Inhibition of α-, ß-, γ-, δ-, ζ- and η-class carbonic anhydrases from bacteria, fungi, algae, diatoms and protozoans with famotidine.

Famotidine, an antiulcer drug belonging to the H2 antagonists class of pharmacological agents, was recently shown to potently inhibit human (h) and bacterial carbonic anhydrases (CAs, EC 4.2.1.1). We investigated the inhibitory effects of famotidine against all classes of CAs from the pathogenic bacteria Vibrio cholerae, Burkholderia pseudomallei and Mycobacterium tuberculosis Rv3273 ß-CA, as well as the CAs from the nonpathogenic bacteria/cyanobacteria Sulfurihydrogenibium yellowstonensis, S. azorense, Pseudoalteromonas haloplanktis, Colwellia psychrerythraea and Nostoc commune. The δ- and ζ-CAs from the diatom Thalassiosira weissflogii, the fungal enzymes from Cryptococcus neoformans, Candida glabrata and Malassezia globosa, as well as the protozoan enzymes from Trypanosoma cruzi and Plasmodium falciparum, were also investigated. Anopheles gambiae ß-CA was also investigated. All these enzymes were effectively inhibited by famotidine, with affinities between the low nanomolar to the micromolar range. The best inhibition was observed against C. glabrata ß-CA and TweCAζ, with KIs ranging between 13.6 and 22.1 nM.

Kinetic investigation of Famotidine S-oxidation reaction using potassium caroate. Development and validation of the titrimetric method for the quantitative determination of Famotidine in pure substance and medical preparation / Estudio cinético de la reacción de Famotidina S-oxidación utilizando caroato de potasio. Desarrollo y validación del método titrimétrico para la determinación cuantitativa de Famotidina en sustancia pura y preparación médica

Aims: The kinetic studies of Famotidine (FMT) pure substance and medicinal preparation have been carried out in buffer solutions under second-order conditions at the temperature 293 K for the first time. New titrimetric procedures are described for the FMT determination. Materials and Methods: FMT pure substance and tablets have been used in analytical reaction with of KHSO5. The kinetic behavior has been studied by the iodometric method in different pH medium. Results: FMT oxidation reaction has been studied for the S-oxide product under pH=2.0-5.0 and Sulfone product under pH=7.0-8.4. The reaction studied corresponds to the total second order. The Sulfone formation from FMT S-oxide reaction rate constant is in the interval from 14.49 to 32 min-1 L mol-1. FMT has been treated with a measured excess of standard potassium caroate in buffer solution with pH 7, after a contact time of 20 min, the residual oxidant back has been determined by the iodometric titration method. The titrimetric method is applicable over 1-10 mg mL-1 concentration range and the reaction follows 1:2 (FMT:KHSO5) stoichiometry. The method has been validated for precision, accuracy, linearity, robustness and LOQ. The recovery percent ranged from 99.2 to 100.5%, RSD from 1.09 to 1.70 %, LOQ = 0.03 mg mL-1 for pure substance. RSD for tablet formulations has been in the limits from 1.17-2.87 %. Conclusions: The conditions of FMT S-oxide and Sulfone formation have been optimized. The developed procedures are rapid, simple and inexpensive and could be applied to pharmaceutical preparation

Objetivos: Los estudios cinéticos de substancia y medicamento Famotidina (FMT) han sido realizados en las soluciones amortiguadoras en las condiciones de reacción del segundo orden a temperatura de 293 K. Nuevos métodos titrimétricos están descritos para determinar FMT. Materiales y métodos: La substancia y los comprimidos FMT han sido usados en la reacción analítica con KHSO5. El comportamiento cinético ha sido estudiado por el método de yodometría en diferentes ambientes de pH. Resultados: La reacción de oxidación de FMT se estudiaba para el producto del óxido S con pH = 2,0-5,0 y de la sulfona con pH = 7,0-8,4. La reacción a estudiar corresponde al segundo orden general. Las constantes de velocidad de la reacción de la formación de sulfona del óxido S FMT se encuentra en el intervalo de 14,49 a 32 l mol-1 min-1. La FMT fue determinada mediante la medición del exceso de solución estándar del caroata de potasio en la solución amortiguadora con pH 7 dentro de 20 minutos desde el inicio de la reacción, luego el oxidante restante fue determinado por el método de titulación yodométrica. El método titrimétrico se aplica en el diapasón de 1-10 mg, la reacción corresponde a la estequiometría 1: 2 (FMT: KHSO5). El método ha sido validado a la precisión, reproducción, linealidad, robustez y LOQ. El contenido del principio activo es del 99,2 al 100,5%, RSD del 1,09 al 1,70%, LOQ = 0,03 mg / ml para substancia. RSD para comprimidos se encuentra dentro del 1,17 al 2,87%. Conclusión: Han sido optimizadas las condiciones de formación del óxido S de FMT y sulfona. Los métodos elaborados son rápidos, sencillos y baratos y podrán aplicarse para determinar el fármaco de preparación farmacética

Solid-state supramolecular synthesis based on the N-H O heterosynthon: an approach to solve the polymorphism problem in famotidine.

