Search

A novel analogue of hybrid spirooxindoles was synthesized employing a systematic multistep synthetic approach. The synthetic protocol was designed to obtain a series of spirooxindole derivatives incorporating triazolyl-s-triazine framework via [3 + 2] cycloaddition (32CA) reaction of azomethine ylide (AY) with the corresponding chalcones (6a-d). Unexpectedly, the reaction underwent an alternate route, leading to the cleavage of the s-triazine moiety and yielding a series of spirooxindole derivatives incorporating a triazole motif. A comprehensive investigation of the 32CA reaction mechanism was conducted using Molecular Electron Density Theory (MEDT). The viability of all compounds was evaluated through an MTT assay, and the IC50 values were determined using Prism Software. The antiproliferative efficacy of the synthesized chalcones and the corresponding spirooxindole derivatives was assessed against two cancer cell lines: MDA-MB-231 (triple-negative breast cancer) and HepG2 (human hepatoma). These findings were compared with Sorafenib, which was used as a positive control. The results revealed that chalcones (6c and 6d) were the most active among the tested chalcones, with IC50 values of 7.2 ± 0.56 and 7.5 ± 0.281 µM for (6c) and of 11.1 ± 0.37 and 11.0 ± 0.282 µM for (6d), against MDA-MB-231 and HepG2, respectively. Spirooxindoles (9b, 9c, 9h, and 9i) exhibited the highest activity with IC50 values ranging from 16.8 ± 0.37 µM to 31.3 ± 0.86 µM against MDA-MB-231 and 13.5 ± 0.92 µM to 24.2 ± 0.21 µM against HepG2. In particular, spirooxindole derivatives incorporating 2,4-dichlorophenyl moiety were the most active, with an IC50 of 16.8 ± 0.37 µM for (9h) against MDA-MB-23 and 13.5 ± 0.92 µM for (9i) against HepG2. Interestingly, the IC50 of compound (6c) (7.2 µM) exhibited better activity than that of Sorafenib (positive control) (9.98 µM) against MDA-MB-231. Molecular docking, ADMET, and molecular dynamic simulations were conducted for the promising candidates (6b, 6c, and 9h) to explore their binding affinity in the EGFR active site.

Metastatic hepatocellular carcinoma (HC) is a serious health concern. The stemness of cancer stem cells (CSCs) is a key driver for HC tumorigenesis, apoptotic resistance, and metastasis, and functional mitochondria are critical for its maintenance. Cuproptosis is Cu-dependent non-apoptotic pathway (mitochondrial dysfunction) via inactivating mitochondrial enzymes (pyruvate dehydrogenase “PDH” and succinate dehydrogenase “SDH”). To effectively treat metastatic HC, it is necessary to induce selective cuproptosis (for halting cancer stemness genes) with selective oxidative imbalance (for increasing cell susceptibility to cuproptosis and inducing non-CSCs death). Herein, two types of Cu oxide nanoparticles (Cu4O3 “C(I + II)” NPs and Cu2O “C(I)” NPs) were used in combination with diethyldithiocarbamate (DD, an aldehyde dehydrogenase “ALDH” inhibitor) for comparative anti-HC investigation. DC(I + II) NPs exhibited higher cytotoxicity, mitochondrial membrane potential, and anti-migration impact than DC(I) NPs in the treated human HC cells (HepG2 and/or Huh7). Moreover, DC(I + II) NPs were more effective than DC(I) NPs in the treatment of HC mouse groups. This was mediated via higher selective accumulation of DC(I + II) NPs in only tumor tissues and oxidant activity, causing stronger selective inhibition of mitochondrial enzymes (PDH, SDH, and ALDH2) than DC(I)NPs. This effect resulted in more suppression of tumor and metastasis markers as well as stemness gene expressions in DC(I + II) NPs-treated HC mice. In addition, both nanocomplexes normalized liver function and hematological parameters. The computational analysis found that DC(I + II) showed higher binding affinity to most of the tested enzymes. Accordingly, DC(I + II) NPs represent a highly effective therapeutic formulation compared to DC(I) NPs for metastatic HC.

The molecular and supramolecular structures of some M(II) complexes (M = Co, Mn, Cu, Ni, Zn) with a hydrazone-s-triazine ligand (BMPyTr) were discussed based on single crystal X-ray diffraction (SCXRD), Hirshfeld and DFT analyses. A new Co(II) complex of the same ligand was synthesized and its structure was confirmed to be [Co(BMPyTr)Cl2]·H2O based on FTIR and UV–Vis spectra, elemental analysis and SCXRD. The geometry around Co(II) was a distorted square pyramidal configuration (τ5 = 0.4), where Co(II) ion is coordinated to one NNN-tridentate ligand (BMPyTr) and two Cl- ions. A Hirshfeld analysis indicated all potential contacts within the crystal structure, where the percentages of O⋯H, N⋯H, C⋯H, and H⋯H contacts in one unit were 11.2, 9.3, 11.4, and 45.9%, respectively, while the respective values for the other complex unit were 10.3, 8.8, 10.6, and 48.0%. According to DFT calculations, the presence of strongly coordinating anions, such as Cl-, in addition to the large metal ion size, were found to be the main reasons for the small M-BMPyTr interaction energies in the cases of [Mn(BMPyTr)Cl2] (260.79 kcal/mol) and [Co(BMPyTr)Cl2]·H2O (307.46 kcal/mol) complexes. Interestingly, the Co(II) complex had potential activity against both Gram-positive (S. aureus and B. subtilis) and Gram-negative (E. coli and P. vulgaris) bacterial strains with inhibition zone diameters of 13, 15, 16, and 18 mm, respectively. Also, the new [Co(BMPyTr)Cl2]·H2O (IC50 = 131.2 ± 6.8 μM) complex had slightly better cytotoxic activity against HCT-116 cell line compared to BMPyTr (145.3 ± 7.1 μM).

4,6-Bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-phenyl-1,3,5-triazin-2-amine (PTA-1), N-(4-bromophenyl)-4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2-amine (PTA-2) and 4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(4-methoxyphenyl)-1,3,5-triazin-2-amine (PTA-3) were synthesized and characterized. Their corrosion inhibition of carbon C-steel in 0.25 M H2SO4 was studied by electrochemical impedance. The inhibition efficiency (IE%) of triazine was superior due to the cumulative inhibition of triazine core structure and pyrazole motif. Potentiodynamic polarizations suggested that s-triazine derivatives behave as mixed type inhibitors. The IE% values were 96.5% and 93.4% at 120 ppm for inhibitor PTA-2 and PTA-3 bearing –Br and –OCH3 groups on aniline, respectively. While PTA-1 without an electron donating group showed only 79.0% inhibition at 175 ppm. The adsorption of triazine derivatives followed Langmuir and Frumkin models. The values of adsorption equilibrium constant K°ads and free energy change ΔG°ads revealed that adsorption of inhibitor onto steel surface was favoured. A corrosion inhibition mechanism was proposed suggesting the presence of physical and chemical interactions. Density functional theory computational investigation corroborated nicely with the experimental results. Monte Carlo simulation revealed that the energy associated with the metal/adsorbate arrangement dE ads/dN i, for both forms of PTA-2 and PTA-3 with electron donating groups (−439.73 and −436.62 kcal mol−1) is higher than that of PTA-1 molecule (−428.73 kcal mol−1). This aligned with experimental inhibition efficiency results.

