Duvelisib: A comprehensive profile.

Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and characterized by dual phosphoinositide-3-kinase (PI3K)- and PI3K-inhibitory activity. The Food and Drug Administration (FDA) recently approved DUV for the management of small lymphocytic lymphoma (SLL) and relapsed or refractory chronic lymphocytic leukemia (CLL) in adult patients. DUV is marketed under the brand name of Copiktra® (Verastem, Inc., Needham, MA, USA). This chapter provides a critical extensive review of the literature, the description of DUV in terms of its names, formulae, elemental composition, appearance, and use in the treatment of CLL, SLL, and follicular lymphoma. The chapter also describes the methods for preparation of DUV, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.

New Indazol-Pyrimidine-Based Derivatives as Selective Anticancer Agents: Design, Synthesis, and In Silico Studies.

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds-4f, 4i, 4a, 4g, and 4d-possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC50 values of 1.629, 1.841, 2.958, 4.680, and 4.798 µM, respectively, compared to the reference drug with an IC50 value of 8.029 µM, thus demonstrating promising suppression power. Compounds 4i, 4g, 4e, 4d, and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i, werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein-ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski's rule of five and Veber's rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents.

Synthesis and Biological Evaluation of Imadazo[1,2-a]pyrazines as Anticancer and Antiviral Agents through Inhibition of CDK9 and Human Coronavirus.

In this work, novel imadazo[1,2-a]pyrazine derivatives were synthesized and evaluated as CDK9 inhibitors. The results of CDK9 assay showed that the derivatives with pyridin-4-yl in position 2 and benzyl in position 3 of imadazo[1,2-a]pyrazine 3c displayed the most potent CDK9 inhibitory activity with IC50 of 0.16 µM. The anti-proliferative effect of the new compounds was examined against breast cancer (MCF7), colorectal cancer (HCT116), and chronic myelogenous leukaemia (K652) cell lines. The data of MTT assay showed that the cytotoxic effect of the inhibitors is correlated to their inhibitory activity against CDK9. Compound 3c exhibited the most potent cytotoxicity effect with average IC50s of three cell lines of 6.66 µM. The drug likeness properties of 3c were predicated in silico and demonstrated that 3c have reasonable physiochemical and pharmacokinetic properties. Selected derivatives were assessed in antiviral assay against human coronavirus 229E. The results of this assay showed that the derivative with pyridin-4-yl in position 2 and cyclohexyl in position 3 of imadazo[1,2-a]pyrazine 3b exhibited the most potent anti-coronaviral activity with IC50 of 56.96 µM and selectivity index of 7.14. The target predication result revealed that 3b showed high affinity to protease enzyme. Docking studies of 3b with COVID-19 main protease was conducted and showed good binding affinity, which confirmed the in vitro assay data.

X-ray and theoretical investigation of (Z)-3-(adamantan-1-yl)-1-(phenyl or 3-chlorophenyl)-S-(4-bromobenzyl)isothioureas: an exploration involving weak non-covalent interactions, chemotherapeutic activities and QM/MM binding energy.

A detailed exploration of crystal packing of two adamantane-isothiourea hybrid derivatives along with a known closely related structure has been performed to delineate the effect of halogen substituents and the role of weak intermolecular interactions in their supramolecular architectures. The adamantane-isothiourea hybrid derivatives used in the present study are (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-phenylisothiourea (1), C24H27BrN2S and (Z)-3-(Adamantan-1-yl)-S-(4-bromobenzyl)-1-(3-chlorophenyl)isothiourea (2), C24H26BrClN2S, characterized by X-ray crystallography. The X-ray structures revealed that the molecular conformation of 1 and 2 are different and stabilized by intramolecular C-H···N interactions. In addition, a short intramolecular H···H contact is formed in 2. The Hirshfeld surface analysis was used to delineate the nature of different intermolecular interactions and their contributions toward crystal packing. The quantitative analysis of strengths of molecular dimers existed in 1 and 2 has been performed using the PIXEL method. The electrostatic potential map clearly revealed nature and strength of σ-holes at Br and Cl atoms. The topological analysis was used to characterize the nature and the strength of various intermolecular interactions including the type I Br···Br contact. Interestingly, all the H-H bonding observed in 1 and 2 show closed-shell in nature. Further, an in-vitro antimicrobial activity studies suggest that the title compounds exhibited potent antibacterial activity against all the tested Gram-positive bacterial strains and Gram-negative Escherichia coli. Compound 2 showed marked anti-proliferative activity against MCF-7 and HeLa cell lines.Communicated by Ramaswamy H. Sarma.

