Trimethoprim Cations Research Articles

Hydrogen Bonding Patterns in Trimethoprimium Cinnamate 1.52 Hydrate

In the title compound, [C14H19N4O3 +, C9H5 O2 −, H2O, O0.52] the asymmetric unit contains a protonated trimethoprim cation and a cinnamate anion and two water molecules. The crystal structure was determined by single crystal X-ray diffraction. This compound crystallized in the triclinic system; space group P−1 with the unit cell parameters a = 10.010(2) A, b = 10.339(3) A, c = 13.486(8) A, α = 105.32(3)°, β = 109.88(3)°, γ = 100.89(3)°, V = 1204.6(10) A3, Z = 2. The cinnamate group is disordered. The trimethoprim (TMP) molecule is protonated at one of the pyrimidine nitrogen atoms. The carboxylate group of the cinnamate anion interacts with the protonated pyrimidine atom N1 and the 2-amino group via a pair of N–H···O hydrogen bonds, generating the R 2 2 (8) ring motif. The inversion related TMP cations are paired via N–H···N hydrogen bonds. In addition to the base pairing, the O1W atom bridges the 2-amino and 4-amino groups on either side of the paired bases, resulting in a self complementary DADA array. Two inversion related TMP cations and water molecules (O1W) are linked via N–H···O and O–H···O hydrogen bonds, forming a 22 membered ring with graph-set R 4 4 (22). The protonated trimethoprim cation interacts with the cinnamate anion through a pair of N-H…O hydrogen bonds, generating the R 2 2 (8) ring motif. .

Bis[2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium]DL-malate

Racemic malic acid and trimethoprim [5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine] form a 1:2 salt (monoclinic, P2(1)/c), 2C(14)H(19)N(4)O(3)(+).C(4)H(4)O(5)(2-), in which the malate component is disordered across a centre of inversion. The crystal structure of the salt consists of protonated trimethoprim residues and a malate dianion. The carboxylate group of the malate ion interacts with the trimethoprim cation in a linear fashion through pairs of N-H...O hydrogen bonds to form a cyclic hydrogen-bonded motif. This is similar to the carboxylate-trimethoprim cation interaction observed earlier in the complex of dihydrofolate reductase with trimethoprim. The structure of the salt of trimethoprim with racemic DL-malic acid reported here is the first of its kind. The present study investigates the conformations and the hydrogen-bonding interactions, which are very important for biological functions. The pyrimidine plane makes a dihedral angle of 78.08 (7) degrees with the benzene ring of the trimethoprim cation. The cyclic hydrogen-bonded motif observed in this structure is self-organized, leading to novel types of hydrogen-bonding motifs in supramolecular patterns.

Crystal engineering of analogous and homologous organic compounds: hydrogen bonding patterns in trimethoprim hydrogen phthalate and trimethoprim hydrogen adipate.

BackgroundTrimethoprim [2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine] is an antifolate drug. It selectively inhibits the bacterial dihydrofolate reductase (DHFR) enzyme.ResultsIn the crystal structures of trimethoprim (TMP)-hydrogen phthalate (1) and trimethoprim-hydrogen adipate (2), one of the N atoms of the pyrimidine ring is protonated and it interacts with the deprotonated carboxylate oxygens through a pair of nearly parallel N-H...O hydrogen bonds to form a fork-like interaction. In the compound 1, the pyrimidine moieties of the TMP cations are centrosymmetrically paired through a pair of N-H...N hydrogen bonds involving 4-amino group and the N (N3) atom of the pyrimidine rings to form a 8-membered hydrogen bonded ring [R22(8)]. The 4-amino group of one TMP moiety and 2-amino group of another TMP moiety (both moieties are members of a base pair) are bridged by the carbonyl oxygen of the phthalate moiety through N-H...O hydrogen bonds forming 8-membered hydrogen-bonded ring [R22(8)]. The characteristic hydrogen-bonded rings observed in the structure aggregate into a supramolecular ladder consisting of a pair of chains, each of which is built up of alternate TMP and hydrogen phthalate ions. In the compound 2, two TMP cations and two hydrogen adipate anions are arranged about an inversion center so that the complementary DDAA (D = donor, A = acceptor) arrays of quadruple hydrogen-bonding patterns are formed. The head-to-tail arrangement of the hydrogen adipate ions leads to a hydrogen-bonded supramolecular chain. From crystal engineering point of view, it is interesting to note that the compound 1 has a hydrogen-bonded network remarkably identical with its aliphatic analogue, trimethoprim hydrogen maleate. Similarly the compound 2, resembles its homolog trimethoprim hydrogen glutarate.ConclusionIn the crystal structure of trimethoprim hydrogen phthalate, the hydrogen-bonded network is remarkably identical with its aliphatic analogue, trimethoprim hydrogen maleate. Similarly in the crystal structure of trimethoprim hydrogen adipate the hydrogen bonded network resembles its homolog trimethoprim hydrogen glutarate.