The development of effective therapy for eradicating glioblastoma stem cells remains a major challenge due to their aggressive growth, chemoresistance and radioresistance which are mainly conferred by aldehyde dehydrogenase (ALDH)1A1. The latter is the main stemness mediator via enhancing signaling pathways of Wnt/β-catenin, phosphatidylinositol 3-kinase/AKT, and hypoxia. Furthermore, ALDH1A1 mediates therapeutic resistance by inactivating drugs, stimulating the expression of drug efflux transporters, and detoxifying reactive radical species, thereby apoptosis arresting. Recent reports disclosed the potent and broad-spectrum anticancer activities of the unique nanocomplexes of diethyldithiocarbamate (DE, ALDH1A1 inhibitor) with ferrous oxide nanoparticles (FeO NPs) mainly conferred by inducing lipid peroxidation-dependent non-apoptotic pathways (iron accumulation-triggered ferroptosis), was reported. Accordingly, the anti-stemness activity of nanocomplexes (DE-FeO NPs) was investigated against human and mouse glioma stem cells (GSCs) and radioresistant GSCs (GSCs-RR). DE-FeO NPs exhibited the strongest growth inhibition effect on the treated human GSCs (MGG18 and JX39P), mouse GSCs (GS and PDGF-GSC) and their radioresistant cells (IC50 ≤ 70 and 161 μg/mL, respectively). DE-FeO NPs also revealed a higher inhibitory impact than standard chemotherapy (temozolomide, TMZ) on self-renewal, cancer repopulation, chemoresistance, and radioresistance potentials. Besides, DE-FeO NPs surpassed TMZ regarding the effect on relative expression of all studied stemness genes, as well as relative p-AKT/AKT ratio in the treated MGG18, GS and their radioresistant (MGG18-RR and GS-RR). This potent anti-stemness influence is primarily attributed to ALDH1A1 inhibition and ferroptosis induction, as confirmed by significant elevation of cellular reactive oxygen species and lipid peroxidation with significant depletion of glutathione and glutathione peroxidase 4. DE-FeO NPs recorded the optimal LogP value for crossing the blood brain barrier. This in vitro novel study declared the potency of DE-FeO NPs for collapsing GSCs and GSCs-RR with improving their sensitivity to chemotherapy and radiotherapy, indicating that DE-FeO NPs may be a promising remedy for GBM. Glioma animal models will be needed for in-depth studies on its safe effectiveness.

This study discusses the synthesis and use of a new library of spirooxindole-benzimidazole compounds as inhibitors of the signal transducer and activator of p53, a protein involved in regulating cell growth and cancer prevention. The text includes the scientific details of the [3 + 2] cycloaddition (32CA) reaction between azomethine ylide 7a and ethylene 3a within the framework of Molecular Electron Density Theory. The mechanism of the 32CA reaction proceeds through a two-stage one-step process, with emphasis on the highly asynchronous transition state structure. The anti-cancer properties of the synthesized compounds, particularly 6a and 6d, were evaluated. The inhibitory effects of these compounds on the growth of tumor cells (MDA-MB 231 and PC-3) were quantified using IC50 values. This study highlights activation of the p53 pathway by compounds 6a and 6d, leading to upregulation of p53 expression and downregulation of cyclin D and NF-κB in treated cells. Additionally, we explored the binding affinity of spirooxindole analogs, particularly compound 6d, to MDM2, a protein involved in regulation of p53. The binding mode and position of compound 6d were compared with those of a co-crystallized standard ligand, suggesting its potential as a lead compound for further preclinical research.

A one-pot multi-component reaction was employed for the stereoselective synthesis of a novel set of dispiro-oxindolopyrrolizidines analogs incorporating a thiazolo[3,2-a]benzimidazole scaffold based on the [3 + 2] cycloaddition (32CA) reaction approach. The desired novel dispiro-oxindolopyrrolizidines 9a–d were achieved using the 32CA reaction of new ethylene derivatives based on thiazolo[3,2-a]benzimidazole moiety seven with thiazolidine derivatives eight and different substituted isatin compounds 5a–d (R = H, Cl, NO2, and Br). The final dispiro-oxindolopyrrolizidines cycloadducts were separated, purified, and fully characterized by means of a set of spectroscopic tools including IR, HNMR, CNMR, and MS. The Molecular Electron Density Theory (MEDT) was applied to explain the mechanism and stereoselectivity in the of the key 32CA reaction step. The reactive pseudo(mono)radical electronic structure of the in situ generated azomethine ylides and the high polar character of the corresponding 32CA reactions account for the low computed activation Gibbs free energies and total endo stereoselectivity of this kinetically controlled exergonic reaction. The computed relative Gibbs free activation energies of competitive reaction paths and regioisomers ratio distribution of 80:20 justify the major formation of 9a via the most favorable ortho/endo reaction path.

The [ZnL(ONO2)2] 1 and [ZnL(NCS)2] 2 complexes were synthesized using self-assembly of the s-triazine tridentate ligand (L) with Zn(NO3)2·6H2O and Zn(ClO4)2·6H2O/NH4SCN, respectively. The Zn(II) is further coordinated by two nitrate and two isothiocyanate groups as monodentate ligands in 1 and 2, respectively. Both complexes have distorted square pyramidal coordination environments where the extent of distortion is found to be greater in 2 (τ5 = 0.41) than in 1 (τ5 = 0.28). Hirshfeld calculations explored the significant C···O, C···C, N···H, and O···H contacts in the molecular packing of both complexes. The energy framework analysis gave the total interaction energies of −317.8 and −353.5 kJ/mol for a single molecule in a 3.8 Å cluster of 1 and 2, respectively. The total energy diagrams exhibited a strong resemblance to the dispersion energy frameworks in both complexes. NBO charge analysis predicted the charges of the Zn(II) in complexes 1 and 2 to be 1.217 and 1.145 e, respectively. The electronic configuration of Zn1 is predicted to be [core] 4S0.32 3d9.98 4p0.45 4d0.02 5p0.01 for 1 and [core] 4S0.34 3d9.97 4p0.53 4d0.02 for 2. The increased occupancy of the valence orbitals is attributed to the donor→acceptor interactions from the ligand groups to Zn(II). The Zn(II) complexes were examined for their cytotoxic and antimicrobial activities. Both 1 and 2 have good cytotoxic efficiency towards HCT-116 and A-549 cancerous cell lines. We found that 1 is more active (IC50 = 29.53 ± 1.24 and 35.55 ± 1.69 µg/mL) than 2 (IC50 = 41.25 ± 2.91 and 55.05 ± 2.87 µg/mL) against both cell lines. Also, the selectivity indices for the Zn(II) complexes are higher than one, indicating their suitability for use as anticancer agents. In addition, both complexes have broad-spectrum antimicrobial activity (IC50 = 78–625 μg/mL) where the best result is found for 2 against P. vulgaris (IC50 = 78 μg/mL). Its antibacterial activity is found to be good compared to gentamycin (5 μg/mL) as a positive control against this microbe.

Cancer represents a global challenge, and the pursuit of developing new cancer treatments that are potent, safe, less prone to drug resistance, and associated with fewer side effects poses a significant challenge in cancer research and drug discovery. Drawing inspiration from pyrrolidinyl-spirooxindole natural products, a novel series of spirooxindoles has been synthesized through a one-pot three-component reaction, involving a [3 + 2] cycloaddition reaction. The cytotoxicity against breast cancer cells (MCF-7 and MDA-MB-231) and safety profile against WISH cells of the newly developed library were assessed using the MTT assay. Compounds 5l and 5o exhibited notable cytotoxicity against MCF-7 cells (IC50 = 3.4 and 4.12 μM, respectively) and MDA-MB-231 cells (IC50 = 8.45 and 4.32 μM, respectively) compared to Erlotinib. Conversely, compounds 5a-f displayed promising cytotoxicity against MCF-7 cells with IC50 values range (IC50 = 5.87–18.5 μM) with selective activity against MDA-MB-231 cancer cells. Compound 5g demonstrated the highest cytotoxicity (IC50 = 2.8 μM) among the tested compounds. Additionally, compounds 5g, 5l, and 5n were found to be safe (non-cytotoxic) against WISH cells with higher IC50 values ranging from 39.33 to 47.2 μM. Compounds 5g, 5l, and 5n underwent testing for their inhibitory effects against EGFR and CDK-2. Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04 μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557 μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%). RT-PCR analysis was performed on both untreated and 5g-treated MCF-7 cells to confirm apoptotic cell death. Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost‐effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.

