Design, synthesis, docking, and antiviral evaluation of some novel pyrimidinone-based α-aminophosphonates as potent H1N1 and HCoV-229E inhibitors.

Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO4 catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR, 1H NMR, 13C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively.

Vibrational spectroscopic (FT-IR and FT-Raman) studies, HOMO-LUMO, NBO analysis and MEP of 6-methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]oxy}methyl)-1,2,3,4-tetra-hydroquinazoline-2,4-dione, a potential chemotherapeutic agent, using density functional methods.

6-Methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]oxy}methyl)-1,2,3,4-tetra-hydro quinazoline-2,4-dione was prepared via treatment of silylated 6-methylquinazoline-2,4-dione with bis-[(E)-2-methyl-3-phenylallyloxy]methane. FT-IR and FT-Raman spectra were recorded and analyzed. The vibrational wavenumbers were computed using DFT methods and are assigned with the help of potential energy distribution method. The first hyperpolarizability, infrared intensities and Raman activities also reported. The geometrical parameters of the title compound obtained from XRD studies are in agreement with the calculated (B3LYP) values. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. MEP was performed by the B3LYP method and from the MEP it is evident that the negative charge covers the CO group and the positive region is over the phenyl ring and NH group.

Theoretical investigations on the molecular structure, vibrational spectra, HOMO-LUMO analyses and NBO study of 1-[(Cyclopropylmethoxy)methyl]-5-ethyl-6-(4-methylbenzyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione.

The FT-IR and FT-Raman spectra of 1-[(Cyclopropylmethoxy)methyl]-5-ethyl-6-(4-methylbenzyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione were recorded. In this work, experimental and theoretical study on the molecular structure and vibrational wavenumbers of the title compound are presented. The vibrational wavenumbers were obtained theoretically at the DFT level and were compared with the experimental results. The study is extended to calculate the HOMO-LUMO energy gap, NBO, mapped molecular electrostatic potential and first hyperpolarizability. The calculated first hyperpolarizability of the title compound is 9.15 times that of urea and hence the title compound and the series of compounds it represents are attractive candidates for further studies in non linear optical applications. In the title compound, the HOMO of π nature is delocalized over the phenyl ring while the LUMO is located over the pyrimidine ring. The inter-molecular hydrogen bonding at O7 and N1H25 positions in each monomer give rise to a C2-symmetry dimer which is predicted to be about 10kcalmol(-1) more stable than the monomeric form.

Molecular structure and vibrational spectra of 2-Ethoxymethyl-6-ethyl-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione, a potential chemotherapeutic agent, by density functional methods.

In this work, the vibrational spectral analysis was carried out using FT-IR and FT-Raman spectroscopy for 2-Ethoxymethyl-6-ethyl-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione, which is a potential chemotherapeutic agent derivative. Theoretical calculations were performed by density functional methods. The complete vibrational assignments of the wavenumbers were made on the basis of potential energy distribution. The results of the calculations were applied to simulated spectra of the title compound, which show excellent agreement with the observed spectra. The frontier orbital energy gap and related properties of the molecule illustrates the high reactivity of the title compound. The first order hyperpolarizability, dipole moment and polarizability are also calculated. Stability of the molecule arising from hyper-conjugative interactions and charge delocalization has been analyzed using natural bond orbital analysis. Molecular electrostatic potential map is also constructed. The calculated geometrical parameters are in agreement with the XRD results.

Vibrational spectra, NBO analysis, HOMO-LUMO and first hyperpolarizability of 2-{[(2-Methylprop-2-en-1-yl)oxy]methyl}-6-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione, a potential chemotherapeutic agent based on density functional theory calculations.

The experimental FT-IR and FT-Raman spectra of 2-{[(2-Methylprop-2-en-1-yl)oxy]methyl}-6-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione were recorded. The optimized geometric parameters, normal mode frequencies and corresponding vibrational assignments of the compound have been examined by means of density functional theory. Reliable vibrational assignments and molecular orbital have been investigated by the potential energy distribution and natural bonding orbital analyses, respectively. The calculated first hyperpolarizability of the title compound is 2.82×10(-30) esu which is 21.69 times that of the standard NLO material urea. MEP was performed by the B3LYP level and the predicted infrared intensities and Raman activities have also been reported. Quantum chemical parameters were arrived from the frontier molecular orbital theory. The calculated geometrical parameters are in agreement with experimental results. From the MEP it is evident that the negative charge covers the CO groups and the positive region is over the rings and NH group.

4-Benzyl-3-(thio-phen-2-yl)-4,5-di-hydro-1H-1,2,4-triazole-5-thione.

