Design and synthesis of new dihydropyrimidine/sulphonamide hybrids as promising anti-inflammatory agents via dual mPGES-1/5-LOX inhibition.

A novel series of dihydropyrimidine/sulphonamide hybrids 3a-j with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound 3j was the most potent dual inhibitor with IC50 values of 0.92 µM and 1.98 µM, respectively. In vivo, anti-inflammatory studies demonstrated that compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-α, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives' binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation.

Quinazolin-4-one/3-cyanopyridin-2-one Hybrids as Dual Inhibitors of EGFR and BRAFV600E: Design, Synthesis, and Antiproliferative Activity.

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects.

A combined crystallographic and theoretical investigation of noncovalent interactions in 1,3,4-oxadiazole-2-thione-N-Mannich derivatives: in vitro bioactivity and molecular docking.

Two 1,3,4-oxadiazole-2-thione-N-Mannich derivatives, specifically 5-(4-chlorophenyl)-3-[(2-trifluoromethylphenylamino)methyl]-1,3,4-oxadiazole-2(3H)-thione (1) and 5-(4-chlorophenyl)-3-[(2,5-difluorophenylamino)methyl]-1,3,4-oxadiazole-2(3H)-thione (2), were synthesized and then characterized by elemental analysis and NMR (1H and 13C) spectroscopy and the single crystal X-ray diffraction method. The formed weak intermolecular interactions in the solid-state structures of these derivatives were thoroughly investigated utilizing a variety of theoretical tools such as Hirshfeld surface analysis and quantum theory of atoms in molecules (QTAIM). Furthermore, the CLP-PIXEL and density functional theory calculations were used to study the energetics of molecular dimers. Numerous weak intermolecular interactions such as C-H⋯S/Cl/F/π interactions, a directional C-Cl⋯Cl halogen bond, π-stacking, type C-F⋯F-C contact and a short F⋯O interaction, help to stabilize the crystal structure of 1. Crystal structure 2 also stabilizes with several weak intermolecular contacts, including N-H⋯S, C-H⋯N//Cl/F interactions, a highly directional C1-Cl1⋯C(π) halogen bond and C(π)⋯C(π) interaction. In vitro antimicrobial potency of compounds 1 and 2 was assessed against various Gram-positive and Gram-negative bacterial strains and the pathogenic yeast-like Candida albicans. Both compounds showed marked activity against all tested Gram-positive bacteria and weak activity against Escherichia coli and lacked inhibitory activity against Pseudomonas aeruginosa. In addition, compounds 1 and 2 displayed good in vitro anti-proliferative activity against hepatocellular carcinoma (HepG-2) and mammary gland breast cancer (MCF-7) cancer cell lines. Molecular docking studies revealed the binding modes of title compounds at the active sites of prospective therapeutic targets.

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways.

A series of novel 3-cyanopyridone/pyrazoline hybrids (21-30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.

Synthesis and Structure Determination of Substituted Thiazole Derivatives as EGFR/BRAFV600E Dual Inhibitors Endowed with Antiproliferative Activity.

2,3,4-trisubstituted thiazoles 3a-i, having a methyl group in position four, were synthesized by the reaction of 1,4-disubstituted thiosemicarbazides with chloroacetone in ethyl acetate/Et3N at room temperature or in ethanol under reflux. The structures of new compounds were determined using NMR spectroscopy, mass spectrometry, and elemental analyses. Moreover, the structure of compound 3a was unambiguously confirmed with X-ray analysis. The cell viability assay of 3a-i at 50 µM was greater than 87%, and none of the tested substances were cytotoxic. Compounds 3a-i demonstrated good antiproliferative activity, with GI50 values ranging from 37 to 86 nM against the four tested human cancer cell lines, compared to the reference erlotinib, which had a GI50 value of 33 nM. The most potent derivatives were found to be compounds 3a, 3c, 3d, and 3f, with GI50 values ranging from 37 nM to 54 nM. The EGFR-TK and BRAFV600E inhibitory assays' results matched the antiproliferative assay's results, with the most potent derivatives, as antiproliferative agents, also being the most potent EGFR and BRAFV600E inhibitors. The docking computations were employed to investigate the docking modes and scores of compounds 3a, 3c, 3d, and 3f toward BRAFV600E and EGFR. Docking computations demonstrated the good affinity of compound 3f against BRAFV600E and EGFR, with values of -8.7 and -8.5 kcal/mol, respectively.

Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents.

A small set of indole-based derivatives, IV and Va-I, was designed and synthesized. Compounds Va-i demonstrated promising antiproliferative activity, with GI50 values ranging from 26 nM to 86 nM compared to erlotinib's 33 nM. The most potent antiproliferative derivatives-Va, Ve, Vf, Vg, and Vh-were tested for EGFR inhibitory activity. Compound Va demonstrated the highest inhibitory activity against EGFR with an IC50 value of 71 ± 06 nM, which is higher than the reference erlotinib (IC50 = 80 ± 05 nM). Compounds Va, Ve, Vf, Vg, and Vh were further tested for BRAFV600E inhibitory activity. The tested compounds inhibited BRAFV600E with IC50 values ranging from 77 nM to 107 nM compared to erlotinib's IC50 value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAFV600E, and VEGFR-2.

Design, synthesis, apoptotic, and antiproliferative effects of 5-chloro-3- (2-methoxyvinyl)-indole-2-carboxamides and pyrido[3,4-b]indol-1-ones as potent EGFRWT/EGFRT790M inhibitors.

A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c, 5d, 5f, 5 g, 6e, and 6f have the highest antiproliferative activity with GI50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 = 33 nM). Compounds 5d, 5f, and 5 g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFRT790M with IC50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFRWT and EGFRT790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.

Design, Synthesis, Antiproliferative Actions, and DFT Studies of New Bis-Pyrazoline Derivatives as Dual EGFR/BRAFV600E Inhibitors.

Some new Bis-pyrazoline hybrids 8-17 with dual EGFR and BRAFV600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.

One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAFV600E Inhibitors.

In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1H)-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67-79%). The various NMR, mass spectra, and elemental analyses verified the structures of all the newly obtained compounds. The antiproliferative effects of 6a-e, 7a, and 7b against four cancer cells were investigated. The most effective antiproliferative compounds were 6b, 6e, and 7b. Compounds 6b and 7b inhibited EGFR with IC50 values of 84 and 78 nM, respectively. Additionally, 6b and 7b were the most effective inhibitors of BRAFV600E (IC50 = 108 and 96 nM, respectively) and cancer cell proliferation (GI50 = 35 and 32 nM against four cancer cell lines, respectively). Finally, the apoptosis assay results revealed that compounds 6b and 7b had dual EGFR/BRAFV600E inhibitory properties and showed promising antiproliferative and apoptotic activity.

Metabolites Profiling and In Vitro Biological Characterization of Different Fractions of Cliona sp. Marine Sponge from the Red Sea Egypt.