Abstract Recently, cancer research protocols have introduced clinical-stage spirooxindole-based MDM2 inhibitors. However, several studies reported tumor resistance to the treatment. This directed efforts to invest in designing various combinatorial libraries of spirooxindoles. Herein, we introduce new series of spirooxindoles via hybridization of the chemically stable core spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one and the pyrazole motif inspired by lead pyrazole-based p53 activators, the MDM2 inhibitor BI-0252 and promising molecules previously reported by our group. Single crystal X-ray diffraction analysis confirmed the chemical identity of a representative derivative. Fifteen derivatives were screened for cytotoxic activities via MTT assay against a panel of four cancer cell lines expressing wild-type p53 (A2780, A549, HepG2) and mutant p53 (MDA-MB-453). The hits were 8h against A2780 (IC50 = 10.3 µM) and HepG2 (IC50 = 18.6 µM), 8m against A549 (IC50 = 17.7 µM), and 8k against MDA-MB-453 (IC50 = 21.4 µM). Further MTT experiments showed that 8h and 8j potentiated doxorubicin activity and reduced its IC50 by at least 25% in combinations. Western blot analysis demonstrated that 8k and 8m downmodulated MDM2 in A549 cells. Their possible binding mode with MDM2 were simulated by docking analysis.

Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, 10–13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10–13 were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds 10–13. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is E. Biological results revealed that all the screened compounds 10–13 might serve as selective COX-1 inhibitors. They showed IC50 values ranging from 0.71 μM to 4.82 μM against COX-1 and IC50 values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC50 values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC50 value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC50 values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC50 value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.

According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer statistics continues to rise, it is imperative to explore new avenues in the ongoing battle against this disease. Therefore, a number of new indolyl-hydrazones were synthesized by reacting the ethyl 3-formyl-1H-indole-2-carboxylate 1 with thiosemicarbazide, semicarbazide.HCl, 4-nitrophenyl hydrazine, 2,4-dinitrophenyl hydrazine, and 4-amino-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione to afford the new hit compounds, which were assigned chemical structures as thiosemicarbazone 3, bis(hydrazine derivative) 5, semicarbzone 6, Schiff base 8, and the corresponding hydrazones 10 and 12 by NMR, elemental analysis, and X-ray single-crystal analysis. The MTT assay was employed to investigate the compounds’ cytotoxicity against breast cancer cells (MCF-7). Cytotoxicity results disclosed potent IC50 values against MCF-7, especially compounds 5, 8, and 12, with IC50 values of 2.73 ± 0.14, 4.38 ± 0.23, and 7.03 ± 0.37 μM, respectively, compared to staurosproine (IC50 = 8.32 ± 0.43 μM). Consequently, the activities of compounds 5, 8, and 12 in relation to cell migration were investigated using the wound-healing test. The findings revealed notable wound-healing efficacy, with respective percentages of wound closure measured at 48.8%, 60.7%, and 51.8%. The impact of the hit compounds on cell proliferation was assessed by examining their apoptosis-inducing properties. Intriguingly, compound 5 exhibited a significant enhancement in cell death within MCF-7 cells, registering a notable increase of 39.26% in comparison to the untreated control group, which demonstrated only 1.27% cell death. Furthermore, the mechanism of action of compound 5 was scrutinized through testing against kinase receptors. The results revealed significant kinase inhibition, particularly against PI3K-α, PI3K-β, PI3K-δ, CDK2, AKT-1, and EGFR, showcasing promising activity, compared to standard drugs targeting these receptors. In the conclusive phase, through in vivo assay, compound 5 demonstrated a substantial reduction in tumor volume, decreasing from 106 mm³ in the untreated control to 56.4 mm³. Moreover, it significantly attenuated tumor proliferation by 46.9%. In view of these findings, the identified leads exhibit promises for potential development into future medications for the treatment of breast cancer, as they effectively hinder both cell migration and proliferation.

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY), derived from isatin and L-proline, with phenyl vinyl sulphone has been studied within Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. ELF topological analysis of AY classifies it as a pseudo(mono)radical species with two monosynaptic basins at the C1 carbon, integrating a total of 0.76 e. While vinyl sulphone has a strong electrophilic character, AY is a supernucleophile, suggesting a high polar character and low activation energy for the reaction. The nucleophilic Parr functions indicate that the pseudoradical C1 carbon is the most nucleophilic center. The 32CA reaction presents an activation Gibbs free energy of 13.1 kcal·mol−1 and is exergonic by −26.8 kcal·mol−1. This reaction presents high endo stereoselectivity and high meta regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable meta/endo TS, 0.31 e, accounts for the high polar character of this 32CA reaction, classified by forward electron density flux (FEDF). A Bonding Evolution Theory (BET) study along the most favorable meta/endo reaction path characterizes this 32CA reaction, taking place through a non-concerted two-stage one-step mechanism, as a pseudo(mono)radical-type 32CA reaction, in agreement with the ELF analysis of the AY.

The synthesis of 4-methyl/phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one 4 and 7 has been reported with ninhydrin via a reaction first with ethyl acetoacetate or ethyl benzoylacetate and then a reaction of the resultant esters with hydrazine hydrate. The mechanism of hydrazinolysis and cyclization to obtain tetraazafluoranthen-3(2H)-ones is ambiguous, and the previously proposed mechanism was not based on facts because the actual intermediates were not isolated. Herein, the important intermediates involved in the hydrazinolysis–cyclization mechanistic pathway were isolated and characterized using NMR and X-ray single-crystal analysis. The intermediates demonstrate that the reaction carried out via two hydrazinolysis–cyclization reactions, the first of which includes the condensation of one hydrazine molecule with two ketone groups and the second of which includes the reaction of another hydrazine molecule with the ester and then condensation with the other ketone group. The stability of hydrazide 11 enabled the hydrazine to reduce the carbonyl of the ketone group to form 12 via a Wolff–Kishner-like reduction. The structure of the three intermediates was confirmed using X-ray crystallographic analysis. It was found that the three fused ring systems deviated from planarity to different extents, with their deviation from being coplanar reaching up to 5.3°. The possible non-covalent interactions which control the molecular packing of these intermediates were elucidated with the aid of Hirshfeld analysis.