In the title compound, C13H11N3S2, the triazole and thio-phene rings are coplanar [dihedral angle = 6.22 (13)°]. By contrast, the phenyl ring is perpendicular to the triazole ring [dihedral angle = 85.58 (13)°], so that the mol-ecule has an L-shape. The thio-phene S atom is syn with the ring imine N atom. In the crystal, eight-membered {⋯HNCS}2 synthons form between centrosymmetrically related mol-ecules, leading to dimeric aggregates that are connected into a supra-molecular layer parallel to (101) by π-π inter-actions between centrosymmetrically related triazole rings [centroid-centroid distance = 3.6091 (15) Å] and C-H⋯π inter-actions.

Synthesis of novel 2-(substituted amino)alkylthiopyrimidin-4(3H)-ones as potential antimicrobial agents.

5-Alkyl-6-(substituted benzyl)-2-thiouracils 3a,c were reacted with (2-chloroethyl) diethylamine hydrochloride to afford the corresponding 2-(2-diethylamino)ethylthiopyrimidin- 4(3H)-ones 4a,b. Reaction of 3a-c with N-(2-chloroethyl)pyrrolidine hydrochloride and/or N-(2-chloroethyl)piperidine hydrochloride gave the corresponding 2-[2-(pyrrolidin-1-yl)ethyl]-thiopyrimidin-4(3H)-ones 5a-c and 2-[2-(piperidin-1-yl)ethyl]thiopyrimidin-4(3H)-ones 6a,b, respectively. Treatment of 3a-d with N-(2-chloroethyl)morpholine hydrochloride under the same reaction conditions formed the corresponding 2-[2-(morpholin-4-yl)ethyl]thiopyrimidines 6c-f. On the other hand, 3a,b were reacted with N-(2-bromoethyl)phthalimide and/or N-(3-bromopropyl)phthalimide to furnish the corresponding 2-[2-(N-phthalimido)ethyl]-pyrimidines 7a,b and 2-[3-(N-phthalimido)-propyl]pyrimidines 7c,d, respectively. Compounds 3a-d, 4a,b, 5a-c, 6a-f and 7a-d were screened against Gram-positive bacteria (Staphylococcus aureus ATCC 29213, Bacillus subtilis NRRL 4219 and Bacillus cereus), yeast-like pathogenic fungus (Candida albicans ATCC 10231) and a fungus (Aspergillusniger NRRL 599). The best antibacterial activity was displayed by compounds 3a, 3b, 4a, 5a, 5b, 6d, 6f, 7b and 7d, whereas compounds 4b, 5b, 5c, 6a, 6b and 6f exhibited the best antifungal activity.

3-(Adamantan-1-yl)-4-[(E)-(2,6-difluoro-benzyl-idene)amino]-1-[(4-phenyl-piperazin-1-yl)meth-yl]-1H-1,2,4-triazole-5(4H)-thione.

The imine residue [C=N = 1.268 (3) Å; conformation = E] is twisted [N-N-C-N = 87.8 (2)°] out of the plane (r.m.s. deviation = 0.016 Å) of the central 1,2,4-triazole ring in the title compound, C(30)H(34)F(2)N(6)S. A small twist also occurs between the imine and terminal benzene rings [N-C-C-C = -169.8 (2)°]. The piperazine ring (chair conformation) occupies a position almost normal to the central plane [N-N-C-N = 87.8 (2)°]. In the crystal, the mol-ecules are consolidated into a three-dimensional architecture via C-H⋯S, C-H⋯π and π-π inter-actions, the latter between centrosymmetrically related difluoro-benzene rings [inter-centroid distance = 3.9389 (18) Å].

2-Benzyl-sulfanyl-4-[(4-methyl-phen-yl)sulfan-yl]-6-pentyl-pyrimidine-5-carbonitrile.

In the title compound, C(24)H(25)N(3)S(2), the S-bound benzene rings have orthogonal [dihedral angle = 85.31 (9)°] and splayed [67.92 (11)°] orientations with respect to the pyrimidine ring; the dihedral angle between the benzene rings is 48.18 (12)°. The pentyl group has an extended all-trans conformation and lies to one side of the pyrimidine ring [the N(py)-C(py)-C(p)-C(p) torsion angle = -85.7 (2)°; py = pyrimidine and p = pent-yl].

2-[(4-Chloro-benz-yl)sulfanyl]-4-(2-methyl-prop-yl)-6-[3-(trifluoro-meth-yl)anilino]-pyrimidine-5-carbonitrile.

Three independent mol-ecules comprise the asymmetric unit of the title compound, C(23)H(20)ClF(3)N(4)S. The conformations of the mol-ecules are similar with the chloro-benzene and CF(3)-benzene rings almost perpendicular to, and almost co-planar with, the pyrimidinyl ring [range of dihedral angles = 80.36 (13)-88.07 (14) and 11.89 (14)-23.30 (14)°, respectively]; the benzene rings are roughly orthogonal to each other [64.81 (16)-72.16 (15)°]. In the crystal, two of the independent mol-ecules associate via weak N-H⋯N(cyano) hydrogen bonds and 12-membered {⋯HNC(3)N}(2) synthons; the third independent mol-ecule self-associates similarly but about a centre of inversion. The sample studied was found to be a non-merohedral twin and the minor twin component refined to 47.16 (7)%.