Red Sea marine sponges are an important source of biologically active natural products. Therefore, the present study aimed to investigate, for the first time, the components of n-hexane, dichloromethane, and ethyl acetate fractions of Cliona sp. marine sponge collected from the Red Sea, Egypt using UPLC-ESI-MS/MS (Ultra-performance liquid chromatography electrospray ionization tandem mass spectrometry) analysis. The analysis revealed the tentative identification of 23, 16, and 24 compounds from the n-hexane, dichloromethane, and ethyl acetate fractions of Cliona sp., respectively. In addition, the examination of these fractions resulted in the isolation and identification of three sterols and one amino acid. The identification of the isolated compounds was confirmed by 1D and 2D NMR (Nuclear Magnetic Resonance), and MS (Mass spectrometry), and IR (Infrared) spectroscopy. The in vitro cytotoxic, antioxidant, and antimicrobial activities of the total ethanolic extract and its sub-fractions were also evaluated. Interestingly, the ethyl acetate fraction showed potent cytotoxic activity against colon (HCT-116) and human larynx carcinoma (HEP-2) cell lines with IC50 (Half-maximal Inhibitory Concentration) 6.11 ± 0.2 and 12.6 ± 0.9 µg/mL, respectively. However, the dichloromethane fraction showed strong antioxidant activity, with IC50 75.53 ± 3.41 µg/mL. Notably, the total ethanolic extract showed the strongest antibacterial activity against Staphylococcus aureus and Escherichia coli, with MIC (Minimum Inhibitory Concentration) 62.5 ± 0.82 and 125 ± 0.62 µg/mL, respectively, compared to other fractions. In conclusion, this is the first report on the secondary metabolites content and biological activities of Cliona sp. from the Red Sea, Egypt. It also highlights the need for further research on the most active fractions against various cancer cell lines and resistant bacterial and fungal strains. Cliona sp. extract and its fractions could be a potential source of novel and safe natural drugs with a wide range of medicinal and pharmaceutical applications.

Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-indole-2-carboxylate and Pyrrolo[3,4-b]indol-3-one Derivatives as Potent Inhibitors of EGFRT790M/BRAFV600E Pathways.

Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate 3a-e, 4a-c and pyrrolo[3,4-b]indol-3-ones 5a-c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative activity. The cell viability assay results of 3a-e, 4a-c, and 5a-c revealed that none of the compounds tested were cytotoxic, and that the majority of those tested at 50 µM had cell viability levels greater than 87%. Compounds 3a-e, 4a-c, and 5a-c had significant antiproliferative activity with GI50 values ranging from 29 nM to 78 nM, with 3a-e outperforming 4a-c and 5a-c in their inhibitory actions against the tested cancer cell lines. Compounds 3a-e were tested for EGFR inhibition, with IC50 values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m-piperidinyl derivative 3e (R = m-piperidin-1-yl), with an IC50 value of 68 nM, which was 1.2-fold more potent than erlotinib (IC50 = 80 nM). Interestingly, all the tested compounds 3a-e had higher anti-BRAFV600E activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward EGFRT790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAFV600E and EGFRT790M enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a-e revealed safety and good pharmacokinetic profile.

Virtual screening and molecular dynamics simulation study of abyssomicins as potential inhibitors of COVID-19 virus main protease and spike protein.

The lack of any effective cure for the infectious COVID-19 disease has created a sense of urgency and motivated the search for effective antiviral drugs. Abyssomicins are actinomyces-derived spirotetronates polyketides antibiotics known for their promising antibacterial, antitumor, and antiviral activities. In this study, computational approaches were used to investigate the binding mechanism and the inhibitory ability of 38 abyssomicins against the main protease (Mpro) and the spike protein receptor-binding domain (RBD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The results identified abyssomicins C, J, W, atrop-O-benzyl abyssomicin C, and atrop-O-benzyl desmethyl abyssomicin C as the most potential inhibitors of Mpro and RBD with binding energy ranges between -8.1 and -9.9 kcal mol-1; and between -6.9 and -8.2 kcal mol-1, respectively. Further analyses of physicochemical properties and drug-likeness suggested that all selected active abyssomicins, with the exception of abyssomicin J, obeyed Lipinski's rule of five. The stability of protein-ligand complexes was confirmed by performing molecular dynamics simulation for 100 ns and evaluating parameters such as such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), total number of contacts, and secondary structure. Prime/MM-GBSA (Molecular Mechanics-General Born Surface Area) and principal component analysis (PCA) analyses also confirmed the stable nature of protein-ligand complexes. Overall, the results showed that the studied abyssomicins have significant interactions with the selected protein targets; therefore, they were deemed viable candidates for further in vitro and in vivo evaluation.Communicated by Ramaswamy H. Sarma.

Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway.

A new series of piperine-carboximidamide hybrids VIa-k was developed as a new cytotoxic agent targeting EGFR, BRAF, and CDK2. The antiproliferative effect against four cancer cells was investigated against erlotinib. Hybrids VIc, VIf, VIg, VIi, and VIk have the highest antiproliferative activity. Compounds VIc, VIf, VIg, VIi, and VIk inhibited EGFR with IC50 values ranging from 96 to 127 nM. Compounds VIf and VIk had the most potent inhibitory activity as BRAFV600E (IC50 = 49 and 40 nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI50 = 44 and 35 nM against four cancer cell lines, respectively). Compound VIk, the most effective derivative as an antiproliferative agent, demonstrated potent anti-CDK2 action with an IC50 value of 12 nM, which is 1.5-fold more potent than the reference dinaciclib. Finally, VIc, VIf, and VIk have a high capacity to inhibit LOX-IMVI cell line survival.

Chemical constituents from Centaurothamnus maximus and their antimicrobial activity.

A new sesquiterpene lactone, 3ß,10α-dihydroxy-10ß-(hydroxymethyl)-8α-(4-hydroxymethacrylate)-1αH,5αH,6ßH,7αH-guai-4(15), 11(13)-dien-6,12-olide (1), along with twenty-one known compounds, were identified from the aerial parts of Centaurothamnus maximus. The structures of the isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. Compounds (2, 3, 5‒13 and 15‒22) were identified from C. maximus for the first time. Antibacterial and antifungal activities of the isolated compounds were tested using the agar disc diffusion method. Compounds that demonstrated promising antimicrobial activity were evaluated for their minimum inhibitory concentration (MIC). The results showed that compounds 3 and 7 were the most effective antibacterial compounds against B. subtilis ATCC 6633, S. aureus ATCC 25923 and S. pyogenes ATCC 27736, with MIC estimates between 8 and 32 mg/mL. In addition, compound 2 exhibited the strongest antifungal activity against C. albicans ATCC 14243 and C. krusei ATCC 14243 with MIC 8 mg/mL.

Twenty-two compounds were first isolated from Centaurothamnus maximusThe structure of the new sesquiterpene lactone, thamnolide (1), was established.Antibacterial and antifungal activities were tested for the isolated compounds.Compounds 3 and 7 were the strongest antibacterial compounds whilst 2 exhibited the strongest antifungal activity.

X-ray Structures and Computational Studies of Two Bioactive 2-(Adamantane-1-carbonyl)-N-substituted Hydrazine-1-carbothioamides.

Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP-Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N-H···S, N-H···O, C-H···S, C-H···O, H-H bonding and C-H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N-H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds.

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11ß-HSD1 Molecular Docking and ADMET Prediction.

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1-3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P21/c, P21 and P21/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1-3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1-3 were determined using in silico techniques. Molecular docking of the compounds into the 11ß-HSD1 active site showed comparable binding affinity scores (-7.50 to -8.92 kcal/mol) to the 11ß-HSD1 co-crystallized ligand 4YQ (-8.48 kcal/mol, 11ß-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.

Structural and Energetic Properties of Weak Noncovalent Interactions in Two Closely Related 3,6-Disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole Derivatives: In Vitro Cyclooxygenase Activity, Crystallography, and Computational Investigations.

