Folate antagonists. 5. Antimalarial and antibacterial effects of 2,4-diamino-6-(aryloxy and aralkoxy)quinazoline antimetabolites

2 Various4-diamino-6-(phenoxy, naphthyloxy, and phenalkoxy)quinazolines (VIII, XIV) were synthesized for antimalarial and antibacterial evaluation. Treatment of the anion of the requisite phenol or naphthol with 5-chloro-2-nitrobenzonitrile (V) gave the corresponding 2-nitro-5-(phenoxy and naphthyloxy)benzonitriles (VI) (33–78%). Alternatively, alkylation of 5-hydroxy-2-nitrobenzaldehyde (IX) with the appropriate phenalkyl halide afforded the 2-nitro-5-(phenalkoxy)benzaldehydes (X) (27–62%), which were converted to the 2-nitro-5-(phenalkoxy)benzonitriles (XII) via the intermediate oximes XI (62–87% overall). Reduction of the 2-nitrobenzonitriles (VI, XII) with stannous chloride-hydrochloric acid provided the corresponding 2-amino-5-(phenoxy, naphthyloxy, and phenalkoxy)benzonitriles (VII, XIII) (30–83%), which upon cyclization with chloroformamidine hydrochloride gave the 2,4-diaminoquinazolines VIII and XIV (12–85%). Against Plasmodium berghei in mice, eleven compounds were active orally at doses ranging from 6.3 to 174 mg./kg./day for 6 days, while seven substances displayed activity subcutaneously following single doses of 40–640 mg./kg. Fifteen compounds exhibited in vitro antibacterial activity against Streptococcus faecalis (MGH-2), normal (UC-76) and drug-resistant (S18713) Staphylococcus aureus, Escherichia coli (Vogel), and Shigella sonnei (C-10) with MIC's ranging from < 0.25 to 20 μg./ml. (gradient plate). Data on the inhibitory effects of representative compounds against Streptococcus faecalis R (S. faecium var. durans), S. faecalis A (amino-pterin, methotrexate-resistant), and Lactobacillus plantarum are presented, and overall structure-activity relationships are discussed.     

Folate antagonists. 6. Synthesis and antimalarial effects of fused 2,4-diaminothieno[2,3-d]pyrimidines

2,4-Diamino-5,7-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrirnidine, 2,4-diamino-9H-mdeno[1′,2′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-5H-indeno[2′,1′:4,5]thieno[2,3-d]pyrimidine, 9,11-diamino-5,6-dihydronaphtho[1′,2′:4,5]thieno[2,3-d]pyrimidine, 7,9-diamino-5,6-dihydronaphtho[2′,1′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-7-benzy]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine, and various 2,4-diamino-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidines were synthesized by cyclization of the requisite fused 2-aminothio-phenene-3-carbonitriles utilizing chloroformamidine hydrochloride in diglyme. Several compounds exhibited strong inhibitory effects against Streptococcus faecalis (MGH-2), Staphylococcus aureus (UC-76), Streptococcus faecium (ATCC 8043), Lactobacillus casei (ATCC 7469), and Pediococcus cerevisiae (ATCC 8081) in vitro, and three compounds displayed antimalarial activity against Plasmodium berghei in mice and P. falciparum (Uganda I) in vitro.     

Folate antagonists. 16. Antimalarial and antibacterial effects of 2,4-diamino-6-[(heterocyclic)thio,sulfinyl, and sulfonyl]quinazolines

The reaction of 5-chloro-2-nitrobenzonitrile with a variety of mercaptoheterocycles provided the corresponding 2-nitro-5-[(heterocyclic)thio]benzonitriles. Reduction to the amine followed by cyclization with chloroformamidine hydrochloride afforded a series of 2,4-diamino-6-[(hetero-cyclic)thio]quinazolines. Bromination, oxidation, and amidine formation were accomplished with 2,4-diamino-6-[(4-phenyl-2-thiazolyl)thio]quinazoline (23) to provide additional analogs. Several of these compounds exhibited suppressive antimalarial activity against drug-sensitive lines of Plasmodium berghei in mice.     