Synthesis and Evaluation of New Coumarin Derivatives as Antioxidant, Antimicrobial, and Anti-Inflammatory Agents.

New pyranocoumarin and coumarin-sulfonamide derivatives were prepared and evaluated for their antioxidant, antimicrobial, and/or anti-inflammatory activities. Coumarin-sulfonamide compounds 8a-d demonstrated significant antioxidant activity, while 7c,d, 8c,d, and 9c,d exhibited antimicrobial activity equal to or higher than the standard antimicrobials against at least one tested microorganism. Regarding the anti-inflammatory testing, pyranocoumarins 2b, 3a,b and 5c and coumarin-sulfonamide compound 9a showed more potent antiproteinase activity than aspirin in vitro; however, five compounds were as potent as aspirin. The anti-inflammatory activity of the promising compounds was further assessed pharmacologically on formaldehyde-induced rat paw oedema and showed significant inhibition of oedema. For in vitro COX-inhibitory activity of coumarin derivatives, pyranocoumarin derivative 5a was the most selective (SI = 152) and coumarin-sulfonamide derivative 8d was most active toward COX-2 isozyme. The most active derivatives met the in silico criteria for orally active drugs; thus, they may serve as promising candidates to develop more potent and highly efficient antioxidant, antimicrobial, and/or anti-inflammatory agents.

Synthesis, Antimicrobial and Hypoglycemic Activities of Novel N-(1-Adamantyl)carbothioamide Derivatives.

The reaction of 1-adamantyl isothiocyanate 4 with the various cyclic secondary amines yielded the corresponding N-(1-adamantyl)carbothioamides 5a-e, 6, 7, 8a-c and 9. Similarly, the reaction of 4 with piperazine and trans-2,5-dimethylpiperazine in 2:1 molar ratio yielded the corresponding N,N'-bis(1-adamantyl)piperazine-1,4-dicarbothioamides 10a and 10b, respectively. The reaction of N-(1-adamantyl)-4-ethoxycarbonylpiperidine-1-carbothioamide 8c with excess hydrazine hydrate yielded the target carbohydrazide 11, in addition to 4-(1-adamantyl)thiosemicarbazide 12 as a minor product. The reaction of the carbohydrazide 11 with methyl or phenyl isothiocyanate followed by heating in aqueous sodium hydroxide yielded the 1,2,4-triazole analogues 14a and 14b. The reaction of the carbohydrazide 11 with various aromatic aldehydes yielded the corresponding N'-arylideneamino derivatives 15a-g. The compounds 5a-e, 6, 7, 8a-c, 9, 10a, 10b, 14a, 14b and 15a-g were tested for in vitro antimicrobial activity against certain strains of pathogenic Gram-positive and Gram-negative bacteria and the yeast-like fungus Candida albicans. The compounds 5c, 5d, 5e, 6, 7, 10a, 10b, 15a, 15f and 15g showed potent antibacterial activity against one or more of the tested microorganisms. The oral hypoglycemic activity of compounds 5c, 6, 8b, 9, 14a and 15b was determined in streptozotocin (STZ)-induced diabetic rats. Compound 5c produced significant reduction of serum glucose levels, compared to gliclazide.