Oxidative stress, COX-2, LDHA and hyperglycemia are interlinked contributing pathways in the etiology, progression and metastasis of colon cancer. Additionally, dysregulated apoptosis in cells with genetic alternations leads to their progression in malignant transformation. Therefore, quinazolinones 3a–3h and 5a–5h were synthesized and evaluated as antioxidants, enzymes inhibitors and cytotoxic agents against LoVo and HCT-116 cells. Moreover, the most active cytotoxic derivatives were evaluated as apoptosis inducers. The results indicated that 3a, 3g and 5a were efficiently scavenged DPPH radicals with lowered IC50 values (mM) ranging from 0.165 ± 0.0057 to 0.191 ± 0.0099, as compared to 0.245 ± 0.0257 by BHT. Derivatives 3h, 5a and 5h were recognized as more potent dual inhibitors than quercetin against α-amylase and α-glucosidase, in addition to 3a, 3c, 3f and 5b–5f against α-amylase. Although none of the compounds demonstrated a higher efficiency than the reference inhibitors against COX-2 and LDHA, 3a and 3g were identified as the most active derivatives. Molecular docking studies were used to elucidate the binding affinities and binding interactions between the inhibitors and their target proteins. Compounds 3a and 3f showed cytotoxic activities, with IC50 values (µM) of 294.32 ± 8.41 and 383.5 ± 8.99 (LoVo), as well as 298.05 ± 13.26 and 323.59 ± 3.00 (HCT-116). The cytotoxicity mechanism of 3a and 3f could be attributed to the modulation of apoptosis regulators (Bax and Bcl-2), the activation of intrinsic and extrinsic apoptosis pathways via the upregulation of initiator caspases-8 and -9 as well as executioner caspase-3, and the arrest of LoVo and HCT-116 cell cycles in the G2/M and G1 phases, respectively. Lastly, the physicochemical, medicinal chemistry and ADMET properties of all compounds were predicted.

The synthesis and X-ray structure analysis of the new [PdLCl2]*0.5 CH2Cl2 complex where L is hydrazono-s-triazine di-morpholine derivative, were presented. In the neutral inner sphere of this complex, the organic ligand L is acting as a NN-bidentate chelate via the pyridine and hydrazone N-atoms. The coordination configuration of the Pd(II) is completed by two chloride ions at cis-positions. The tetra-coordinated Pd(II) showed a distorted square planar geometry. The outer sphere comprised half methylene chloride molecule per [PdLCl2] as crystal solvent. The crystal stability is dominated by a number of weak C-H…N, C-H…Cl, and C-H…O non-covalent interactions. Based on Hirshfeld analysis, the H…H, N…H, H…Cl, O…H, Pd…C, and Cl…C intermolecular interactions contributed by 45.2, 9.3, 21.5, 5.8, 2.3, and 3.4%, respectively. DFT studies revealed closed shell characters for the Pd-N and Pd-Cl coordinate bonds. The net charge of Pd is also predicted to be 0.311 e and the amount of electron density transferred from the ligand groups is 1.689 e. The Pd(II) complex exhibited potent cytotoxic activity against MCF-7, HepG2, and A549 cells with IC50 values of 1.18, 4.74, and 5.22 μg/mL, compared to cisplatin with IC50 values of 4.1, 9.7, and 12.3 μg/mL, respectively. Additionally, it exhibited poor cytotoxicity against WISH cells with much higher IC50 values (IC50 = 37.2 μg/mL). Investigating apoptosis-induction, the Pd(II) complex induced apoptotic cell death by an 11-fold change in MCF-7 cells arresting the cell phase at the G0–G1 phase. Accordingly, Pd(II) complex can be developed as a promising anti-breast cancer agent.

A new Ag(I) adduct was synthesized by the reaction of 4-amino-4H-1,2,4-triazole (L) with AgNO3. Its chemical structure was approved to be [Ag2(L)2(NO3)]n(NO3)n utilizing elemental analysis, FTIR spectra, and single crystal X-ray diffraction (SC-XRD). According to SC-XRD, there are two independent silver atoms which are coordinated differently depending on whether the nitrate anion is coordinated or not. The coordination geometry of Ag1 is a slightly bent configuration while Ag2 has a distorted tetrahedral structure. The 4-amino-4H-1,2,4-triazole ligand and one of the nitrate groups adopt bridging mode, which connects the crystallographically independent Ag1 and Ag2 atoms resulting in the formation of two-dimensional coordination polymer. Hirshfeld surface analysis displays that the intermolecular O···H (34.0%), Ag···N (10.6%), H···H (10.4%), Ag···O (9.3%), and N···H (9.0%) contacts are the most abundant interactions. Regarding anticancer activity, the [Ag2(L)2(NO3)]n(NO3)n demonstrates stronger cytotoxic efficacy against lung (IC50 = 3.50 ± 0.37 µg/mL) and breast (IC50 = 2.98 ± 0.26 µg/mL) carcinoma cell lines than the anticancer medication cis-platin. The [Ag2(L)2(NO3)]n(NO3)n complex showed interesting antibacterial and antifungal activities compared to the free components (AgNO3 and 4-amino-4H-1,2,4-triazole). The investigated silver(I) complex exhibits remarkable antibacterial activity against E. coli (MIC = 6.1 µg/mL) that may be on par with Gentamycin (MIC = 4.8 µg/mL). As a result, the newly synthesized Ag(I) complex could be suggested for anticancer and antibacterial treatments.

Two novel silver(I) coordination polymers, [Ag(4BP)(SCN)]n (1) and {(4BPH)+[Ag(SCN)2]−}n (2) (4BP = 4-benzoyl pyridine), have been synthesized. The two complexes were prepared using almost the same reagents, which were AgNO3, 4BP and NH4SCN. The only difference was the presence of 1:1 (v/v) HNO3 in the synthesis of 2. In the two complexes, the Ag(I) has distorted tetrahedral coordination geometry. The structure of both complexes and the involvement of the thiocyanate anion as a linker between the Ag(I) centers were confirmed using single-crystal X-ray diffraction. 4BP participated as a monodentate ligand in the coordination sphere of complex 1, while in 2 it is found protonated (4BP-H)+ and acts as a counter ion, which balances the charge of the anionic [Ag(SCN)2]− moiety. The thiocyanate anion shows different coordination modes in the two complexes. In complex 1, the thiocyanate anion exhibits a µ1,1,3 bridging mode, which binds three Ag(I) ions to build a boat-like ten-membered ring structure leading to a two-dimensional coordination polymer. In 2, there are mixed µ1,1 and µ1,3 bridging thiocyanate groups, which form the one-dimensional polymeric chain running in the a-direction. Several interactions affected the stability of the crystal structure of the two complexes. These interactions were examined using Hirshfeld surface analysis. The coordination interactions (Ag-S and Ag-N) have a great impact on the stability of the polymeric structure of the two complexes. Additionally, the hydrogen-bonding interactions are crucial in the assembly of these coordination polymers. The O…H (10.7%) and C…H (34.2%) contacts in 1 as well as the N···H (15.3%) and S···H (14.9%) contacts in 2 are the most significant. Moreover, the argentophilic interaction (Ag…Ag = 3.378 Å) and π- π stacking play an important role in the assembly of complex 2.

A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole 4 was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time. The final synthesized chemical architecture has differently characterized electronic effects. An MEDT study of the key 32CA reaction between in situ generated azomethine ylide (AY) and chalcones explained the low reaction rates and the total selectivities observed. The supernucleophilic character of AY and the strong electrophilicity of chalcones favor these reactions through a highly polar two-stage one-step mechanism in which bond formation at the β-conjugated carbon of the chalcones is more advanced. The present combined experimental and theoretical study reports the synthesis of new spirooxindoles with potential biological activities and fully characterizes the molecular mechanisms for their formation through the key 32CA reaction step.