Derivatives of 2,4-diamino-6-methylpteridine

Eighteen derivatives of 2,4-diamino-6-methylpteridine related to methotrexate and aminopterin have been prepared from 6-(bromomethyl)-2,4-pteridinediamine by nucleophilic displacement reactions. None of these compounds showed any antileukemic acitivity.     

Synthesis of 6-benzyl- and 6-phenethyl-2,4-diamino-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidines

The preparation of ten aralkyl derivatives of 2,4-diamino-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidines ( 6 ) has been accomplished. The title compounds were prepared in a simple one step reaction from 2,4,6-triaminopyrimidine ( 4 ), formaldehyde ( 2 ), and either substituted benzylamines ( 1a-d ) or substituted phenethylamines ( 1e-j ). This modified Mannich reaction has been shown to be a general method for such derivatives. Elemental analysis, ¹H nmr and mass spectral data have confirmed the proposed structures. None of the compounds exhibited either antimalarial or antitrypanosomal activity.     

Near ultraviolet spectroscopic studies of 2,4-diamino-6-piperidinopyrimidine-3-oxide (minoxidil) and 2,4-diamino-6-piperidinopyrimidine (desoxyminoxidil)

The near u.v. spectra of 2,4-diamino-6-piperidinopyrimidine (desoxyminoxidil) and 2,4-diamino-6-piperidinopyrimidine-3-oxide (minoxidil) can be viewed as perturbed pyrimidine spectra. The u.v. properties of pyrimidine and a series of aminopyrimidines, specifically 2,4,6-triaminopyrimidine, are examined to obtain u.v. spectral assignments for desoxyminoxidil and minoxidil. Minoxidil and its desoxy counterpart have C_s symmetry, and all π → π* absorptions are allowed ¹A′ ← ¹A′ transitions. The two lowest energy π →- π* absorptions observed in minoxidil (262 nm, 292 nm) are tentatively assigned as very mild oxygen → pyrimidine ring charge-transfer transitions. Intensity decreases in protic solvents, and the results of simple Hückel molecular orbital calculations indicate that the 292 nm transition has more charge-transfer character than the 262 nm absorption. The protonated species of desoxyminoxidil and minoxidil have very similar u.v. spectra. This is due to the lack of oxygen-related charge transfer in protonated minoxidil, and the high probability that the positive charge resides in similar environments in the minoxidil and desoxyminoxidil molecular frameworks.     

Studies on pyrazines. 26. Synthesis of 2,4-diamino-6-methylpteridine 5-oxide and the inertness of the 6-methyl-group functionalization

Synthesis of 2,4-diamino-6-methylpteridine 5-oxide was achieved in a five-step sequence of reaction starting from 5-methylpyrazinecarboxamide. Several attempts to introduce functionality into the 6-methyl group are described.     

Synthesis and antimalarial activity of a series of 2,4-diamino-6-[(N-alkylanilino)methyl]quinazolines

A series of 2,4-diamino-6-[(N-alkylanilino)methyl]quinazolines were prepared by bromination of 2,4-dibenz-amido-6-methylquinazoline followed by treatment with secondary arylamines and deblocking with base. A variety of analogs demonstrated substantial activity against Plasmodium berghei infections in mice.     

2,4-diamino-6-(acetohydrazidomethylsulfinylmethyl)-1,3,5-triazine. State in solution, acid-base and complexing properties

Solutions of a new drug, 2,4-diamino-6-(acetylhydrazidomethylsulfonylmethyl)-1,3,5-triazine, exhibiting tuberculocidal activity were studied using the methods of pH-metry, spectrophotometry, mathematical simulation of equilibria (CPESSP software), and molecular mechanics. Protolytic properties of the compound in the medium of aqueous dimethylsulfoxide (40 vol % of DMSO) were characterized. The composition of the copper(II) complex of this compound was determined and its stability constants were calculated. Based on the absorption spectra in the UV and visible regions the complexing ability of 2,4-diamino-6-(acetylhydrazidomethylsulfonylmethyl)-1,3,5-triazine toward nickel(II) and cobalt(II) were characterized in comparison with copper(II) under the same conditions.     