FT-IR and FT-Raman spectroscopic signatures, vibrational assignments, NBO, NLO analysis and molecular docking study of 2-{[5-(adamantan-1-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}-N,N-dimethylethanamine.

FT-Raman and FT-IR spectra of the title compound 2-{[5-(adamantan-1-yl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}-N,N-dimethylethanamine were recorded and investigated. The DFT/B3LYP/6-311++G(d,p) method was used to compute the vibrational wavenumbers. A good coherence between experimental and theoretical wavenumbers shows the preciseness of the assignments. NLO properties like the dipole moment, polarizability, first static hyperpolarizability, molecular electrostatic potential surface and contour map have been calculated to get a better cognizance of the properties of the title molecule. Natural bond orbital analysis has been applied to estimate the stability of the molecule arising from charge delocalization. The molecular docking studies concede that title compound may exhibit HIV-1 Protease 1N49 inhibitory activity.

Antimicrobial and hypoglycemic activities of novel N-Mannich bases derived from 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thiones.

The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).

Vibrational spectroscopic studies (FT-IR, FT-Raman) and quantum chemical calculations on 5-(Adamantan-1-yl)-3-[(4-fluoroanilino)methyl]-2,3-dihydro-1,3,4-oxadiazole-2-thione, a potential chemotherapeutic agent.

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 5-(Adamantan-1-yl)-3-[(4-fluoroanilino)methyl]-2,3-dihydro-1,3,4-oxadiazole-2-thione are investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of normal modes vibrations was done using GAR2PED program. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The calculated geometrical parameters are in agreement with the XRD data. The calculated first hyperpolarizability is high and the title compound is an attractive candidate for further studies in non-linear optical applications. To estimate the chemical reactivity of the molecule, the molecular electrostatic potential is calculated for the optimized geometry of the molecule.

Theoretical investigations on the molecular structure, vibrational spectra, HOMO-LUMO analyses and NBO study of 1-[(Cyclopropylmethoxy)methyl]-5-ethyl-6-(4-methylbenzyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione.

The FT-IR and FT-Raman spectra of 1-[(Cyclopropylmethoxy)methyl]-5-ethyl-6-(4-methylbenzyl)-1,2,3,4-tetrahydropyrimidine-2,4-dione were recorded. In this work, experimental and theoretical study on the molecular structure and vibrational wavenumbers of the title compound are presented. The vibrational wavenumbers were obtained theoretically at the DFT level and were compared with the experimental results. The study is extended to calculate the HOMO-LUMO energy gap, NBO, mapped molecular electrostatic potential and first hyperpolarizability. The calculated first hyperpolarizability of the title compound is 9.15 times that of urea and hence the title compound and the series of compounds it represents are attractive candidates for further studies in non linear optical applications. In the title compound, the HOMO of π nature is delocalized over the phenyl ring while the LUMO is located over the pyrimidine ring. The inter-molecular hydrogen bonding at O7 and N1H25 positions in each monomer give rise to a C2-symmetry dimer which is predicted to be about 10kcalmol(-1) more stable than the monomeric form.

Spectroscopic (FT-IR, FT-Raman, and UV-visible) and quantum chemical studies on molecular geometry, Frontier molecular orbitals, NBO, NLO and thermodynamic properties of 1-acetylindole.

Quantum chemical calculations of ground state energy, geometrical structure and vibrational wavenumbers of 1-acetylindole were carried out using density functional (DFT/B3LYP) method with 6-311++G(d,p) basis set. The FT-IR and FT-Raman spectra were recorded in the condensed state. The fundamental vibrational wavenumbers were calculated and a good correlation between experimental and scaled calculated wavenumbers has been accomplished. Electric dipole moment, polarizability and first static hyperpolarizability values of 1-acetylindole have been calculated at the same level of theory and basis set. The results show that the 1-acetylindole molecule possesses nonlinear optical (NLO) behavior with non-zero values. Stability of the molecule arising from hyper-conjugative interactions and charge delocalization has been analyzed using natural bond orbital (NBO) analysis. UV-Visible spectrum of the molecule was recorded in the region 200-500nm and the electronic properties like HOMO and LUMO energies and composition were obtained using TD-DFT method. The calculated energies and oscillator strengths are in good correspondence with the experimental data. The thermodynamic properties of the compound under investigation were calculated at different temperatures.