5-(Adamantan-1-yl)-3-[(4-benzyl-piperazin-1-yl)meth-yl]-1,3,4-oxadiazole-2(3H)-thione.

The mol-ecule of the title compound, C(24)H(32)N(4)OS, is a functionalized 1,3,4-oxadiazole-2-thione with substituted piperazine and adamantanyl substituents attached at the 3- and 5-positions, respectively, of the oxadiazole spacer with an approximately C-shaped conformation. In the crystal, mol-ecules form dimers via C-H⋯S inter-action. The piperazine ring has a chair conformation; the substituents S, methyl-ene C and adamantane C of the essentially planar oxadiazole ring are approximately in the same plane, with distances of -0.046 (2), -0.085 (5) and 0.003 (4) Å, respectively. The dihedral angle between the planes of the phenyl and oxadiazole rings is 31.3 (3)°.

N'-(Adamantan-2-yl-idene)benzo-hydrazide.

The title mol-ecule, C(17)H(20)N(2)O, is a functionalized hydrazine with benzoyl and adamantyl substituents attached to the two hydrazine N atoms. In the crystal, mol-ecules are linked via N-H⋯N hydrogen bonds, forming chains propagating along the a-axis direction. There are also C-H⋯O, C-H⋯N and C-H⋯π inter-actions present within the chains.

6-Methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]-oxy}meth-yl)-1,2,3,4-tetra-hydro-quinazoline-2,4-dione.

In the title compound, C(20)H(20)N(2)O(3), the ten atoms comprising the quinazoline ring are essentially planar (r.m.s. deviation = 0.024 Å), and this plane is almost orthogonal to the terminal phenyl ring [dihedral angle = 82.87 (7)°]. The conformation about the ethyl-ene bond [1.335 (2) Å] is E and there is a significant twist between this residue and the adjacent phenyl ring [C-C-C- torsion angle = -48.4 (3)°]. The crystal structure features centrosymmetric dimeric units linked by pairs of N-H⋯O hydrogen bonds between the amide groups which lead to eight-membered {⋯HNCO}(2) synthons. These are consolidated into a three-dimensional architecture by C-H⋯O, C-H⋯π and π-π inter-actions [centroid-centroid distances = 3.5087 (8) and 3.5645 (9) Å].

6-Chloro-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]-oxy}meth-yl)-1,2,3,4-tetra-hydro-quinazoline-2,4-dione.

In the title compound, C(19)H(17)ClN(2)O(3), the conformation about the ethyl-ene bond [1.333 (2) Å] is E. The ten atoms comprising the quinazoline ring are essentially planar (r.m.s. deviation = 0.032 Å) and their mean plane forms a dihedral angle of 13.89 (7)° with the terminal phenyl ring; the mol-ecule has an open conformation as these substituents are directed away from each other. In the crystal, centrosymmetrically related mol-ecules are connected via N-H⋯O hydrogen bonds between the amide groups, leading to eight-membered {⋯HNCO}(2) synthons. These are consolidated into a three-dimensional architecture by C-H⋯O, C-H⋯π and π-π inter-actions [ring centroid(N(2)C(4))⋯centroid(C(6)) distance = 3.5820 (11) Å].

5-Meth-oxy-2-[(5-meth-oxy-1H-indol-1-yl)carbon-yl]-1H-indole.

The asymmetric unit of the title compound, C(19)H(16)N(2)O(3), comprises three independent mol-ecules (A, B and C). The inversion-related molecule of A is virtually superimposable upon the other two molecules. In each mol-ecule, there is a twist in the link between the approximately syn carbonyl and amine groups [the N-C-C-O torsion angles range from 19.73 (19) to -21.2 (2)°]. Each mol-ecule has a bent shape quanti-fied in terms of the dihedral angle between the indole and indole fused-ring systems [range = 45.69 (5)-47.91 (5)°]. In the crystal, the A and B mol-ecules form dimeric aggregates via ten-membered {⋯HNC(2)O}(2) synthons, while the C mol-ecules self-associate similarly but about a centre of inversion.

2-[(Cyclo-hex-3-en-1-ylmeth-oxy)meth-yl]-6-phenyl-1,2,4-triazine-3,5(2H,4H)-dione.