Synthesis and biological activities of tetrahydroquinazoline analogs of aminopterin and methotrexate

(6R,6S)-5,8-Dideaza-5,6,7,8-tetrahydroaminopterin ( 1 ) and (6R,6S)-5,8-dideaza-5,6,7,8-tetrahydromethotrexate ( 2 ) were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Cyclohexanone-4-carboxaldehyde dimethyl acetal, a key intermediate [10] was synthesized from cyclohexane-1,4-dione monoethylene ketal, which was converted via a Wittig reaction to its exocyclic 4-methylene derivative which in turn, was converted to the 4-aldehyde via a hydroboration-oxidation sequence. Selective protection of the 4-aldehyde as the dimethylacetal and cyclization with dicyandiamide afforded the 6-dimethylacetal of 2,4-diamino-5,6,7,8-tetrahydroquinazoline. Protection of the 2,4-diamino moieties and selective deprotection of the 6-aldehyde followed by reductive amination with p-aminobenzoyl-L-glutamate afforded 2,4-bisacetamido-5,8-dideaza-5,6,7,8-tetrahydroaminopterin ( 11 ). Deprotection of 11 afforded 1 . Compound 2 was obtained from 11 via N¹⁰-methylation and deprotection. The N¹⁰-methyl analogue 2 was 2–10 fold more potent than 1 as an inhibitor of various DHFRs. In the in vitro preclinical screening program of the National Cancer Institute, compound 2 inhibited the growth of eighteen of the twenty nine tumor cell lines in culture at a GI₅₀ > 1.0 × 10^?8 M.     

Theoretical study of substituent effects on electronic and structural properties of 2,4-diamino-5-para-substituted-phenyl-6-ethyl-pyrimidines

Density functional theory (DFT) method at the level of B3LYP with 6?C311G(d) basis set was used to investigate the effects of a variety of substituents (H, NH₂, NMe₂, OCH₃, CH₃, Cl, Br, CN, NO₂) on the electronic and structural properties of 2,4-diamino-5-p-substituted-phenyl-6-ethyl-pyrimidines. The investigation showed that the atomization energy was affected by substitution. Likewise, the molecular orbitals HOMO and LUMO and energy gap ??E were affected by the substituent. Dipole moment was also affected by the introduction of the substituent. On the other hand, the Mulliken charges at only C1??, C2 and N7, were correlated with both MSP and DSP models.     

A new method for the synthesis of 2,4-diamino-6-arylpyrimidines

A method for the synthesis of 2,4-diamino-6-arylpyrimidines from guanidine and α-chlorocinnamonitriles was developed. The starting nitriles can be easily prepared by catalytic olefination reaction.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 249–251, January, 2005.     

Synthesis of 2,4-diamino-9H-indeno[2,1-d]pyrimidines

As part of a search for new antifolic, antimalarial, and antitumor agents, a series of 2,4-diamino-9H-indeno[2,1-d]pyrimidines was prepared by condensation of guanidine with substituted 2-alkoxy-3-cyano-1H-indenes. Base-catalyzed cyclization of 1,2-bis(cyanomethyl)benzenes afforded 2-amino-3-cyano-1H-indenes, which were converted into 3-cyano-2-methoxy-1H-indenes by acid hydrolysis and treatment of the resultant 1-cyano-2-indanones with diazomethane. Alternatively, 2-amino-3-cyano-1H-indenes could be transformed directly into 2-ethoxy-3-eyano-1H-indenes by reaction with ethanol and sulfuric acid. The 2,4-diamino-9H-indeno[2,1-d]-pyrimidines represent a new type of planar, tricyclic pyrimethamine analog, in which free rotation of the phenyl and pyrimidine rings is prevented by means of a methylene bridge.     

