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 of Tricyclic Pterolobirin H Analogue: Evaluation of Anticancer and Anti-Inflammatory Activities and Molecular Docking Investigations.

Pterolobirin H (3), a cassane diterpene isolated from the roots of Pterolobium macropterum, exhibits important anti-inflammatory and anticancer properties. However, its relatively complex tetracyclic structure makes it difficult to obtain by chemical synthesis, thus limiting the studies of its biological activities. Therefore, we present here a short route to obtain a rational simplification of pterolobirin H (3) and some intermediates. The anti-inflammatory activity of these compounds was assayed in LPS-stimulated RAW 264.7 macrophages. All compounds showed potent inhibition of NO production, with percentages between 54 to 100% at sub-cytotoxic concentrations. The highest anti-inflammatory effect was shown for compounds 15 and 16. The simplified analog 16 revealed potential NO inhibition properties, being 2.34 higher than that of natural cassane pterolobirin H (3). On the other hand, hydroxyphenol 15 was also demonstrated to be the strongest NO inhibitor in RAW 264.7 macrophages (IC50 NO = 0.62 ± 0.21 µg/mL), with an IC50NO value 28.3 times lower than that of pterolobirin H (3). Moreover, the anticancer potential of these compounds was evaluated in three cancer cell lines: HT29 colon cancer cells, Hep-G2 hepatoma cells, and B16-F10 murine melanoma cells. Intermediate 15 was the most active against all the selected tumor cell lines. Compound 15 revealed the highest cytotoxic effect with the lowest IC50 value (IC50 = 2.45 ± 0.29 µg/mL in HT29 cells) and displayed an important apoptotic effect through an extrinsic pathway, as evidenced in the flow cytometry analysis. Furthermore, the Hoechst staining assay showed that analog 15 triggered morphological changes, including nuclear fragmentation and chromatin condensation, in treated HT29 cells. Finally, the in silico studies demonstrated that cassane analogs exhibit promising binding affinities and docking performance with iNOS and caspase 8, which confirms the obtained experimental results.

Novel Hydrazono-2-Iminothiazolidin-4-Ones Based on a Monoterpenic Skeleton as Potential Antitumor Agents: Synthesis, DFT Studies, in†Vitro Cytotoxicity, Apoptosis Inducing Properties and Molecular Docking.

A series of novel 2-iminothiazolidin-4-one analogs have been synthesized from limonaketone, and structurally characterized by HR-MS, 1 H-NMR and 13 C-NMR spectroscopy techniques, and the structure of compound 4 was elucidated by XRD. The newly synthesized products were biologically evaluated in vitro for their cytotoxic activity against human cancer cell lines HT-1080, A549, and MCF-7. Thiazolidinones 9 and 10 were the most active compounds in HT-1080 cell lines (IC50 =15.85±1.75 and 16.13±1.55 µM, respectively). The apoptosis induction of the derivatives 9 and 10 were studied using annexin V staining, caspase-3/7 activity and cell cycle analysis. Compound 10 showed the highest ability of apoptosis induction and caspase-3/7 activation associated with S-phase growth arrest in HT-1080. Meanwhile, compound 9 has a moderate apoptotic effect and G0/G1-phase arrest in the after-mentioned cell. The molecular docking suggested that compounds 9 and 10 formed stable ligand-caspase-3 complexes. Besides, the presence of phenyl moiety in ligand 10 is responsible for the enhancement of the caspase-3 activation by the apparition of two additional hydrogen bonds with Cys163 and Gln161amino acids.

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.

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.

Design, Hemiysnthesis, crystal structure and anticancer activity of 1, 2, 3-triazoles derivatives of totarol.

A new series of diverse triazoles linked to the hydroxyl group of totarol were synthesized using click chemistry approach. The structures of these compounds were elucidated by HRMS, IR and NMR spectroscopy. The structure of compound 3 g was also confirmed by x-ray single crystal diffraction. The cytotoxicity of these compounds was evaluated by the MTT method against four cancer cell lines, including fibrosarcoma HT-1080, lung carcinoma A-549 and breast adenocarcinoma (MDA-MB-231 and MCF-7), and the results indicated that all compounds showed weak to moderate activities against all cancer cell lines with IC50 values ranging from 14.44 to 46.25 µM. On the basis of our research the structure-activity relationships (SAR) of these compounds were discussed. This work provides some important hints for further structural modification of totarol towards developing novel and highly effective anticancer drugs respectively. It is interesting to note that compound 3 g indicated a very significant cytotoxicity against HT-1080 and A-549 cell lines. The molecular docking showed that compound 3 g activated the caspase-3 and inhibited tubulin by forming stable protein-ligand complexes.

Thiazolidinone-linked1,2,3-triazoles with monoterpenic skeleton as new potential anticancer agents: Design, synthesis and molecular docking studies.

A novel series of 1,2,3-triazole-thiazolidinone-carvone hybrid compounds has been designed and synthesized using the copper-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition (CuAAC) process based on (R)-Carvone-O-propargylated 5-hydroxybenzylidene-thiazolidin-4-one derivative as starting material. All compounds were characterized and identified based on their NMR and HRMS spectroscopic data. HMBC correlations confirm that under the CuAAC reaction conditions, only the 1,4-disubstituted triazole regioisomers were formed. The targeted 1,2,3-triazole-thiazolidinone-carvone hybrids and their precursors were evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231). The obtained data showed that most of these compounds have moderate anti-proliferative activity with IC50 values between 15.04 ± 0.71 and 42.22 ± 1.20 µM. The mechanism of action of the most active compounds 14e and 14f suggested that they induce apoptosis through caspase-3/7 activation, and the compound 14e elicited S-phase arrest, while compound 14f evoked G2/M phase blockade. The molecular docking confirmed that compounds 14e and 14f were nicely bonded with caspace-3 leading up to stable protein-ligand complexes.

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 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, 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.

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, 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.