Design, synthesis, and molecular modeling studies of novel 2-quinolone-1,2,3-triazole-α-aminophosphonates hybrids as dual antiviral and antibacterial agents.

With the aim to identify new antiviral agents with antibacterial properties, a series of 2-quinolone-1,2,3-triazole derivatives bearing α-aminophosphonates was synthesized and characterized by 1H NMR, 13C NMR, 31P NMR, single crystal XRD and HRMS analyses. These compounds were examined against five RNA viruses (YFV, ZIKV, CHIKV, EV71 and HRV) from three distinct families (Picornaviridae, Togaviridae and Flaviviridae) and four bacterial strains (S. aureus, E. feacalis, E. coli and P. aeruginosa). The α-aminophosphonates 4f, 4i, 4j, 4k, 4p and 4q recorded low IC50 values of 6.8-10.91 µM, along with elevated selectivity indices ranging from 2 to more than 3, particularly against YFV, CHIKV and HRV-B14. Besides, the synthesized compounds were generally more sensitive toward Gram-positive bacteria, with the majority of them displaying significant potency against E. feacalis. Specifically, an excellent anti-enterococcus activity was obtained by compound 4q with MIC and MBC values of 0.03 µmol/mL, which were 8.7 and 10 times greater than those of the reference drugs ampicillin and rifampicin, respectively. Also, compounds 4f, 4p and 4q showed potent anti-staphylococcal activity with MIC values varying between 0.11 and 0.13 µmol/mL, compared to 0.27 µmol/mL for ampicillin. The results from DFT and molecular docking simulations were in agreement with the biological assays, proving the binding capability of hybrids 4f, 4i, 4j, 4k, 4p and 4q with viral and bacterial target enzymes through hydrogen bonds and other non-covalent interactions. The in silico ADME/Tox prediction revealed that these molecules possess moderate to good drug-likeness and pharmacokinetic properties, with a minimal chance of causing liver toxicity or carcinogenic effects.

Synthesis of new 3-acetyl-1,3,4-oxadiazolines combined with pyrimidines as antileishmanial and antiviral agents.

A new series of 3-acetyl-1,3,4-oxadiazoline hybrid molecules was designed and synthesized using a condensation between acyclonucleosides and substituted phenylhydrazone. All intermediates and final products were screened against Leishmania donovani, a Protozoan parasite and against three viruses SARS-CoV-2, HCMV and VZV. While no significant activity was observed against the viruses, the intermediate with 6-azatymine as thymine and 5-azathymine-3-acetyl-1,3,4-oxadiazoline hybrid exhibited a significant antileishmanial activity. The later compound was the most promising, exhibiting an IC50 value at 8.98 µM on L. donovani intramacrophage amastigotes and a moderate selectivity index value at 2.4.

Synthesis, characterization, molecular docking, and anticancer activities of new 1,3,4-oxadiazole-5-fluorocytosine hybrid derivatives.

Analogs of pyrimidine and 1,3,4-oxadiazole are two well established class of molecules proven as potent antiviral and anticancer agents in the pharmaceutical industry. We envisioned designing new molecules where these two heterocycles were conjugated with the goal of enhancing biological activity. In this vein, we synthesized a series of novel pyrimidine-1,3,4-oxadiazole conjugated hybrid molecules as potential anticancer and antiviral agents. Herein, we present a new design for 5-fluorocytosine-1,3,4-oxadiazole hybrids (5a-h) connected via a methylene bridge. An efficient synthesis of new derivatives was established, and all compounds were fully characterized by NMR and MS. Eight compounds were evaluated for their cytotoxic activity against fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), lung carcinoma (A-549), and for their antiviral activity against SARS-CoV-2. Among all compounds tested, the compound 5e showed marked growth inhibition against all cell lines tested, particularly in HT-1080, with IC50 values of 19.56 µM. Meanwhile, all tested compounds showed no anti-SARS-CoV-2 activity, with EC50 >100 µM. The mechanism of cell death was investigated using Annexin V staining, caspase-3/7 activity, and analysis of cell cycle progression. The compound 5e induced apoptosis by the activation of caspase-3/7 and cell-cycle arrest in HT-1080 and A-549 cells at the G2M phase. The molecular docking suggested that the compound 5e activated caspase-3 via the formation of a stable complex protein-ligand.

Discovery of novel furo[2,3-d]pyrimidin-2-one-1,3,4-oxadiazole hybrid derivatives as dual antiviral and anticancer agents that induce apoptosis.