Quinazolines. XI. Synthesis of 2,4-diamino-5, 10-diliydrobenzo[g] quinazolines

An unequivocal synthesis of 2,4-diamino-5,10-dihydrobenzo[g]quinazolines is described, starting from methyl 2-tetralone-3-carboxylates. Condensation with guanidine yielded 2-amino-4-hydroxy derivatives, which were thiated with phosphorus pentasulfide and S-alkylated with dimethyl sulfate. The resultant 2-amino-4-methylthio compounds were converted into 2,4-diamino derivatives by amination at elevated temperature and pressure. Attempted synthesis from 3-cyano-1,4-dihydro-2-methoxynaphthalene and guanidine was unsuccessful.     

Synthesis and antimalarial properties of 2,4-diamino-6-[(aryl)thio,sulfinyl, and sulfonyl]pyrido[3,2-d]pyrimidines

The synthesis and antimalarial activity of a series of 2,4-diamino-6-[(aryl)thio, sulfinyl and sulfonyl]pyrido-[3,2-d]pyrimidines is described. Nitration of 2,6-dichloropyridine provided the 3-nitro derivative which was converted to 6-chloro-3-nitro-2-pyridinecarbonitrile (V) with cuprous cyanide. Condensation of an aryl thiol with V gave the 6-arylthiopyridines VI which were reduced with iron in hydrochloric acid and condensed with chloroformamidine to give the 6-arylthiopyrido[3,2-d]pyrimidin-2,4-diamines X. Alternatively V was reduced to the amine VIII condensed with chloroformamidine and the resulting 6-chloropyrido[3,2-d]pyrimidine (IX) was treated with an arylthiol. Oxidation of X provided sulfinyl and sulfonyl analogs.     

Synthesis and properties of derivatives of symtriazine. 17. Synthesis of 2-methyl-4,6-disubstituted and 2,4-dimethyl-6-substituted sym-triazines by reduction of the corresponding trichloromethyl derivatives

The reduction of trichloromethyl groups in sym-triazine derivatives to methyl groups is studied. It is shown that 2-R-4, 6-bis (trichloromethyl)-sym-triazines can be reduced to 2-R-4, 6-dirnethyl-sym-triazines with zinc dust in ethanol or with lithium aluminum hydride in THF. 2-Amino, N-substituted 2-amino-, and 2-alkoxy-4-trichloromethyl-6-R-sym-triazines are reduced to the corresponding methyl derivatives by boiling with lithium aluminum hydride in dibutyl ether.I. M. Gubkin State Petroleum and Gas Academy, Moscow 117917. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 667–673, May, 1995. Original article submitted March 23, 1995.     

Crystalline and molecular structure of 2,4-diamino-6-dinitromethyl-1,3,5-triazine potassium salt

An X-ray diffraction study of 2,4-diamino-6-dinitromethyl-1,3,5-triazine potassium salt is reported. Crystals are monoclinic: a = 7.697(2) Å, b = 11.147(2) Å, c = 12.612(4) Å, β = 117.95(2)°, V = 955.9(4) ų, space group P2₁/c; Z = 4, ρ_calc = 1.885 g/cm³. The compound crystallizes as a crystalline hydrate with one molecule of water. Anion consists of two planar fragments: dinitromethyl and diamino-1,3,5-triazine, the geometrical parameters of which were analyzed. The coordination of potassium cations and multiple hydrogen bonds leading to the formation of a complex three-dimensional skeleton has been detected.     

The reaction of 2,4-diamino-6-piperidinopyrimidine 3-oxide with acid anhydrides

2,4-Diamino-6-piperidinopyrimidine 3-oxide reacts preferentially with acid anhydrides at the 4-amino group. The structures of amide products are readily assigned by the position of the 5-H.