The complex [Co(L)(H2O)4](NO3)2 of (E)-4-(2-(3-methyl-5-oxo-1-(pyridin-2-yl)-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-N-(pyrimidin-2-yl)benzenesulfonamide (L) was synthesized via the self-assembly technique. Its molecular and supramolecular structures were analyzed using FTIR, elemental analyses, and single-crystal X-ray diffraction, as well as Hirshfeld calculations. This complex crystallized in the triclinic space group P1¯ with Z = 2. The crystallographic asymmetric unit comprised one complex cation and two nitrate counter anions. This complex had distorted octahedral geometry around the Co(II) ion. Numerous intermolecular interactions affecting the molecular packing of this complex were conformed using Hirshfeld investigations. The most significant contacts for the cationic inner sphere [Co(L)(H2O)4]2+ were O···H (38.8%), H···H (27.8%), and N···H (9.9%). On the other hand, the main interactions for the counter NO3¯ ions were the O···H (79.6 and 77.8%), O···N (8.0%), and O···C (9.1%). A high propensity for making interactions for each atom pair in the contacts O…H, N…C, N…H, and C…C was revealed by enrichment ratio values greater than 1. The antibacterial efficacy of the complex and the free ligand were assessed. The free ligand had higher antibacterial activity (MIC = 62.5–125 µg/mL) than the [Co(L)(H2O)4](NO3)2 complex (MIC ≥ 250 µg/mL) versus all the studied bacteria.

The synthesis and X-ray crystal structure analyses of the azido complex [Zn(N3)(Arg)2](N3)·3H2O, where Arg is L-arginine, were presented. The molecular structure of the complex was further studied using FT-IR spectra as well as atoms in molecules (AIM) theory. An analysis of the crystal data indicated monoclinic crystal system and P21 space group with a = 13.0283(5) Å, b = 15.2032(7) Å, c = 13.3633(6) Å, β = 114.3580(10)°, V = 2411.28(18) Å3, and Z = 4. Two of the [Zn(N3)(Arg)2](N3)·3H2O formulae represent the asymmetric unit of this complex where the geometric parameters of both units are slightly different. In [Zn(N3)(Arg)2](N3)·3H2O, the central Zn(II) ion is penta-coordinated with two Arg molecules as a bidentate ligand and one terminally coordinated azide ion. Each of the two Arg molecules are located trans to one another and coordinated with the Zn(II) via the N and O atoms of the amino and carboxylate groups, respectively. Hence, Zn(II) is five-coordinated and has a distorted square pyramidal coordination geometry. The supramolecular structure of the [Zn(N3)(Arg)2](N3)·3H2O complex was inspected using the Hirshfeld analysis. The O···H (26.6–28.4%), H···H (32.3–35.3%), and N···H (30.4–34.0%) contacts are the most significant interactions in the crystal structure of the [Zn(N3)(Arg)2](N3)·3H2O complex. The Zn–N, and Zn–O bonds have slight covalent interactions based on the AIM study.

A series of pyrazolyl-s-triazine compounds with an indole motif was designed, synthesized, and evaluated for anticancer activity targeting dual EGFR and CDK-2 inhibitors. The compounds were tested for cytotoxicity using the MTT assay. Compounds 3h, 3i, and 3j showed promising cytotoxic activity against two cancer cell lines, namely A549, MCF-7, and HDFs (non-cancerous human dermal fibroblasts). Compound 3j was the most active candidate against A549, with an IC50 of 2.32 ± 0.21 μM. Compounds 3h and 3i were found to be the most active hybrids against MCF-7 and HDFs, with an IC50 of 2.66 ± 0.26 μM and 3.78 ± 0.55 μM, respectively. Interestingly, 3i showed potent EGFR inhibition, with an IC50 of 34.1 nM compared to Erlotinib (IC50 = 67.3 nM). At 10 μM, this candidate caused 93.6% and 91.4% of EGFR and CDK-2 inhibition, respectively. Furthermore, 3i enhanced total lung cancer cell apoptosis 71.6-fold (43.7% compared to 0.61% for the control). Given the potent cytotoxicity exerted by 3i through apoptosis-mediated activity, this compound emerges as a promising target-oriented anticancer agent.

The [Ag(3ADMT)(NO3)]n complex was synthesized by the self-assembly of 3-amino-5,6-dimethyl-1,2,4-triazine (3ADMT) and AgNO3. Its molecular structure was analyzed utilizing FTIR spectra, elemental analysis, and single crystal X-ray diffraction (SC-XRD). There is one crystallographically independent Ag atom, which is tetra-coordinated by two nitrogen atoms from two 3ADMT and two oxygen atoms from two nitrate anions where all ligand groups are acting as connectors between the Ag1 sites. The geometry around the Ag(I) center is a distorted tetrahedron with a AgN2O2 coordination sphere augmented by strong argentophilic interactions between Ag atoms, which assist the aggregation of the complex units in a wavy-like and coplanar pattern to form a one-dimensional polymeric chain. The O...H (37.2%) and N...H (18.8%) intermolecular interactions contributed significantly to the molecular packing based on Hirshfeld surface analysis. The [Ag(3ADMT)(NO3)]n complex demonstrates promising cytotoxicity against lung (IC50 = 2.96 ± 0.31 μg/mL) and breast (IC50 = 1.97 ± 0.18 μg/mL) carcinoma. This remarkable cytotoxicity exceeds those of 3ADMT, AgNO3, and the anticancer medication cis-platin towards the tested cancer cell lines. In addition, the complex has a wide-spectrum antimicrobial action where the high antibacterial potency of the [Ag(3ADMT)(NO3)]n complex against P. vulgaris (MIC = 6.1 µg/mL) and B. subtilis (MIC = 17.2 µg/mL) could be comparable to the commonly used drug Gentamycin (MIC = 4.8 µg/mL). These results confirm that the components of the [Ag(3ADMT)(NO3)]n complex work together synergistically, forming a powerful multifunctional agent that could be exploited as an effective antimicrobial and anticancer agent.

The unexpected tetranuclear [Cu4(DPPT)2Cl6] complex was obtained by self-assembly of CuCl2.2H2O and (E)-2,4-di(piperidin-1-yl)-6-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)-1,3,5-triazine, (HDPPT) in ethanol. In this tetranuclear [Cu4(DPPT)2Cl6] complex, the organic ligand acts as mononegative chelate bridging two crystallographically independent Cu(II) sites. The DPPT− anion acts as a bidentate ligand with respect to Cu(1), while it is a tridentate for Cu(2). The Cu(1)N2Cl3 and Cu(2)N3Cl spheres have square pyramidal and square planar coordination geometries with some distortion, respectively. Two of the chloride ions coordinating the Cu(1) are bridging between two crystallographically related Cu(1) sites connecting two [Cu2(DPPT)Cl3] units together, leading to the tetranuclear formula [Cu4(DPPT)2Cl6]. The packing of the [Cu4(DPPT)2Cl6] complex is dominated by C-H…Cl contacts, leading to one-dimensional hydrogen-bond polymeric structure. According to Hirshfeld surface analysis of molecular packing, the non-covalent interactions H…H, Cl…H, Cl…C, C…H, and N…H are the most significant. Their percentages are 52.8, 19.0, 3.2, 7.7, and 9.7%, respectively. Antimicrobial assessment showed good antifungal activity of the Cu(II) complex against A. fumigatus and C. albicans compared to Ketoconazole as positive control. Moreover, the [Cu4(DPPT)2Cl6] complex has higher activity against Gram-positive bacteria than Gentamycin as positive control. The opposite was observed when testing the tetranuclear [Cu4(DPPT)2Cl6] complex against the Gram-negative bacteria.

