthesis by inhibiting the biosynthesis of ergosterol or other sterols, thereby damaging the fungal cell membrane, altering its permeability, and promoting the loss of essential intracellular components. Teconazole is effective against Candida spp. (NCI04). Drug Indications For the treatment of vulvar and vaginal candidiasis (a yeast-like fungal infection). FDA Label Mechanism of Action Teconazole likely exerts its antifungal activity by disrupting the normal permeability of the fungal cell membrane. Terconazole and other triazole antifungals inhibit cytochrome P450 14α-demethylase in susceptible fungi, leading to the accumulation of lanosterol and other methylated sterols, as well as a decrease in ergosterol concentration. The depletion of ergosterol in the cell membrane disrupts the structure and function of fungal cells, resulting in reduced or inhibited fungal growth.

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Pharmacodynamics
Teraconazole is a triazole antifungal drug that can be used vaginally. The structure of terconazole is related to imidazole antifungals, but terconazole and other triazole compounds contain three nitrogen atoms on their azole ring. Terconazole inhibits ergosterol synthesis by inhibiting 14α-demethylase (lanosterol 14α-demethylase). The reduction of ergosterol in the fungal cell membrane disrupts the structure and many functions of the fungal cell membrane, thereby inhibiting fungal growth.
Terconazole is approved by the FDA for the treatment of vulvovaginal candidiasis. It is available in various topical formulations including vaginal cream (0.4% and 0.8%) and vaginal suppositories. The recommended treatment duration varies from 1 to 7 days depending on the formulation and severity of infection. Terconazole is a drug of choice for uncomplicated vulvovaginal candidiasis. Its mechanism involves selective inhibition of fungal CYP51 with lower affinity for mammalian cytochrome P450 enzymes, contributing to its safety.

C26H31CL2N5O3

532.466

531.18

67915-31-5

Terconazole-d4;1398065-50-3

441383

White to off-white solid powder

1.35g/cm3

681.8ºC at 760mmHg

126.3ºC

366.2ºC

1.64

4.465

0

7

8

36

693

2

CC(C)N1CCN(CC1)C2=CC=C(C=C2)OC[C@H]3CO[C@](O3)(CN4C=NC=N4)C5=C(C=C(C=C5)Cl)Cl

BLSQLHNBWJLIBQ-OZXSUGGESA-N

InChI=1S/C26H31Cl2N5O3/c1-19(2)31-9-11-32(12-10-31)21-4-6-22(7-5-21)34-14-23-15-35-26(36-23,16-33-18-29-17-30-33)24-8-3-20(27)13-25(24)28/h3-8,13,17-19,23H,9-12,14-16H2,1-2H3/t23-,26-/m0/s1

1-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-propan-2-ylpiperazine

R 42,470; R-42,470; R42,470

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 30 mg/mL (~56.34 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)