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Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity.

ABSTRACT: Co-crystallization is a phenomenon widely employed to enhance the physio-chemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methyl-ideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of co-crystals of exemestane with thio-urea by liquid-assisted grinding. The purity and homogeneity of the exemestane-thio-urea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N-H?O hydrogen bonding between the amine (NH2) groups of thio-urea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC50 = 3.86 ± 0.31?µg?ml-1) compared with the API (exemestane), which was found to be inactive, and the co-former (thio-urea) (IC50 = 21.0 ± 1.25?µg?ml-1), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of co-crystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.

SUBMITTER: Fatima SS

PROVIDER: S-EPMC6949591 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity.

Fatima Syeda Saima SS Kumar Rajesh R Choudhary M Iqbal MI Yousuf Sammer S

IUCrJ 20200101 Pt 1

Co-crystallization is a phenomenon widely employed to enhance the physio-chemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methyl-ideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of co-crystals of exemestane with thio-urea by liquid-assisted grinding. The purity and homogeneity of the exemestane ...[more]

PMID: 31949910

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Project description:Catheter-associated urinary tract infections (CAUTIs) account for over 30% of acute nosocomial infections in the U.S. and generate $340 million in healthcare costs annually. A major causative agent of CAUTIs is Proteus mirabilis, an understudied Gram-negative pathogen noted for its ability to form urinary stones via the activity of urease. Urease mutants cannot induce stones and are attenuated in a murine UTI model, indicating this enzyme is essential to P. mirabilis pathogenesis. The ability to induce urinary stone formation requires an active urease, a nickel metalloenzyme that hydrolyzes urea. This reaction produces ammonia as a byproduct, which can serve as a nitrogen source and weak base that raises the local pH. The resulting alkalinity induces the precipitation of polyvalent cations and anions to form stones. Expression of urease genes is activated by transcriptional regulator UreR in a urea-dependent manner. Thus, urease genes are highly expressed in the urinary tract where urea is abundant (~400 mM in human urine). Production of mature urease also requires the import of nickel into the cytoplasm and its incorporation into the urease apoenzyme. Urease accessory proteins primarily acquire nickel from the Ynt transporter and facilitate the incorporation of nickel to form mature urease. P. mirabilis encodes a second, low-affinity transport system (Nik) that can provide nickel when this metal is abundant. In this study, we identified UreR as the first defined regulator of nickel transport in P. mirabilis. We also offer evidence for direct regulation of the ynt promoter by UreR. Using bioinformatics, we identified UreR-regulated urease loci in 15 Morganellaceae family species across three genera. Additionally, we located two mobilized UreR-regulated urease loci that also encode the ynt transporter, implying that UreR regulation of ynt is a conserved regulatory relationship. Our study demonstrates that UreR regulates all genes required to produce mature urease, an essential virulence factor for P. mirabilis uropathogenesis.

Dataset Information

Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity.

Publications

Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity.

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