Hydrogen-bonding patterns in trimethoprim picolinate and 2-amino-4,6-dimethylpyrimidinium picolinate hemihydrate

In the title compounds, namely 2,4-diamino-5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidin-1-ium pyridine-2-carboxylate, C14H19N4O3+.C6H4NO2-, (I), and 2-amino-4,6-dimethylpyrimidin-1-ium pyridine-2-carboxylate hemihydrate, C6H10N3+.C6H4NO2-.0.5H2O, (II), the trimethoprim and 2-amino-4,6-dimethylpyrimidin-1-ium cations are protonated at one of the pyrimidine N atoms. In (I), bifurcated hydrogen bonds are observed between a picolinate O atom, the protonated N atom and the 2-amino group; the graph-set designator is R2(1)(6). The pyrimidine moieties of the trimethoprim cations are centrosymmetrically paired through a pair of N-H...N hydrogen bonds. In addition to the base pairing, one of the picolinate O atoms bridges the 2- and 4-amino groups on either side of the paired bases, resulting in a complementary DADA array. In (II), the carboxylate group of the picolinate anion binds with the protonated pyrimidine N atom and the 2-amino group of the pyrimidine moiety through a pair of N-H...O hydrogen bonds, leading to the common ring motif R2(2)(8). The water molecule, which resides on a twofold rotation axis, bridges the carboxylate group of the picolinate anion via O-H...O hydrogen bonds.

Hydrogen-bonding patterns in trimethoprim tetrafluoroborate

In the title compound [systematic name: 2,4-diamino-5-(3,4,5-trimethoxy­benz­yl)pyrimidinium tetrafluoroborate], C14H19N4O3+·BF4−, the trimethoprim (TMP) mol­ecule is protonated at one of the pyrimidine N atoms. The protonated N atom and 2-amine group of the TMP cation inter­act with the tetrafluoroborate anion through a pair of N—H⋯F hydrogen bonds [graph set R22(8)]. The inversion-related TMP cations are linked through a pair of N—H⋯N hydrogen bonds. The 2-amine group of one TMP cation and the 4-amine group of another cation are bridged by a meth­oxy O atom, via N—H⋯O hydrogen bonds.

Hydrogen-bonding patterns in bis(trimethoprim) dipicolinate pentahydrate

In the title compound, 2C14H19N4O3+·C7H3NO42−·5H2O, the asymmetric unit contains two trimethoprim cations (A and B), a dipicolinate anion and five water mol­ecules. One of the picolinate carboxyl­ate groups inter­acts with cation A via a pair of N—H⋯O hydrogen bonds, forming a ring motif R{_2^2}(8). A loop of O—H⋯O hydrogen bonds is formed between four water mol­ecules and the two carboxyl­ate groups to form a supramolecular chain along the a axis. Mol­ecules A and B constitute a base pair via N—H⋯N hydrogen bonds, and these base pairs are cross-linked by N—H⋯O and C—H⋯O hydrogen bonds.

