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The alkylation of 3,5-dihydro-4H-pyridazino[4,5-b]indole-4-thione with benzyl bromide, ethyl chloroacetate, and allyl bromide in the presence of potassium carbonate (K2CO3) yielded new alkylsulfanylpyridazino[4,5-b]indole derivatives (i.e., compounds 4–6). Hydrazinolysis of ester 6 resulted in hydrazide 7. The structure of compound 6 was verified by X-ray single-crystal analysis. Among the synthesized compounds, compound 6 exhibited the most promising cytotoxicity toward MCF-7 cells with an IC50 value of 12 µM. It showed potential inhibition activity toward EGFR, PI3K, and AKT in MCF-7 cells, with 0.26-, 0.49-, and 0.31-fold reductions in concentration compared to an untreated control. Additionally, it showed apoptosis-inducing activity in MCF-7 cells (47.98-fold); overall apoptosis increased to 38.87% compared to 0.81% in the untreated control, which disrupted the cell cycle at pre-G1 and S phases. Moreover, compound 6 exhibited good binding affinities toward the tested proteins (EGFR, PI3K, and AKT) and had binding energies ranging from −15.87 to −24.87 Kcal/mol. It also formed good interactions with essential amino acids inside the binding sites. Hence, compound 6 is recommended as an anti-breast cancer chemotherapeutic due to its effects on the EGFR-PI3K-AKT pathway.

A straightforward one-pot route for the synthesis of a new 4-phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one is reported form the direct hydrazinolysis of triketo ester and hydrazine hydrate in ethanol. 4-Phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one was subjected to aza-Michael addition and N-alkylation on reaction with a set of alkylating agents in the presence of K2CO3. Hydrazinolysis of 4-phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one ester to hydrazide and conversion of hydrazide to thiosemicarbazide were successful. X-Ray single crystals analysis and 1H, 13C NMR were used for unambiguous structure confirmation. The O…H, N…H, C…N and C…C in 2, and the N…H, C…N, C…C, C…O and H…H interactions in 6 are the most important in the molecular packing based on Hirshfled analysis. Moreover, the presence of short C…C and C…N contacts in both compounds revealed the presence of π–π stacking interactions.

A new compounds named 3-4′-bipyrazoles 2 and 3 were synthesized in high chemical yield from a reaction of pyran-2,4-diketone 1 with aryl hydrazines under thermal conditions in MeOH. Compound 2 was unambiguously confirmed by single-crystal X-ray analysis. It crystalizes in a triclinic crystal system and space group P-1. Its crystal structure was found to be in good agreement with the spectral characterizations. With the aid of Hirshfeld calculations, the H…H (54.8–55.3%) and H…C (28.3–29.2%) intermolecular contacts are the most dominant, while the O…H (5.8–6.5%), N…H (3.8–4.6%) and C…C (3.0–4.9%) are less dominant. The compound has a polar nature with a net dipole moment of 6.388 Debye. The BD(2)C31-C32→BD*(2)N4-C34 (27.10 kcal/mol), LP(1)N5→BD*(2)C31-C32 (36.90 kcal/mol), BD(1)C32-C34→BD*(1)C18-C31 (6.78 kcal/mol) and LP(1)N4→BD*(1)N5-C31 (7.25 kcal/mol) are the strongest π→π*, n→π*, σ-σ* and n→σ* intramolecular charge transfer processes, respectively.

Four different new Schiff basses tethered indolyl-triazole-3-thione hybrid were designed and synthesized. X-ray single crystal structure, tautomerism, DFT, NBO and Hirshfeld analysis were explored. X-ray crystallographic investigations with the aid of Hirshfeld calculations were used to analyze the molecular packing of the studied systems. The H···H, H···C, S···H, Br···C, O···H, C···C and N···H interactions are the most important in the molecular packing of 3. In case of 4, the S···H, N···H, S···C and C···C contacts are the most significant. The results obtained from the DFT calculations indicated that the thione tautomer is energetically lower than the thiol one by 13.9545 and 13.7464 kcal/mol for 3 and 4, respectively. Hence, the thione tautomer is the most stable one which agree with the reported X-ray structure. In addition, DFT calculations were used to compute the electronic properties while natural bond orbital calculations were used to predict the stabilization energies due to conjugation effects. Both compounds are polar where 4 (3.348 Debye) has a higher dipole moment than 3 (2.430 Debye).