The hydrazones 3a–c, were synthesized from the reaction of indole-3-carbaldehyde and nicotinic acid hydrazide, isonicotinic acid hydrazide, and benzoic acid hydrazide, respectively. Their structures were confirmed using FTIR, 1HNMR, and 13CNMR spectroscopic techniques. Exclusively, hydrazones 3b and 3c were confirmed using single crystal X-ray crystallography to exist in the Eanti form. With the aid of DFT calculations, the most stable configuration of the hydrazones 3a–c in gas phase and in nonpolar solvents (CCl4 and cyclohexane) is the ESyn form. Interestingly, the DFT calculations indicated the extrastability of the EAnti in polar aprotic (DMSO) and polar protic (ethanol) solvents. Hirshfeld topology analysis revealed the importance of the N…H, O…H, H…C, and π…π intermolecular interactions in the molecular packing of the studied systems. Distribution of the atomic charges for the hydrazones 3a–c was presented. The hydrazones 3a–c showed a polar character where 3b has the highest polarity of 5.7234 Debye compared to the 3a (4.0533 Debye) and 3c (5.3099 Debye). Regarding the anti-toxoplasma activity, all the detected results verified that 3c had a powerful activity against chronic toxoplasma infection. Compound 3c showed a considerable significant reduction percent of cyst burden in brain homogenates of toxoplasma infected mice representing 49%.

The two group IIB complexes [Cd(DMPT)Cl2] (6) and [Zn(DMPT)Cl2] (7) of the tridentate ligand (DMPT), 2,4-bis(morpholin-4-yl)-6-[(E)-2-[1-(pyridin-2-yl) ethylidene]hydrazin-1-yl]-1,3,5-triazine were synthesized, and their structural aspects were elucidated with the aid of X-ray crystallography. Both complexes crystallized in the monoclinic crystal system, with P21/n as a space group. The unit cell parameters for 6 are a = 14.1563(9) Å, b = 9.4389(6) Å, c = 16.5381(11) Å and β = 91.589(5)° while the respective values for 7 are 11.3735(14), 13.8707(13), 14.9956(16), and 111.646(2)°. The unit cell volume is slightly less (2198.9(4) Å3) in complex 7 compared to complex 6 (2209.0(2) Å3). Both complexes have a penta-coordination environment around the metal ion, where the DMPT ligand acts as a neutral tridentate NNN-chelate via the pyridine, hydrazone, and one of the s-triazine N-atoms. The penta-coordination environment of the Cd(II) in complex 6 is close to a square pyramidal configuration with some distortion. On the other hand, the ZnN3Cl2 coordination environment is highly distorted and located intermediately between the trigonal bipyramidal and square pyramids. Supramolecular structure analysis of 6 with the aid of Hirshfeld calculations indicated the importance of the Cl…H, O…H, and C…H interactions. Their percentages were calculated to be 20.9, 9.1, and 8.7%, respectively. For 7, the Cl…H, O…H, C…H, and N…H contacts are the most important. Their percentages are 20.3, 9.0, 7.0, and 8.4%, respectively. In both complexes, the major intermolecular interaction is the hydrogen–hydrogen interactions which contributed 45.5 and 46.6%, respectively.

A new ethylene derivative was synthesized as a precursor for the [3+2] cycloaddition (32CA) reaction to access a novel spirooxindole embodied with benzimidazole with a pyridine spacer. The chalcone derivatives 3a–j is obtained with condensation of the acetyl derivative with aryl aldehydes. The one-pot multi-component reaction of the ethylene derivative, 5-Cl-isatin, and octahydroindole-2-carboxylic acid enables the construction of a highly functionalized quaternary center spirooxindole scaffold in a high chemical yield. A study using the Molecular Electron Density Theory (MEDT) explains the complete regio- and stereoselectivity of the reaction, resulting in the exclusive formation of the ortho/endo-cycloadduct under kinetic control. The low activation Gibbs free energy is the result of the supernucleophilic character of the in situ-generated azomethine ylide and the strong electrophilic character of the ethylene derivatives.

The regiospecific S-benzylation/allylation of two 4-aryl-5-indolyl-1,2,4-triazole-3-thione precursors was carried out using Et3N as a base. Allyl group migration from exocyclic sulfur to the triazole nitrogen (N3) was successfully achieved in a short time via thermal fusion without the need for any catalyst. The allylation of indole nitrogen, along with exocyclic sulfur or triazole nitrogen (N3), was carried out using K2CO3 as stronger base. S,N-Diallylated products were converted to N,N-diallylated analogues using a simple fusion approach. Structural analyses of the two newly synthesized hybrids 2b and 5b investigated via the X-ray diffraction of a single crystal combined with Hirshfeld calculations. The compound 5b was crystallized in a monoclinic crystal system and the P21/c space group, whereas in compound 2b, the crystal system comprises the less symmetric triclinic and P − 1 space group. The asymmetric unit contains one and two molecules of 5b and 2b, respectively, while the unit cell contains four molecules in both cases. Hirshfeld analysis was performed in both systems to analyze the non-covalent interactions that control molecular packing. For 5b, C…H, N…H, S…H, Cl…N and H…H interactions are the most significant. Their percentages are 23.7, 8.8, 4.5, 1.2 and 48.2, respectively. In the case of 2b, the Cl…C, S…N, C…H, H…H and N…H interactions have the upper hand in molecular packing. In one unit, the percentages of these contacts are 2.3, 0.9, 26.8, 38.7 and 9.3%, while in the other unit, the corresponding values are 4.4, 1.3, 22.1, 43.6 and 9.0%, respectively.

The hit compound 1,2,4-triazolo[4’,3’:2,3]pyridazino[4,5-b]indole 3 was synthesized from the reflux of 4-amino-5-indolyl-1,2,4-triazole-3-thione 1 with 4′-bromoacetophenone 2 in methanol catalyzed by concentrated HCl and the desired final molecule was obtained by recrystallization from methanol. The suggested structures of compounds 1 and 3 based on the spectral characterizations were confirmed by X-ray single crystal diffraction analysis. Compound 3 crystallized in the triclinic crystal system and P-1 space group with a = 5.9308(2) Å, b = 10.9695(3) Å, c = 14.7966(4) Å, α = 100.5010(10)°, β = 98.6180(10)°, and γ = 103.8180(10)°. On the other hand, the crystal system of 1 is monoclinic, where a = 6.23510(10) Å, b = 26.0156(4) Å, c = 12.4864(2) Å, β = 93.243(2)° and the space group is P21. The triazole and indole rings are found twisted from each other in both compounds. The twist angle is higher in 3 (12.65°) than 1 (4.94–7.22°). In the case of the former, the H…H (39.6%), H…C (22.0%), N…H (12.8%) and Br…H (13.2%) contacts are the most dominant while the C…C, C…H, Br…H, N…H and S…S contacts have the characteristics of strong interactions. In the latter, the C…H, N…H, S…H, S…S, and C…C contacts are the most important. In this case, the percentages of the H…H, C…H, N…H and S…H contacts are in the range of 34.9–37.4, 20.5–24.0, 12.2–13.6, 14.0–15.8, respectively. In both systems, the shape index and curvedness of surfaces confirmed the presence of π–π stacking interactions.