A new series of furo[2,3-d]pyrimidine-1,3,4-oxadiazole hybrid derivatives were synthesized via an environmentally friendly, multistep synthetic tool and a one-pot Songoashira-heterocyclization protocol using, for the first time, nanostructured palladium pyrophosphate (Na2 PdP2 O7 ) as a heterogeneous catalyst. Compounds 9a-c exhibited broad-spectrum activity with low micromolar EC50 values toward wild and mutant varicella-zoster virus (VZV) strains. Compound 9b was up to threefold more potent than the reference drug acyclovir against thymidine kinase-deficient VZV strains. Importantly, derivative 9b was not cytostatic at the maximum tested concentration (CC50 > 100 µM) and had an acceptable selectivity index value of up to 7.8. Moreover, all synthesized 1,3,4-oxadiazole hybrids were evaluated for their cytotoxic activity in four human cancer cell lines: fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A549). Data showed that compound 8f exhibits moderate cytotoxicity, with IC50 values ranging from 13.89 to 19.43 µM. Besides, compound 8f induced apoptosis through caspase 3/7 activation, cell death independently of the mitochondrial pathway, and cell cycle arrest in the S phase for HT1080 cells and the G1/M phase for A549 cells. Finally, the molecular docking study confirmed that the anticancer activity of the synthesized compounds is mediated by the activation of caspase 3.

Design, synthesis, biological evaluation and molecular docking of new 1,3,4-oxadiazole homonucleosides and their double-headed analogs as antitumor agents.

A novel series of homonucleosides and their double-headed analogs containing theophylline, 1,3,4-oxadiazole, and variant nucleobases was designed and synthesized. The new derivatives were fully characterized by HRMS, FT-IR, 1H NMR, and 13C NMR. The cytotoxic activities of all prepared compounds were screened in vitro against four cell lines, including fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). The double-headed analogue 18 showed marked growth inhibition against all the cell lines tested, specifically in HT-1080, with an IC50 values of 17.08 ± 0.97 µM. The possible mechanism of apoptosis was investigated using Annexin V staining, caspase-3/7 activity, and analysis cell cycle progression. The compound 18 induced apoptosis through caspase-3/7 activation and cell-cycle arrest in HT-1080 and A-549 cells. The molecular docking confirms that the compound 18 activated caspase-3 via the formation of hydrogen bonds and hydrophobic interactions.

Efficient one-pot, three-component procedure to prepare new α-aminophosphonate and phosphonic acid acyclic nucleosides.

An efficient one-pot three-component Kabachnik-Fields reaction of aldehydes (acyclic nucleosides), amines (or amino acid), and triethyl phosphite proceeded for the synthesis of aminophosphonates using natural phosphate coated with iodine (I2@NP) as a catalyst. The novel α-aminophosphonate and phosphonic acid acyclic nucleosides were tested for their anti-HCV and anti-HIV activities. The molecular docking showed that the non-activity of these compounds could be due to the absence of hydrophobic pharmacophores.

Design, synthesis, biological evaluation and molecular docking of new uracil analogs-1,2,4-oxadiazole hybrids as potential anticancer agents.

A new series of uracil analogues-1,2,4-oxadiazole hybrid derivatives were synthesized by a new, simple, and efficient method using for the first time HAP-SO3H as an heterogenous acid catalyst for the condensation and cyclization between amidoxime and aldehyde. The new derivatives were characterized by HRMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques. The synthesized 1,2,4-oxadiazole hybrids were evaluated for their cytotoxic activity in five human cancer cell lines: melanoma (A-375), fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). Data showed that compounds 22 and 23 were potent cytotoxic agents against HT-1080 and MFC-7 cells with IC50 inferior to 1 µM. The possible mechanism of apoptosis induction by the derivatives was investigated using Annexin V staining, caspase-3/7 activity, mitochondrial membrane potential measurement, and analysis cell cycle progression. The compound 22 induced apoptosis through caspase-3/7 activation and S-phase arrest in HT-1080 and A549 cells. The molecular docking showed that compound 22 activated the caspase-3 by forming a stable protein-ligand complex.

Design, synthesis, chemical characterization, biological evaluation, and docking study of new 1,3,4-oxadiazole homonucleoside analogs.

Herein, we report the synthetic strategies and characterization of some novel 1,3,4-oxadiazole homonucleoside analogs that are relevant to potential antitumor and cytotoxic activities. The structure of all compounds is confirmed using various spectroscopic methods such as 1H-NMR, 13C-NMR, HRMS, and FTIR. These compounds were evaluated against three human cancer cell lines (MCF-7, SKBR3, and HL60 Cell Line). Preliminary investigations showed that the cytotoxic activity was markedly dependent on the nucleobase. Introduction of 5-Iodouracil 4g and theobromine 6b proved to be extremely beneficial even they were more potent than the reference drug (DOX). Also, the synthesized compounds were tested for their antiviral activities against the human varicella-zoster virus (VZV). The product 4h was (6-azauracil derivative) more potent to the reference (acyclovir) against the deficient TK - VZV strain by about 2-fold. Finally, molecular docking suggested that the anticancer activities of compounds 6b and 4g mediated by inhibiting dual proteins EGFR/HER2 with low micromolar inhibition constant Ki range. The 1,3,4-oxadiazole homonucleosides showed a strong affinity to binding sites of target proteins by forming H-bond, carbon-hydrogen bond, Pi-anion, Pi-sulfur, Pi-sigma, alkyl, and Pi-alkyl interactions.

