Carboxylic acid

About: Carboxylic acid is a research topic. Over the lifetime, 48544 publications have been published within this topic receiving 605696 citations.

Reactivity differences of indomethacin solid forms with ammonia gas

Abstract: The present study deals with the acid-base reaction of three solid-state forms of the nonsteroidal antiinflammatory drug indomethacin with ammonia gas. X-ray powder diffraction, optical microscopy, gravimetry, and spectroscopic methods were employed to establish the extent of the reaction as well as the lattice changes of the crystal forms. The glassy amorphous form readily reacts with ammonia gas to yield a corresponding amorphous ammonium salt. In addition, the metastable crystal form of indomethacin (the alpha-form) also reacts with ammonia gas, but produces the corresponding microcrystalline ammonium salt. This reaction is anisotropic and propagates along the a-axis of the crystals. The stable crystal form (the gamma-form), however, is inert to ammonia gas. Amorphous indomethacin can react with ammonia gas because it has more molecular mobility and free volume. The reactivity differences between the alpha- and gamma-forms are dictated by the arrangement of the molecules within the respective crystal lattices. The recently determined crystal structure of the metastable alpha-form of indomethacin (monoclinic P2(1) with Z = 6, V = 2501.8 A(3), D(c) = 1.42 g.cm(-3)) has three molecules of indomethacin in the asymmetric unit. Two molecules form a mutually hydrogen-bonded carboxylic acid dimer, while the carboxylic acid of the third molecule is hydrogen bonded to one of the amide carbonyls of the dimer. The carboxylic acid groups of the alpha-form are exposed on the [100] faces and are accessible to attack by ammonia gas. After one layer of molecules reacts, the reactive groups in the subsequent layer are accessible to the ammonia gas. This process proceeds along the a-axis until the ammonia gas has penetrated the entire crystal. In contrast to the alpha-form, the gamma-form has a centrosymmetric crystal structure in which the hydrogen-bonded carboxylic acid dimers are not accessible to ammonia gas because they are caged inside a hydrophobic shield comprising the remainder of the indomethacin molecule. In view of the significantly lower density of the stable gamma-form as compared to the metastable alpha-form (1.37 and 1.42 g cm(-3), respectively), it became apparent that the reactivity of the crystal forms depends exclusively on the molecular arrangement and not on the packing density of the indomethacin crystals.

Cytotoxicity of novel fluorinated alternatives to long-chain perfluoroalkyl substances to human liver cell line and their binding capacity to human liver fatty acid binding protein

Abstract: Although shorter chain homologues and other types of fluorinated chemicals are currently used as alternatives to long-chain perfluoroalkyl substances (PFASs), their safety information remains unclear and urgently needed. Here, the cytotoxicity of several fluorinated alternatives (i.e., 6:2 fluorotelomer carboxylic acid (6:2 FTCA), 6:2 fluorotelomer sulfonic acid (6:2 FTSA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and hexafluoropropylene oxide (HFPO) homologues) to human liver HL-7702 cell line were measured and compared with perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Their binding mode and affinity to human liver fatty acid binding protein (hL-FABP) were also determined. Compared with PFOA and PFOS, 6:2 Cl-PFESA, HFPO trimer acid (HFPO-TA), HFPO tetramer acid (HFPO-TeA), and 6:2 FTSA showed greater toxic effects on cell viabilities. At low exposure doses, these alternatives induced cell proliferation with similar mechanism which was different from that of PFOA and PFOS. Furthermore, binding affinity to hL-FABP decreased in the order of 6:2 FTCA < 6:2 FTSA < HFPO dimer acid (HFPO-DA) < PFOA < PFOS/6:2 Cl-PFESA/HFPO-TA. Due to their distinctive structure, 6:2 Cl-PFESA and HFPO homologues were bound to the hL-FABP inner pocket with unique binding modes and higher binding energy compared with PFOA and PFOS. This research enhances our understanding of the toxicity of PFAS alternatives during usage and provides useful evidence for the development of new alternatives.

Structure Property Relationships of Carboxylic Acid Isosteres

Abstract: The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.

Novel Approaches for Designing 5'-O-Ester Prodrugs of 3'-Azido-2'3'-Dideoxythymidine (AZT)

Abstract: 3-Azido-2,3-dideoxythymidine (AZT, 1 , zidovudine, RetrovirTM) is used to treat patients with human immunodeficiency virus (HIV) infection. AZT, after conversion to AZT-5-triphosphate (AZT-TP) by cellular enzymes, inhibits HIV-reverse transcriptase (HIV-RT). The major clinical limitations of AZT are due to clinical toxicities that include bone marrow suppression, hepatic abnormalities and myopathy, absolute dependence on host cell kinase-mediated activation which leads to low activity, limited brain uptake, a short half-life of about one hour in plasma that dictates frequent administration to maintain therapeutic drug levels, low potential for metabolic activation and/or high susceptibility to catabolism, and the rapid development of resistance by HIV-1. These limitations have prompted the development of strategies for designing prodrugs of AZT. A variety of 5-O-substituted prodrugs of AZT constitute the subject of this review. The drugdesign rationale on which these approaches are based is that the ester conjugate will be converted by hydrolysis and/or enzymatic cleavage to AZT or its 5-monophosphate (AZT-MP). Most prodrug derivatives of AZT have been prepared by derivatization of AZT at its 5-O position to provide two prominent classes of compounds that encompass: A) 5-O-carboxylic esters derived from 1) cyclic 5-O-carboxylic acids such as steroidal 17β-carboxylic acids, 1- adamantanecarboxylic acid, bicyclam carboxylic acid derivatives, O-acetylsalicylic acid, and carbohydrate derivatives, 2) amino acids, 3) 1,4-dihydro-1-methyl-3-pyridinylcarboxylic acid, 4) aliphatic fatty acid analogs such as myristic acid containing a heteroatom, or without a heteroatom such as stearic acid, and 5) long chain polyunsaturated fatty acid analogs such as retinoic acid, and B) masked phosphates such as 1) phosphodiesters that include monoalkyl or monoaryl phosphate, carbohydrate, ether lipid, ester lipid, and foscarnet derivatives, 2) a variety of phosphotriesters that include dialkylphosphotriesters, diarylphosphotriesters, glycolate and lactate phosphotriesters, phosphotriester approaches using simultaneous enzymatic and chemical hydrolysis of bis(4-acyloxybenzyl) esters, bis(S-acyl-2-thioethyl) (SATE) esters, cyclosaligenyl prodrugs, glycosyl phosphotriesters, and steroidal phosphotriesters, 3) phosphoramidate derivatives, 4) dinucleoside phosphate derivatives that possess a second anti-HIV moiety such as AZT-P-ddA, AZT-P-ddI, AZTP2AZT, AZTP2ACV), and 5) 5-hydrogen phosphonate and 5-methylene phosphonate derivatives of AZT. In these prodrugs, the conjugating moiety is linked to AZT via a 5-O-ester or 5-O-phosphate group. 5-O-Substituted AZT prodrugs have been designed with the objectives of improving anti-HIV activity, enhancing blood-brain barrier penetration, modifying pharmacokinetic properties to increase plasma half-life and improving drug delivery with respect to site-specific targeting or drug localization. Bypassing the first phosphorylation step, regulating transport and conferring sustained release of AZT prolong its duration of action, decrease toxicity and improve patient acceptability. The properties of these prodrugs and their anti-HIV activities are now reviewed.