Trimethoprim–hydrogen malonate (1/1)

In the title compound, 2,4-di­amino-5-(3,4,5-tri­methoxy­benzyl)­pyrimidinium hydrogen malonate, C14H19N4O3+·C3H3O4−, the trimethoprim mol­ecule is protonated at one of the pyrimidine N atoms. The carboxyl­ate group of the hydrogen malonate ion accepts a pair of N—H⋯O hydrogen bonds from an adjacent trimethoprim mol­ecule, which is similar to the carboxyl­ate–trimethoprim cation interaction present in the complex of di­hydro­folate reductase with trimethoprim. An O atom of the carboxyl group forms an intramolecular O—H⋯O hydrogen bond with the carboxyl­ate group, leading to a folded conformation for the hydrogen malonate ion. Each hydrogen malonate ion bridges two di­amino­pyrimidine cations, via N—H⋯O and C—H⋯N hydrogen bonds, leading to a supramolecular ribbon made up of alternating cations and anions. Two such inversion-related ribbons are cross-linked by (amino)N—H⋯O(methoxy) hydrogen bonds, (pyrimidine)C—H⋯O(methoxy) hydrogen bonds and π–π stacking involving the benzene planes.

Interplay of coordination and hydrogen bonding modes in the self-assembly of the supramolecular network in copper(II) phthalate–trimethoprim complex (0.5:1:1)

Trimethoprim cations forming self complementary hydrogen-bonded DADA arrays interact with the copper–phthalate supramolecular frameworks through extensive hydrogen bonding.

Supramolecular organisation via hydrogen bonding in trimethoprim sulfonate salts

The present study deals with the crystal structures of four organic salts, namely, trimethoprim benzene sulfonate monohydrate 1, trimethoprim sulfanilate monohydrate 2, trimethoprim p-toluene sulfonate 3 and trimethoprim 3-carboxy-4-hydroxybenzene sulfonate dihydrate 4. Trimethoprim (TMP) is protonated at one of the ring nitrogens of the pyrimidine ring. Generally, in the TMP carboxylate complexes, the protonated pyrimidine ring is hydrogen-bonded to the carboxylate group forming a cyclic fork-like hydrogen-bonded bimolecular motif. In structures 1–3, the sulfonate group plays the role of the carboxylate anion. In compounds 1 and 2, there is no pairing of the pyrimidine rings because the pairing sites are blocked by water molecules donating hydrogen to the unprotonated ring nitrogen. Two of the cyclic motifs are bridged by the water molecule donating two hydrogen atoms, leading to a hydrogen-bonded supramolecular chain. This chain pairs with another chain running in the opposite direction. These two chains are cross-linked by O–H⋯O hydrogen bonds. In compound 2, two of the hydrogen atoms of the amino group of the sulfanilate bridge two methoxy oxygen of the two TMP cations via N–H⋯O hydrogen bonds resulting in a supramolecular zig-zag chain. In compound 3, two inversion related cyclic motifs are paired through a pair of N–H⋯N hydrogen bonds involving the 4-amino group and the N3 atom of the pyrimidine ring. In addition to the pairing, one of the sulfonate oxygen atoms bridges the 2-amino and 4-amino groups on either side of the paired bases, resulting in a self-complementary DADA (D represents the hydrogen bond donor and A represents hydrogen bond acceptor) array of quadruple hydrogen bonding patterns. In compound 4, one of the water molecules forms a hydrogen-bonded dimer with the inversion-related water molecule. The 3-carboxy-4-hydroxybenzene sulfonate moiety self-assembles into a supramolecular chain along the c axis through O–H⋯O hydrogen bonds. Two such oppositely running supramolecular chains are connected by dimeric and monomeric water molecules. The variation of supramolecular organization via hydrogen bonding in the four different trimethoprim sulfonate salts has been discussed.

A pseudo-quadruple hydrogen-bonding motif consisting of six N-H...O hydrogen bonds in trimethoprim formate.