Intra and intermolecular interactions found in the developed crystals of the synthesized py-ron-2,4-dione derivatives play crucial rules in the molecular conformations and crystal stabili-ties, respectively. In this regard, Hirshfeld calculations were used to quantitatively analyze the different intermolecular interactions in the crystal structures of some functionalized py-ran-2,4-dione derivatives. The X-ray structure of pyran-2,4-dione derivative namely (3E,3′E)-3,3′-((ethane-1,2-diylbis(azanediyl))bis(phenylmethanylylidene))bis(6-phenyl-2H-pyran-2,4(3H)-dione) was determined. It crystallized in the monoclinic crystal system and C2/c space group with unit cell parameters: a = 14.0869(4) Å, b = 20.9041(5) Å, c = 10.1444(2) Å and β = 99.687(2)°. Generally, the H…H, H…C, O…H and C…C contacts are the most important interactions in the molecular packing of the studied pyran-2,4-diones. The molecular structure of these compounds is stabilized by intramolecular O…H hydrogen bond. The nature and strength of the O…H hy-drogen bonds were analyzed using atoms in molecules calculations. In all compounds, the O…H hydrogen bond belongs to closed-shell interactions where the interaction energies are higher at the optimized geometry than the X-ray one due to the shortening in the A…H distance as a con-sequence of the geometry optimization. These compounds have polar characters with different charged regions which explored using molecular electrostatic potential map. Their natural charges, reactivity descriptors and NMR chemical shifts were computed, discussed and compared.

Benzylsulfanyl-triazolyl-indole scaffold was synthesized through coupling of 4-amino-5-(1H-indol-2-yl)-1,2,4-triazol-3(2H)-thione and benzyl bromide in EtOH under basic conditions (K2CO3). The benzylation direction was deduced from the 13C NMR signal found at 35.09 ppm, assigned for the methylene carbon of the benzyl group, this value indicates that the benzyl group attacks sulfur, not nitrogen. 1H NMR, 13C NMR, COSY, HMQC, HRMS and X-ray single crystal diffraction analysis were used for structure assignment. The desired compound accomplished in good yield. Hirshfeld analysis revealed the importance of the short N...H (1.994–2.595 Ǻ), S…H (2.282 Ǻ) and C…H (2.670 Ǻ) contacts as well as the weak π-π stacking interactions in the molecular packing of benzylthio-triazolyl-indole scaffold. Its electronic and structural aspects were predicted using density functional theory (DFT) calculations and the reactivity descriptors as well. The Uv-Vis spectral bands were assigned based on the time-dependant density functional theory TD-DFT calculations, while the gauge-including atomic orbitals (GIAO) method was used to predict the 1H and 13C NMR chemical shifts.

The designed target compound of N-acetyl indole linked to a fused triazolo/thiadiazole scaffold was synthesized via the reaction of 4-amino-5-(1H-indol-2-yl)-1,2,4-triazol-3(2H)-thione as the starting material with acetic anhydride under reflux conditions for 6 h, resulting in an excellent and pure chemical yield. The structural features of the designed compound were confirmed using spectroscopic tools including single crystal X-ray diffraction analysis along with 1H-NMR, 13C-NMR, 2D-NMR, and high resolution mass spectrometry. Using Hirshfeld analysis, we determined the molecular packing depends on strong interactions (O···H and N···H) along with weak interactions (S···H, C···H and H···H). The shortest contacts corresponding to the N3···H12 (2.490 Å), N2···H5 (2.503 Å), and O1···H2 (2.490 Å) interactions were confirmed based on the Hirshfeld analysis. The calculated dipole moment was 6.6557 Debye. The atomic charge distribution, molecular electrostatic potential map, and reactivity descriptors are also discussed. The computed NMR spectra of the requisite compound correlated well with the results obtained experimentally. The UV-Vis electronic spectra of the requisite compound were simulated using the TD-DFT method and compared with the experimental data. The different σ→σ*, π→π*, n→σ*, and n→π* donor–acceptor interactions and their interaction energies stabilized the studied system to 9.84, 20.65, 29.33, and 45.82 kcal/mol, respectively.

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.

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.

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.