A new Co(II) perchlorate complex of the bis-morpholino/benzoimidazole-s-triazine ligand, 4,4′-(6-(1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)dimorpholine (BMBIT), was synthesized and characterized. The structure of the new Co(II) complex was approved to be [Co(BMBIT)2(H2O)4](ClO4)2*H2O using single-crystal X-ray diffraction. The Co(II) complex was found crystallized in the monoclinic crystal system and P21/c space group. The unit cell parameters are a = 22.21971(11) Å, b = 8.86743(4) Å, c = 24.38673(12) Å and β = 113.4401(6)°. This heteroleptic complex has distorted octahedral coordination geometry with two monodenatate BMBIT ligand units via the benzoimidazole N-atom and four water molecules as monodentate ligands. The hydration water and perchlorate ions participated significantly in the supramolecular structure of the [Co(BMBIT)2(H2O)4](ClO4)2*H2O complex. Analysis of dnorm map and a fingerprint plot indicated the importance of O···H, N···H, C···H, C···O, C···N and H···H contacts. Their percentages are 27.5, 7.9, 14.0, 0.9, 2.8 and 43.5%, respectively. The sensitivity of some harmful microbes towards the studied compounds was investigated. The Co(II) complex has good antifungal activity compared to the free BMBIT which has no antifungal activity. The Co(II) complex has good activity against B. subtilis, S. aureus, P. vulgaris and E. coli while the free BMBIT ligand has limited activity only towards B. subtilis and P. vulgaris. Hence, the [Co(BMBIT)2(H2O)4](ClO4)2*H2O complex has broad spectrum antimicrobial action compared to the free BMBIT ligand.

The two complexes, [Ni(DPPT)2](NO3)2*1.5H2O (1) and [Ni(DPPT)(NO3)Cl].EtOH (2), were synthesized using the self-assembly of (E)-2,4-di(piperidin-1-yl)-6-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)-1,3,5-triazine (DPPT) with Ni(NO3)2*6H2O in the absence and presence of NiCl2*6H2O, respectively. In both cases, the neutral tridentate DPPT ligand is found coordinated to the Ni(II) via three N-atoms from the hydrazone, pyridine and s-triazine rings. Hence, the homoleptic complex 1 has a NiN6 hexa-coordination environment while two NO3− are counter anions in addition to one-and-a-half crystallized hydration water molecules are found acting as an outer sphere. The heteroleptic complex 2 has a NiN3O2Cl coordination sphere where the coordination environment of the Ni(II) is completed by one bidentate nitrate and one chloride ion leading to a neutral inner sphere while the outer sphere contains one crystallized ethanol molecule. Both complexes have distorted octahedral coordination environments around the Ni(II) ion. Using Hirshfeld analysis, the intermolecular contacts H…H and O…H in 1 and the Cl…H, O…H, N…H, H…H, C…H and C…C in 2 are found to be the most important for crystal stability. The antimicrobial activity of complexes 1 and 2 was assessed against different bacterial and fungal strains, and the results were compared with the free ligand as well as the antibacterial (Gentamycin) and antifungal (Ketoconazole) positive controls. Both Ni(II) complexes are better antibacterial and antifungal agents than the free ligand. Interestingly, both Ni(II) complexes have similar antifungal activity against C. albicans compared to Ketoconazole.

The pandemic of COVID-19, caused by SARS-CoV-2, has globally affected the human health and economy. Since the emergence of the novel coronavirus SARS-CoV-2, the life-threatening virus continues to mutate and evolve. Irrespective of acquired natural immunity and vaccine-induced immunity, the emerging multiple variants are growing exponentially, crossing the territorial barriers of the modern world. The rapid emergence of SARS-CoV-2 multiple variants challenges global researchers regarding the efficacy of available vaccines and variant transmissibility. SARS-CoV-2 surface-anchored S-protein recognizes and interacts with the host-cell ACE2, facilitating viral adherence and entrance into the cell. Understanding the interfacial interactions between the spike protein of SARS-CoV-2 variants and human ACE2 receptor is important for the design and development of antiviral therapeutics against SARS-CoV-2 emerging variants. Despite extensive research, the crucial determinants related to the molecular interactions between the spike protein of SARS-CoV-2 variants and host receptors are poorly understood. Thus, in this study, we explore the comparative interfacial binding pattern of SARS-CoV-2 spike RBD of wild type, Delta, and Omicron with the human ACE2 receptor to determine the crucial determinants at the atomistic level, using MD simulation and MM/GBSA energy calculations. Based on our findings, the substitution of Q493R, G496S, Q498R, and Y505H induced internal conformational changes in Omicron spike RBD, which leads to higher binding affinity than Delta spike RBD with the human ACE2 receptor, eventually contributing to higher transmission and infectivity. Taken together, these results could be used for the structure-based design of effective antiviral therapeutics against SARS-CoV-2 variants.

The pincer ligand 2,4-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methoxy-1,3,5-triazine (bpmt) was used to synthesize the novel [Na(bpmt)2][AuCl4] complex through the self-assembly method. In this complex, the Na(I) ion is hexa-coordinated with two tridentate N-pincer ligands (bpmt). The two bpmt ligand units are meridionally coordinated to Na(I) via one short Na-N(s-triazine) and two slightly longer Na-N(pyrazole) bonds, resulting in a distorted octahedral geometry around the Na(I) ion. In the coordinated bpmt ligand, the s-triazine core is not found to be coplanar with the two pyrazole moieties. Additionally, the two bpmt units are strongly twisted from one another by 64.94°. Based on Hirshfeld investigations, the H···H (53.4%) interactions have a significant role in controlling the supramolecular arrangement of the [Na(bpmt)2][AuCl4] complex. In addition, the Cl···H (12.2%), C···H (11.5%), N···H (9.3%), and O···H (4.9%) interactions are significant. Antimicrobial investigations revealed that the [Na(bpmt)2][AuCl4] complex has promising antibacterial and antifungal activities. The [Na(bpmt)2][AuCl4] complex showed enhanced antibacterial activity for the majority of the studied gram-positive and gram-negative bacteria compared to the free bpmt (MIC = 62.5–125 µg/mL vs. MIC = 62.5–500 µg/mL, respectively) and Amoxicillin (MIC > 500 µg/mL) as a positive control. Additionally, the [Na(bpmt)2][AuCl4] complex had better antifungal efficacy (MIC = 125 µg/mL) against C. albicans compared to bpmt (MIC = 500 µg/mL).

The hydrazine s-triazine ligand (E)-4,4’-(6-(2-(1-(pyridin-2-yl)ethylidene)hydrazinyl)-1,3,5-triazine-2,4-diyl)dimorpholine (DMPT) was used to synthesize two new Ni(II) complexes via a self-assembly technique. The two complexes were synthesized by a one-pot synthesis strategy and characterized by elemental analysis, FTIR and single-crystal X-ray diffraction analysis to be [Ni(DMPT)(H2O)3](NO3)2.3H2O (1) and [Ni(DMPT)(H2O)3](NO3)2.H2O (2). The structures of both complexes were very similar regarding the coordination sphere and counter anions, but differ only in the number of the crystal water molecules. In the case of complex 1, there are three water molecules instead of one H2O molecule as in complex 2. In the two complexes, the DMPT ligand acts as a neutral tridentate NNN-chelate via three Ni–N coordination interactions. The coordination sphere of the Ni(II) ion is completed by three water molecules. As a result, the two complexes exhibit distorted octahedral geometry. The Hirshfeld surfaces around each entity in both complexes have been computed. Subsequently, their corresponding intermolecular interactions were quantified separately. Because the number of crystal water molecules is different in both complexes, their monomeric units are connected differently in their crystal structures where the crystal water molecules act as both hydrogen bond donor and acceptor. The polar O…H interactions are the most dominant in all entities of both complexes. As a result, strong O…H interactions are the driving force in the crystal packing of both complexes, and this is attributed to the presence of the nitrate anions and water molecules. The antimicrobial activity of the free ligand and complex 1 were determined against two selected fungal species, Gram-negative and Gram-positive bacterial strains. The free ligand was found to be inactive against all microbial species. On the other hand, the Ni(II) complex 1 was found active against the Gram-positive bacterial species Bacillus subtilis and also the Gram-negative bacterial species Escherichia coli. The respective inhibition zone diameter of the Ni(II) complex was 12 and 11 mm, respectively.