The title compound, trimethoprim (TMP) formate [systematic name: 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium formate], C(14)H(19)N(4)O(3)(+).CHO(2)(-), reveals a pseudo-quadruple hydrogen-bonding motif consisting of six N-H.O hydrogen bonds involving two unpaired TMP cations and two formate anions which are symmetrically disposed. The hydrogen-bonding motif is strikingly comparable with that observed in other TMP salts where the aminopyrimidine moieties of the TMP cations are centrosymmetrically paired. These conserved hydrogen-bonding motifs may serve as robust synthons in crystal engineering and design. The characteristic pseudo-quadruple hydrogen-bonding motif and other intermolecular hydrogen bonds operating in the crystal form a two-dimensional supramolecular sheet structure.

Hydrogen-bonding patterns in trimethoprim trifluoroacetate

In the title compound, trimethoprim tri­fluoro­acetate [or 2,4-di­amino-5-(3,4,5-tri­methoxy­benzyl)­pyrimidin-1-ium tri­fluoro­acetate], C14H19N4O3+·C2F3O2−, the trimethoprim mol­ecule is protonated at N-1. The carboxyl­ate group of the tri­fluoro­acetate anion binds with the protonated pyrimidine ring of trimethoprim (TMP) by two nearly parallel N—H⋯O hydrogen bonds. This is reminiscent of the carboxyl­ate–trimethoprim interaction observed in di­hydro­folate reductase (DHFR)–trimethoprim complexes. The pyrimidine moieties of the trimethoprim cations are centrosymmetrically paired through a pair of N—H⋯N hydrogen bonds involving the 4-amino group and atom N3. The 2-amino group of one TMP motif and the 4-amino group of another motif (both of these motifs are members of a base pair) are bridged by one of the methoxy O atom of a third TMP motif, leading to a five-membered (excluding H atoms) hydrogen-bonded chelate. One of the H atoms of the 2-amino group is also involved in a bifurcated hydrogen bond involving two methoxy O atoms of a trimethoprim motif, leading to a five-membered (including the H atom) hydrogen-bonded chelate. The pyrimidine ring makes a dihedral angle of 83.69 (10)° with the phenyl ring in the trimethoprim cation. In the tri­fluoro­acetate moiety, the average F—C bond distance is 1.261 A and F—C—C and F—C—F bond angles are 114.7 and 103.7° respectively.

N—H...N hydrogen bonds in trimethoprim salicylate methanol solvate [trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine

In the title compound, trimethoprim salicyl­ate methanol solvate [3,4,5-tri­methoxy­benzyl)­pyrimidin-1-ium salicyl­ate methanol solvate], C14H19N4O3+·C7H5O3−·CH4O, the trimethoprim mol­ecule is protonated at N1. The carboxyl­ate group of the salicyl­ate ion interacts with the protonated pyrimidine moiety of trimethoprim through a pair of nearly parallel N—H⋯O hydrogen bonds. This is reminiscent of the carboxyl­ate–trimethoprim interaction observed in di­hydro­folate reductase–trimethoprim complexes. The pyrimidine moieties of the trimethoprim cations are centrosymmetrically paired through a pair of N—H⋯N hydrogen bonds involving the 4-amino group and the unsubstituted pyrimidine N atom. The pyrimidine plane makes a dihedral angle of 89.5 (4)° with the phenyl ring in the trimethoprim cation.

Hydrogen-bonding patterns in trimethoprim perchlorate [trimethoprim = 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine

In the title crystal, trimethoprim perchlorate [2,4-di­amino-5-(3,4,5-tri­methoxy­benzyl)­pyrimidin-1-ium perchlorate], C14H19N4O3+·ClO4−, the trimethoprim mol­ecule is protonated at N1. The perchlorate ion makes double hydrogen bonds of type N—H⋯O with the 2-amino group and the protonated N1 atom of the trimethoprim cation, reminiscent of the fork-like interactions of the carboxyl­ate group with the trimethoprim (TMP) cation observed in the di­hydro­folate reductase–trimethoprim complex. The pyrimidine moieties of trimethoprim cations are centrosymmetrically paired through a pair of N—H⋯N hydrogen bonds involving the 4-amino group and the pyrimidinium-N atom. The two pairs of TMP cations are linked by N—H⋯O hydrogen bonds to form a supramolecular ladder-like structure. The pyrimidine plane makes a dihedral angle of 83.72 (8)° with the phenyl ring in the TMP cation.