Dihydropyrimidinone/1,2,3-triazole hybrid molecules: Synthesis and anti-varicella-zoster virus (VZV) evaluation.

By combining the structural features of dihydropyrimidinone and 1,2,3-triazole heterocycles, novel hybrid compounds were synthesized using a simple and convenient method. A series of novel mono and bis 1,2,3-triazole was synthesized via copper-catalyzed Huisgen azide-alkyne cycloadditions (CuAAC) under microwave irradiation. The newly synthesized compounds were evaluated for their antiviral activity against varicella-zoster virus (VZV). Compounds 6aa, 7ab, 6ba and 6da showed valuable antiviral activities, with EC50 values ranging from 3.6 to 11.3 µM against TK+ and TK- VZV and without measurable cell-growth inhibition.

Design, Synthesis, and Antiviral Activity of Novel Ribonucleosides of 1,2,3-Triazolylbenzyl-aminophosphonates.

A novel series of ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates was synthesized through the Kabachnik-Fields reaction using I2 as catalyst followed by copper-catalyzed cycloaddition of the azide-alkyne reaction (CuAAC). All structures of the newly prepared compounds were characterized by (1) H NMR, (13) C NMR, and HRMS spectra. The structures of 2e, 2f, 3d, and 3g were further confirmed by X-ray diffraction analysis. These compounds were tested against various strains of DNA and RNA viruses; compounds 4b and 4c showed a modest inhibitory activity against respiratory syncytial virus (RSV) and compound 4h displayed modest inhibitory activity against Coxsackie virus B4.

Crystal structure of 2-benzamido-N-(2,2-di-eth-oxy-eth-yl)benzamide.

In the title compound, C20H24N2O4, both peptide bonds adopt a trans configuration with respect to the -N-H and -C=O groups. The dihedral angle between the aromatic rings is 53.58 (4)°. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond. The crystal packing is characterized by zigzag chains of N-H⋯O hydrogen-bonded mol-ecules running along the b-axis direction.

Benzimidazole-1,2,3-triazole hybrid molecules: synthesis and evaluation for antibacterial/antifungal activity.

A novel series of hybrid molecules 4a-i and 5a-i were prepared by condensation of 4-(trimethylsilylethynyl)benzaldehyde 1 with substituted o-phenylenediamines. These in turn were reacted with 2-(azidomethoxy)ethyl acetate in a Cu alkyne-azide cycloaddition (CuAAC) to generate the 1,2,3-triazole pharmacophore under microwave assistance. The newly synthesized compounds were examined for their in vitro antimicrobial activities against Gram-positive and Gram-negative bacteria and the phytopathogenic fungi Verticillium dahliae and Fusarium oxysporum f. sp. albedinis. 2-((4-(4-(5-Trifluoromethyl benzimidazol-2-yl)phenyl)-1,2,3-triazol-1-yl)methoxy)ethanol 5e showed a moderate inhibition of 30% in the Foa sporulation test.

Synthesis of new 1,2,3-triazol-4-yl-quinazoline nucleoside and acyclonucleoside analogues.

In this study, we describe the synthesis of 1,4-disustituted-1,2,3-triazolo-quinazoline ribonucleosides or acyclonucleosides by means of 1,3-dipolar cycloaddition between various O or N-alkylated propargyl-quinazoline and 1'-azido-2',3',5'-tri-O-benzoylribose or activated alkylating agents under microwave conditions. None of the compounds selected showed significant anti-HCV activity in vitro.

Synthesis of 1,2,3-triazolyl nucleoside analogs as potential anti-influenza A (H3N2 subtype) virus agents.

Montmorillonite K10 impregnated with copper dichloride and potassium iodide (CuCl2 /KI/K10) was used as catalyst in the cycloaddition of azides and propargylnucleobases, to provide the corresponding 1,4-disubstituted 1,2,3-triazoles in good yield. All compounds 16-23 were evaluated for their antiviral activity in vitro. Compound 18 showed moderate inhibition against influenza virus A (H3N2).

Four related diethyl [(arylamino)(4-ethynylphenyl)methyl]phosphonates.