In the title 1,2,4-triazine derivative, C(17)H(19)N(3)O(3), the heterocyclic ring is planar (r.m.s. deviation = 0.040 Å) and effectively coplanar with the adjacent phenyl ring [dihedral angle = 4.5 (2)°] but almost perpendicular to the (cyclo-hex-3-en-1-ylmeth-oxy)methyl residue [N-N-C-O torsion angle = 71.6 (5)°], so that the mol-ecule has an 'L' shape. Supra-molecular chains along [001] are formed in the crystal via N-H⋯O hydrogen bonds where the acceptor O atom is the ether O atom. The adjacent carbonyl O atom forms a complementary C-H⋯O contact resulting in the formation of a seven-membered {⋯HNCO⋯HCO} heterosynthon; the second carbonyl O atom forms an intra-molecular C-H⋯O contact. Chains are connected into a supra-molecular layer in the ac plane by π-π inter-actions [ring centroid-centroid distance = 3.488 (3) Å]. The central atom in the -CH(2)CH(2)C(H)= residue of the cyclo-hexene ring is disordered over two sites, with the major component having a site-occupancy factor of 0.51 (2).

1-{(E)-[3-(1H-Imidazol-1-yl)-1-(4-meth-oxy-phen-yl)propyl-idene]amino}-3-(2-methyl-phen-yl)urea.

In the title compound, C(21)H(23)N(5)O(2), the conformation about the imine bond [1.287 (3) Å] is E. Overall, the mol-ecule has a disk shape, the dihedral angles between the imidazole ring and the meth-oxy-phenyl and methyl-phenyl rings being 49.42 (13) and 42.62 (13)°, respectively; the dihedral angle between the benzene rings is 20.11 (11)°. In the urea moiety, the N-H atoms are anti to each other and one of these forms an intra-molecular N-H⋯N hydrogen bond. In the crystal, centrosymmetric dimers are formed via N-H⋯N(imidazole) hydrogen bonds, which are connected into a three-dimensional architecture by C-H⋯O(carbon-yl) and (methyl-ene)C-H⋯π inter-actions. The crystal studied was a non-merohedral twin with a minor component of 48.3 (1)%.

1-{(E)-[3-(1H-Imidazol-1-yl)-1-phenyl-propyl-idene]amino}-3-(2-methyl-phen-yl)urea.

In the title compound, C(20)H(21)N(5)O, the conformation about the imine bond [1.289 (3) Å] is E. Overall, the mol-ecule is disk-shaped with the imidazole ring located above the remainder of the mol-ecule and with the dihedral angles of 10.97 (15) and 12.11 (15)°, respectively, between the imidazole ring and the phenyl and methyl-benzene rings; the dihedral angle between the aromatic rings is 8.17 (14)°. Within the urea unit, the N-H atoms are anti to each other and one of the N-H atoms forms an intra-molecular N-H⋯N hydrogen bond. Helical supra-molecular chains along [001] are formed via N-H⋯N(imidazole) hydrogen bonds in the crystal structure. These are connected into a three-dimensional architecture by C-H⋯O(carbon-yl) and C-H⋯π inter-actions.

1-{[(2,3-Dihydro-1H-inden-2-yl)-oxy]meth-yl}quinazoline-2,4(1H,3H)-dione.

In the title mol-ecule, C(18)H(16)N(2)O(3), the five-membered ring has an envelope conformation, with the substituted C atom deviating by 0.342 (4) Šfrom the mean plane P calculated for the remainder of the non-H atoms of the 2,3-dihydro-1H-indene fragment. The mean planes of quinazoline-2,4(1H,3H)-dione fragment and P form a dihedral angle of 59.08 (4)°. In the crystal, pairs of N-H⋯O hydrogen bonds link mol-ecules into inversion dimers, and weak C-H⋯O hydrogen bonds and π-π inter-actions between the benzene rings of the quinazoline ring systems [centroid-centroid distance = 3.538 (3) Å] further consolidate the packing.

6-(3,5-Dimethyl-benz-yl)-5-ethyl-1-[(2-phenyl-eth-oxy)meth-yl]pyrimidine-2,4(1H,3H)dione.

In the title pyrimidine derivative, C(24)H(28)N(2)O(3), the uracil unit is essentially planar with an r.m.s. deviation of 0.0054 (1) Šfor the eight non-H atoms. The pyrimidine ring is tilted by a dihedral angle of 77.08 (7)° with respect to the aromatic ring of the 3,5-dimethyl-benzyl substituent, whereas it is nearly parallel to the benzene ring of the pheneth-oxy-methyl unit, with a dihedral angle of 8.17 (8)°. An intra-molecular C-H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked by a pair of amide-uracil N-H⋯O hydrogen bonds into an inversion R(2) (2)(8) dimer. These dimers are stacked along the b axis through π-π inter-actions with a centroid-centroid distance of 3.9517 (8) Å. Weak C-H⋯π inter-actions are also present.