Famotidine (FMT), a histamine H2 -receptor antagonist, is a drug commonly used in treatments of gastroesophageal diseases that presents solid-state polymorphism (A and B forms), the marketed form being the metastable polymorph B. A new stable salt was obtained by combination of FMT and maleic acid as coformer. FMT maleate (FMT-MLT) was prepared either by solvent evaporation or comilling methods. Single-crystal X-ray diffraction reveals that (FMT)(+) in FMT-MLT adopts an extended conformation that is stabilized by classical and nonclassical H-bonds. The three-dimensional packing consists of tapes along the axis b that further develop a columnar array based on H-bonds involving (FMT)(+) side chain. Nonconventional π-stacking interactions between adjacent tapes were also identified. Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, polarized light thermal microscopy, and scanning electron microscopy were employed to characterize the multicomponent complex. According to the solubility values in water and simulated gastric fluid, FMT-MLT exhibits such a performance that improves on the solubility of the commercially available polymorph. Finally, the higher stability of FMT-MLT regarding both FMT forms, as well as its easy preparation from either A or B forms or a mixture of them, also allows to consider this salt as a valuable alternative to avoid the polymorphism issue in marketed formulations containing FMT.

Interesting coordination abilities of antiulcer drug famotidine and antimicrobial activity of drug and its cobalt(III) complex.

Crystal structure of a novel cobalt(III) complex with antiulcer drug famotidine and ethylenediamine was determined. This is the second structure of a transition metal complex with famotidine resolved by a single crystal X-ray analysis, in which famotidine shows different mode of coordination than that observed in the other cases. Drug molecule is coordinated to metal ion as a tetradentate ligand through guanidine N6, thiazole N4, thioether S2 and terminal N3 atom. Two NH(2) groups (N3H(2) and N6H(2)) are deprotonated and drug coordinates as dianion. In the asymmetric unit, one chloride anion and one water molecule were found to complete the complex stoichiometry. The structure of the complex is abundant in atoms, which can be involved in hydrogen bond formation either as hydrogen acceptors or hydrogen donors. Because of that, a great number of hydrogen bonds dominates the crystal packing. Beside the hydrogen bonds, there are two interesting noncovalent interactions: CH(...)pi and NH(...)pi within the famotidine anion, which stabilize the complex structure. The pi(...)pi stacking interactions between neighboring complex cations are also observed. Antibacterial and antifungal activity of famotidine and its newly synthesized complex against representative bacteria: Escherichia coli, Staphilococcus aureus and Micrococcus lysodeikticus and fungi: Aspergillus niger and Candida albicans were examined. The results indicate a higher selectivity of the famotidine-Co(III) complex, as well as better growth inhibitory activity (lower MIC values (MIC, minimal inhibitory concentration)) in comparison with the drug alone.

Photoaffinity labeling of the anionic sites in Caco-2 cells mediating saturable transport of hydrophilic cations ranitidine and famotidine.

The H(2) antagonists, ranitidine and famotidine, exhibit saturable absorptive transport across Caco-2 cell monolayers and human intestine via a yet unidentified mechanism. A photoreactive derivative of famotidine has been synthesized and evaluated as a photoaffinity probe for the putative transporter protein(s). The probe irreversibly inhibited ranitidine transport across Caco-2 cell monolayers and irreversibly increased the transepithelial electrical resistance (TEER) after UV activation. Photoaffinity labeling was protected by a molar excess of famotidine.

A study on the nickel II-famotidine complexes.

Potentiometric studies have shown that Ni(II) forms three pH-dependent complexes with famotidine (L), namely: [NiHL](3+), [NiL](2+) and [NiH(-2)L]. Two of them have been isolated from solution with a Ni/famotidine ratio of 1:1. At pH 6.0, a paramagnetic complex [NiL](2+) with octahedral geometry is formed in which, most likely thiazole N(9) and guanidine N(3) nitrogens are involved in the metal binding. Additionally, two water molecules and two perchlorate anions, ClO(4)(-), fulfil the coordination sphere. The second complex, [NiH(-2)L], that precipitates at pH 8 is diamagnetic and takes square-planar geometry in which four nitrogen donors: N(3), N(9), N(16) and N(20) coordinate to Ni(II). Potentiometric studies, mass spectrometry, FT-IR and Raman spectroscopy are employed to determine and discuss the structure of both complexes. Additionally, 1H, 13C and 15N NMR spectroscopy is used to confirm the binding site in a square-planar complex. The assignment of vibrational bands are made using ab initio HF/CEP-31G method.