Crystal structures are reported for four related diethyl [(arylamino)(4-ethynylphenyl)lmethyl]phosphonate derivatives, namely diethyl [(4-bromoanilino)(4-ethynylphenyl)methyl]phosphonate, C19H21BrNO3P, (I), diethyl ((4-chloro-2-methylanilino){4-[2-(trimethylsilyl)ethynyl]phenyl}methyl)phosphonate, C23H31ClNO3PSi, (II), diethyl ((4-fluoroanilino){4-[2-(trimethylsilyl)ethynyl]phenyl}methyl)phosphonate, C22H29FNO3PSi, (III), and diethyl [(4-ethynylphenyl)(naphthalen-2-ylamino)methyl]phosphonate, C23H24NO3P, (IV). The conformation of the anilinobenzyl group is very similar in all four compounds. The P-C bond has an approximately staggered conformation, with the aniline and ethynylphenyl groups in gauche positions with respect to the P=O double bond. The two six-membered rings are almost perpendicular. The sums of the valence angles about the N atoms vary from 344 (2) to 351 (2)°. In the crystal structures, molecules of (I), (III) and (IV) are arranged as centrosymmetric or pseudocentrosymmetric dimers connected by two N-H···O=P hydrogen bonds. The molecules of (II) are arranged as centrosymmetric dimers connected by C(methyl)-H···O=P hydrogen bonds. The N-H bond of (II) is not involved in hydrogen bonding.

2-({4-[4-(1H-Benzimidazol-2-yl)phen-yl]-1H-1,2,3-triazol-1-yl}meth-oxy)ethanol.

In the title molecule, C(18)H(17)N(5)O(2), the dihedral angle between the benzene plane and the benzimidazole plane is 19.8 (1)° and the angle between the benzene plane and the triazole plane is 16.7 (1)°. In the crystal, mol-ecules are connected by O-H⋯N hydrogen bonds, forming zigzag chains along the c-axis direction. The chains are connected by bifurcated N-H⋯(N,N) hydrogen bonds into layers parallel to (100). These layers are connected along the a-axis direction by weak C-H⋯O contacts, forming a three-dimensional network.

Methyl 2-(3-chloro-benzamido)-benzoate.

In the mol-ecule of the title compound, C15H12ClNO3, the chloro-benzamide and benzoate units are almost co-planar, with a dihedral angle between the six-membered rings of 2.99 (10)°. An intra-molecular N-H⋯O hydrogen bond occurs. In the crystal, each mol-ecule is linked to a symmetry-equivalent counterpart across a twofold rotation axis by weak C-H⋯O and C-H⋯Cl hydrogen bonds, forming dimers. The packing is stabilized through weak π-π stacking along the b-axis direction, leading to π-stacked columns of inversion-related mol-ecules, with an inter-planar distance of 3.46 (2) Šand a centroid-centroid vector of 3.897 (2) Å.

4-{4-[(4-Oxoquinazolin-3-yl)meth-yl]-1H-1,2,3-triazol-1-yl}butyl acetate.

In the heterocyclic title compound, C(17)H(19)N(5)O(3), the quinazolinone ring system forms a dihedral angle of 67.22 (7)° with the triazole ring. The butyl acetate group has a non-linear conformation, with an alternation of synclinal and anti-periplanar torsion angles [N-C-C-C = 58.5 (2)°, C-C-C-C = 170.72 (19)° and C-C-C-O = -65.9 (3)°]. The crystal structure features inter-molecular C-H⋯N and C-H⋯O non-classical hydrogen bonds, building an infinite one-dimensional network along the [100] direction.

4-(4-{[(2-Phenyl-quinazolin-4-yl)-oxy]methyl}-1H-1,2,3-triazol-1-yl)butan-1-ol hemihydrate.

The title compound, C(21)H(21)N(5)O(2)·0.5H(2)O, has two fused six-membered rings linked to a benzene ring and to a triazole ring, which is connected to a butanol group. The quinazoline ring forms a dihedral angle of 7.88 (8)° with the benzene ring, while the triazole ring is approximately perpendicular to the benzene ring and to the quinazoline system, making dihedral angles of 84.38 (10) and 76.55 (8)°, respectively. The stereochemical arrangement of the butanol chain, with a C-C-C-C torsion angle of 178.34 (19)°, corresponds to an anti-periplanar conformation. However the position of the -OH group is split into two very close [O-O = 0.810(3) Å] positions of equal occupancy. The crystal structure features O-H⋯N and O-H⋯O hydrogen bonds, building an infinite three-dimensional network. The water molecule is located on a half-filled general position.

An economical synthesis of D- and L-pyrimidine arabino- and ribonucleosides.

The one-step synthesis of several ß-D/L-arabino- and ribonucleosides was performed in good yields under reflux or microwave-assisted fusion method. A comparison of the two methods showed that better yields were obtained using the reflux conditions.