Synthesis, antimicrobial, and anti-inflammatory activity, of novel S-substituted and N-substituted 5-(1-adamantyl)-1,2,4-triazole-3-thiols.

The reaction of 5-(1-adamantyl)-4-phenyl-1,2,4-triazoline-3-thione (compound 5) with formaldehyde and 1-substituted piperazines yielded the corresponding N-Mannich bases 6a-f. The reaction of 5-(1-adamantyl)-4-methyl-1,2,4-triazoline-3-thione 8 with various 2-aminoethyl chloride yielded separable mixtures of the S-(2-aminoethyl) 9a-d and the N-(2-aminoethyl) 10a-d derivatives. The reaction of compound 5 with 1-bromo-2-methoxyethane, various aryl methyl halides, and ethyl bromoacetate solely yielded the S-substituted products 11, 12a-d, and 13. The new compounds were tested for activity against a panel of Gram-positive and Gram-negative bacteria and the pathogenic fungus Candida albicans. Compounds 6b, 6c, 6d, 6e, 6f, 10b, 10c, 10d, 12c, 12d, 12e, 13, and 14 displayed potent antibacterial activity. Meanwhile, compounds 13 and 14 produced good dose-dependent anti-inflammatory activity against carrageenan-induced paw edema in rats.

Vibrational spectroscopy of N'-(Adamantan-2-ylidene)thiophene-2-carbohydrazide, a potential antibacterial agent.

Vibrational states of the newly synthesized molecule N'-(Adamantan-2-ylidene)thiophene-2-carbohydrazide, a potential antibacterial agent, are examined experimentally for the crystalline phase and analyzed based on quantum chemical modelling of the solitary molecule and of the dimer, and assignment of the observed vibrational frequencies is proposed. Modelling of the title molecule dimer is found to describe better the experimentally observed vibration frequencies for the crystalline phase than calculations performed for a solitary molecule. Contributions from adamantane and thiophene parts within the molecule are identified. Additionally, multiple hydrogen bonds have been revealed both experimentally and computationally, inherent in the crystalline phase contrary to a solitary molecule. The spectroscopic findings correlate with the calculated interatomic distances which were found to change in the dimer versus a single molecule and to correspond better to the X-ray analysis data of the title compound in the crystalline phase.

Use of vibrational spectroscopy to study 4-benzyl-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazole-5-thione: A combined theoretical and experimental approach.

In this study, the experimental and theoretical vibrational frequencies of a newly synthesized potential anti-inflammatory agent namely, 4-benzyl-3-(thiophen-2-yl)-4,5-dihydro-1H-1,2,4-triazole-5-thione have been investigated. The experimental FT-IR (4000-400cm(-1)) and Laser-Raman spectra (4000-100cm(-1)) of the molecule in solid phase have been recorded. The theoretical vibrational frequencies and the optimized geometric parameters (bond lengths, bond angles and dihedral angles) have been calculated using density functional theory methods (DFT/B3LYP: Becke, 3-parameter, Lee-Yang-Parr and DFT/M06-2X: the highly parameterized, empirical exchange correlation function) with 6-311++G(d,p) basis set by Gaussian 09W software, for the first time. The assignments of the vibrational frequencies have been done by potential energy distribution (PED) analysis using VEDA 4 software program. The theoretical optimized geometric parameters and vibrational frequencies have been found to be in good agreement with the corresponding experimental data and results in the literature. In addition, the highest occupied molecular orbital (HOMO) energy, the lowest unoccupied molecular orbital (LUMO) energy and the other related molecular energy values of the compound have been investigated using the same theoretical calculations.