Two 3,6-disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives, namely, 3-(adamantan-1-yl)-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 1 and 6-(2-chloro-6-fluorophenyl)-3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole 2, were prepared, and the detailed analysis of the weak intermolecular interactions responsible for the supramolecular self-assembly was performed using X-ray diffraction and theoretical tools. Analyses of Hirshfeld surface and 2D fingerprint plot demonstrated the effect of adamant-1-yl/phenyl moieties on intermolecular interactions in solid-state structures. The effect of these substituents on H···H/Cl/N contacts was more specific. The CLP-PIXEL and density functional theory methods provide information on the energetics of molecular dimers observed in these compounds. The crystal structure of compound 1 stabilizes with a variety of weak intermolecular interactions, including C-H···N, C-H···π, and C-H···Cl hydrogen bonds, a directional C-S···π chalcogen bond, and unconventional short F···C/N contacts. The crystal structure of compound 2 is stabilized by π-stacking interactions, C-H···N, C-H···π, and C-H···Cl hydrogen bonds, and highly directional attractive σ-hole interactions such as the C-Cl···N halogen bond and the C-S···N chalcogen bond. In addition, S(lp)···C(π) and short N···N contacts play a supportive role in the stabilization of certain molecular dimers. The final supramolecular architectures resulting from the combination of different intermolecular interactions are observed in both the crystal packing. The molecular electrostatic potential map reveals complementary electrostatic potentials of the interacting atoms. The quantum theory of atoms in molecules approach was used to delineate the nature and strength of different intermolecular interactions present in different dimers of compounds 1 and 2. The in vitro experiments suggest that both compounds showed selectivity against COX-2 targets rather than COX-1. Molecular docking analysis showed the binding pose of the compounds at the active sites of COX-1/2 enzymes.

Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors.

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa-j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a-k, 6a-c, and 7. Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds 5a-k, 6a-c, and 7 demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and 5a-k (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than 6a-c and 7, indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI50 = 1.10 µM), compounds 5d, 5e, 5h, 5i, 5j, and 5k were the most effective of the synthesised derivatives, with GI50 ranging from 0.95 µM to 1.50 µM. Compounds 5d, 5e, 5h, 5i, 5j, and 5k were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53.

Supramolecular Self-Assembly Mediated by Multiple Hydrogen Bonds and the Importance of C-S···N Chalcogen Bonds in N'-(Adamantan-2-ylidene)hydrazide Derivatives.

The present article comprehensively examines six N'-(adamantan-2-ylidene)hydrazide derivatives using the Hirshfeld surface analysis, PIXEL energy for molecular dimers, lattice energies for crystal packing, and topological analysis for intramolecular and intermolecular interactions. The crystal structure of one of the N'-(adamantan-2-ylidene)hydrazide derivatives, namely, N'-(adamantan-2-ylidene)-5-bromothiophene-2-carbohydrazide 1, C15H17N2OSBr, has been determined and analyzed in detail along with five closely related structures. The molecular conformation of 1 is locked by an intramolecular C-S···N chalcogen bond as found in one of its closely related structure, namely, N'-(adamantan-2-ylidene)thiophene-2-carbohydrazide. Furthermore, a detailed potential energy surface scan analysis has been performed to highlight the importance of a chalcogen bond. Two of these compounds possess syn-orientation for amide units, whereas the corresponding moiety exhibits anti-conformations in the remaining four structures. The Hirshfeld surface and its decomposed fingerprint plots provide a qualitative picture of acyl substituent effects on the intermolecular interactions toward crystal packing of these six structures. Intermolecular interaction energies for dimers observed in these structures calculated by density functional theory (B97D3/def2-TZVP) and PIXEL (MP2/6-31G**) methods are comparable. This study also identifies that multiple hydrogen bonds, including N/C-H···O/N and C-H···π interactions, are collectively responsible for a self-assembled synthon. The nature and strength of these interactions have been studied using atoms in molecule topological analysis. The in vitro antiproliferative activity of compound 1 was assessed against five human tumor cell lines and showed marked antiproliferative activity.

Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11ß-HSD1 Inhibitors.

The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P21/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO2 and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO2/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO2 group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11ß-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11ß-HSD1 inhibitors were able to accurately dock within the 11ß-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11ß-HSD1 binding affinity scores as well as interactions to a known potent 11ß-HSD1 inhibitor.