5-(1H-Indol-2-yl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione 1a and 4-(4-chlorophenyl)-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1b were galactosylated in the presence of NaHCO3 in ethanol to produce S-galactosides 3,4, whereas, in the presence of K2CO3 in acetone they produced a mixture of S- and N-galactosides 3-6 with a higher yield of S-galactosides over the respective N-galactosides. Improvement in the yields of N-galactosides was produced by thermal migration of the galactosyl moiety from sulfur to nitrogen using fusion. β-Stereoselectivity of galactosylation was determined using the coupling constant value 3J1,2, which exceeded 9.0 Hz in all prepared galactosides. The precursors 1a and 1b alkylated with 3-bromopropan-1-ol 7 in K2CO3 and acetone produced the S-alkylated products 8 and 9, respectively. Structural determinations of new compounds 5 and 9 are presented. The phenyl and indole moieties were found to be twisted from the triazole ring mean in both compounds. For compound 5, the twist angles were 66.24° and 18.86°, respectively, while the corresponding values for 9 were in the ranges of 73.15–77.29° and 13.96–20.70°, respectively. Hence, the crystal system of 9 is triclinic while the space group is P-1. Detailed analysis of the intermolecular interactions in the crystal structure of 5 is presented using Hirshfeld calculations. The O…H, N…H, C…H, and S…H contacts appeared as red spots in the dnorm Hirshfeld surface indicating short distance intermolecular interactions. Their percentages were estimated based on the decomposition of the fingerprint plot to be 25.6, 2.4, 14.0, and 6.3%, respectively.

Rational design for a new spiroxindoles, combined with a benzimidazole scaffold to identify a new murine double minute two (MDM2) inhibitor was synthesized and characterized. The desired spiroxindoles were achieved via a [3+2] cycloaddition reaction approach which afforded the cycloadducts with four asymmetric centers separated in an excellent regioselective and diastereoselective compound. The separated spiroxindoles were subjected to a set of biochemical assays including an NCI cell panel assay, MTT assay, and MDM2 binding analysis by a microscale thermophoresis assay. The anticancer reactivity for the tested compounds showed IC50 (µM) in the range between 3.797–6.879 µM, and compound 7d with IC50 = 3.797 ± 0.205 µM was the most active candidate between the series. The results showed promising results that identified that compound 7a could be inhibited the MDM2 with KD = 2.38 μm. Compound 7a developed a network of interactions with the MDM2 receptor studied in silico by molecular docking.

Two 1D coordination polymers were synthesized by reaction of two ligands, 2-amino-4-picoline (2A4Pic) and quinoline-6-carboxylic acid (Qu-6-COOH) with two metal (II) nitrate (M = Cd and Cu) in the presence of azide as a linker. The synthesized metal complexes [Cd(2A4Pic)2(N3)2]n; (1) and [Cu(Qu-6-COO)(N3)(H2O)]n; (2) were isolated in single crystals and their X-ray structures revealed a 1D polymeric structure. Due to symmetry considerations, the asymmetric formula is half a [Cd(2A4Pic)2(N3)2] unit for 1 and one [Cu(Qu-6-COO)(N3)(H2O)] unit for 2. In complex 1, the Cd(II) is hexa-coordinated with two 2A4Pic molecules and four μ(1,1) azide units. Hence, the CdN6 coordination environment has a slightly distorted octahedral geometry. In 2, the Cu(II) is hexa-coordinated with three different ligands (Qu-6-COO¯, H2O and μ(1,1) N3¯) where all are connectors between the crystallographically related Cu(II) sites. Additionally, complex 2 distorted CuN2O4 octahedral geometry. In both complexes, the polymer arrays are connected by N…H hydrogen bonds and π–π stacking interactions. Based on Hirshfeld analysis, the percentages of N…H contacts are 43.1 and 27.4% for 1 and 2, respectively, while %C...C are 5.6 and 9.3%, respectively. Analysis of Cu-N, Cu-O, and Cd-N bonds using DFT calculations showed predominantly closed-shell coordination interactions with little covalent characters. Additionally, the negatively charged ligand groups were found to compensate the positive charge of the central metal ion to a larger extent than the electrically neutral ligands.

The present synthetic strategy involves the synthesis of indolyl-triazolo-thiadiazole heterocyclic ring systems 8–13 from the condensation of 4-amino-5-(1H-indol-2-yl)-3H-1,2,4-triazole-3-thione 1 with the aromatic carboxylic acid derivatives 2–7 in presence of POCl3 for 1 h. All compounds were obtained in very good yields and have been well-characterized using spectroscopic techniques. Exclusively, good quality crystals from the target organic hybrid 8-(1H-indol-2-yl)-5-(p-tolyl)-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazole 9 were obtained and found suitable for X-ray single crystal diffraction measurement, which is used to confirm and analyze the molecular and supramolecular structure aspects of 9. The solid-state structure of the synthesized molecule 9 agrees very well with other characterizations. The packing of 9 is dominated by the N…H, S…H, C…C and S…C non-covalent interactions, which agree with the Hirshfeld surface analysis. The percentages of these contacts are calculated to be 20.3%, 5.4%, 9.4% and 4.3%, respectively.

The substituted-9-bromo-9,10-dihydro-9,10-ethanoanthracenes ortho 8a-12a and meta 8b-13b have been synthesized via Diels-Alder reaction under microwave conditions. The cycloadduct isomers ortho 8a-11a and meta 8b-11b, with priority to ortho 8a-11a, were obtained from the reaction of 9-bromoanthracene 1 with acrylonitrile 2, 2-chloroacrylonitrile 3, methacryloyl chloride 4 and acrylic acid 5, while ortho 12a and meta 12b, with priority to meta 12b, was obtained from the reaction of 9-bromoanthracene 1 with 1-cynao vinyl acetate 6. Interestingly, the only isomer meta 13b was obtained from the reaction of 9-bromoanthracene 1 with phenyl vinyl sulfone 7. The results proved that the steric or/and electronic nature of the dienophile substituent is/are playing significant roles in the regioselectivity and isomers ratio.

A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for in vitro evaluation of α-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 264.07 ± 1.87 and 448.63 ± 2.46 µM. Molecular docking studies indicated that compounds of 3g, 3i, 3j, and 5 are located close to the active site of α-glucosidase, which may cover the active pocket, thereby inhibiting the binding of the substrate to the enzyme. Thiopyrimidine trione derivatives also inhibited the generation of advanced glycation end-products (AGEs), which cause long-term complications in diabetes. While, compounds 3a–k, 5, and 6 showed significant to moderate anti-glycation activity (IC50 = 31.5 ± 0.81 to 554.76 ± 9.1 µM).

The novel hydrazone-containing thieno[2,3-d]pyrimidine, namely, N′-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)-2-(4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)acetohydrazide 4 was synthesized in a very good yield from the reaction of the triketoester 1 or ninhydrin 2 with the exocyclic acetohydrazide 3 in methanol. Good-quality crystals of 4 were obtained by recrystallization of the compound from the DMF/MeOH solvent mixture. The target product 4 crystallized in the triclinic crystal system and P-1 space group. The topology analysis of molecular packing indicated that the H…H (30.4%), O…H (22.0%) and H…C (17.0%) contacts are the most dominant intermolecular interactions in the crystal of 4, while the O…H, N…H, H…C, N…C, O…C, C…C and O…O are the only contacts which have shorter interaction distances than the vdWs radii sum of the interacting atoms. The structure of 4 is optimized and the calculated structure showed good agreement with the experimental one. Additionally, MEP, HOMO, LUMO and the reactivity descriptors were calculated.