3-(Adamantan-1-yl)-4-ethyl-1-{[4-(2-meth-oxy-phen-yl)piperazin-1-yl]meth-yl}-1H-1,2,4-triazole-5(4H)-thione.

In the title compound, C26H37N5OS, the piperazine ring adopts a chair conformation. The triazole ring forms dihedral angles of 67.85 (9) and 59.41 (9)° with the piperazine and benzene rings, respectively, resulting in an approximate V-shaped conformation for the mol-ecule. An intra-molecular C-H⋯O hydrogen bond generates an S(6) ring motif. The crystal structure features C-H⋯π inter-actions, producing a two-dimensional supramolecular architecture.

3-(Adamantan-1-yl)-4-[(E)-(2,6-di-fluoro-benzyl-idene)amino]-1-[(4-ethyl-piperazin-1-yl)meth-yl]-4,5-di-hydro-1H-1,2,4-triazole-5-thione.

In the title compound, C26H34F2N6S, the triazole ring is linked to a benzene ring via an imine bond [N=C = 1.255 (2) Å; conformation: E], with a dihedral angle of 25.21 (11)° between the rings. The 4-ethyl-piperazinyl residue is folded away from the thione-S atom. In the crystal, helical supra-molecular chains propagating along [010] and sustained by weak C-S⋯π(triazole) inter-actions occur [S⋯centroid distance = 3.2872 (10) Å]. Links between these chains are of the type benzene-C-H⋯N(imine) and π-π [between centrosymmetrically related benzene rings with an inter-centroid distance of 3.9241 (15) Å] and result in a three-dimensional architecture.

3-(Adamantan-1-yl)-1-[(4-benzyl-piperazin-1-yl)meth-yl]-4-ethyl-1H-1,2,4-triazole-5(4H)-thione.

In the title compound, C26H37N5S, the piperazine ring adopts a chair conformation with the exocyclic N-C bonds in pseudo-equatorial orientations. The piperazine ring (all atoms) subtends dihedral angles of 79.47 (9) and 73.07 (9)° with the triazole and benzene rings, respectively, resulting in an approximate U-shape for the mol-ecule. No significant inter-molecular inter-actions are observed in the crystal.

N-(Adamantan-1-yl)-1,2,3,4-tetra-hydro-iso-quinoline-2-carbo-thio-amide.

In the title compound, C20H26N2S, the N-containing six-membered ring adopts a boat conformation and the dihedral angle between the thio-carbamide group and the benzene ring is 49.67 (9)°. An intra-molecular C-H⋯S hydrogen bond generates an S(6) ring motif. The N-H group is sterically hindered and there are no significant inter-molecular inter-actions beyond van der Waals contacts.

5-(Adamantan-1-yl)-3-[(2-meth-oxy-eth-yl)sulfan-yl]-4-phenyl-4H-1,2,4-triazole.

In the title adamantyl derivative, C(21)H(27)N(3)OS, the terminal meth-oxy-ethyl unit is disordered over two orientations with a refined site-occupancy ratio of 0.846 (6):0.154 (6). The 1,2,4-triazole ring is statistically planar [r.m.s. deviation = 0.002 (2) Å] and the phenyl substituent is almost perpendicular to its mean plane [dihedral angle = 83.57 (11)°]. No directional inter-molecular inter-actions were observed in the crystal structure.

3-(Adamantan-1-yl)-4-ethyl-1-[(4-phenyl-piperazin-1-yl)meth-yl]-1H-1,2,4-triazole-5(4H)-thione.

The title compound, C(25)H(35)N(5)S, has an approximately C-shaped conformation. The dihedral angle between the triazole and phenyl planes is 79.5 (2)°. The crystal structure consists of infinite chains parallel to the b axis, constructed by C-H⋯S hydrogen bonds between translation-related mol-ecules. Adjacent chains are linked via weak C-H⋯C inter-actions between the adamantyl and phenyl groups.