N—H...O and O—H...O hydrogen bonds in crystal engineering: trimethoprim hydrogen glutarate

In the title compound, C14H19N4O3+·C5H7O4−, trimethoprim (TMP) is protonated. In the glutarate anion, one of the two carboxyl­ic acid groups is deprotonated while the other exists as —COOH. The carboxyl group of the hydrogen glutarate ion makes a hydrogen-bonding pattern with N—H groups of the trimethoprim cation which is similar to the carboxyl­ate group (of Asp-27 of DHFR)-trimethoprim cation interaction observed in trimethoprim–DHFR complexes. Two TMP cations and two hydrogen glutarate anions are arranged about an inversion center so that complementary DDAA arrays of quadruple hydrogen-bonding patterns are formed. The hydrogen glutarate ion bridges the 2-amino and 4-amino groups of TMP. There are also carboxyl–carboxyl­ate hydrogen-bonding interactions involving a head-to-tail arrangement of hydrogen glutarate ions which leads to hydrogen-bonded supramolecular ribbons.

Aminopyrimidine-carboxyl(ate) interactions in trimethoprim maleate, an antifolate drug.

In the title cocrystal, trimethoprim maleate [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium maleate], C(14)H(19)N(4)O(3)(+).C(4)H(3)O(4)(-), the trimethoprim molecule is protonated at N1. The carboxyl group of the maleate ion makes a specific double hydrogen bond of type N-H.O with the 2-amino group and the protonated N1 atom of the trimethoprim cation which is similar to the carboxylate-trimethoprim cation interaction observed in the complex of dihydrofolate reductase with trimethoprim. The pyrimidine moieties of trimethoprim cations are centrosymmetrically paired through a pair of N-H.N hydrogen bonds involving the 4-amino group and the pyridinium N3 atom of a symmetry-related molecule. One of the O atoms at the maleate carboxylate group bridges the 2-amino and 4-amino groups on either side of the paired trimethoprim cations. The other O atom of the carboxylate group forms an intramolecular O-H.O hydrogen bond with the carboxyl group. These characteristic hydrogen bonds result in infinite two-dimensional aggregation of rings into a supramolecular ladder, which is further crosslinked through weak C-H.O interactions with methoxy groups of neighbouring trimethoprim molecules to form a layered structure.

Hydrogen-Bonding Patterns in Trimethoprim Nitrate, an Antifolate Drug

In the crystal structure of trimethoprim nitrate [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium nitrate], C14H19N4O3+.NO3−, the trimethoprim moiety is protonated at N1 atom. The nitrate anion forms a fork-like hydrogen-bonded pattern with the trimethoprim cation which is similar to the carboxylate–trimethoprim cation interaction observed in the trimethoprim cation–dihydrofolate reductase complex. The pyrimidine ring makes a dihedral angle of 93.8 (1)° with the phenyl ring.

Novel Polymeric Membrane Electrodes for Selective Determination of Trimethoprim

Abstract Trimethoprim (TMP) ion selective PVC membrane electrodes based on the ion-pair complexes of trimethoprim cation with either ammonium reineckate I or sodium tetraphenyl borate IIwere prepared, using dioctyl phthalate (DOP) as the plasticising mediator. The basic analytical parameters of these electrodes were evaluated according to IUPAC recommendations. These electrodes gave linear response with Nernstian Slope (57 and 58 mV / decade) for electrode I and electrode II, respectively. The potentiometric selectivity data show negligible interference from the various species investigated. These electrodes have fast response time (< 30s), good slope stability over the pH range 2.0–5.7 or 2.0–5.5 for period of 45 or 60 days for electrode I and II, respectively. The standard electrode potentials were determined at different temperatures and were used to calculate the isothermal coefficient of these electrodes. Direct potentiometric determination of trimethoprim hydrochloride (TMPCI) in aqueous solutions a...