Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation.

Targeted protein degradation via "hijacking" of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel-Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC's architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.

COVID-19 and Mucormycosis of Orofacial Region: A Scoping Review.

During the second wave of coronavirus disease, or COVID-19, infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in the year 2021 around the globe, there is a surge in the number of cases of mucormycosis or "Black Fungus" that is directly/indirectly associated with COVID-19. In this review article, mucormycosis of the orofacial region has gained importance from the maximum published literature (45 articles) from various databases like PubMed, Google Scholar, Scopus, Web of Science, and Embase. Rhino-orbital cerebral mucormycosis (ROCM) is a fatal condition associated with COVID-19 among categories of mucormycosis such as pulmonary, oral, gastrointestinal, cutaneous, and disseminated. ROCM targets the maxillary sinus, also involving teeth of the maxilla, orbits, and ethmoidal sinus. These are of particular interest to dentists and oral pathologists for proper diagnosis and identification. Co-morbid conditions, especially diabetes mellitus type II, have to be monitored carefully in COVID-19 patients as they have a higher risk of developing mucormycosis. In this review article, various presentations of COVID-19-linked mucormycosis are mentioned having particular emphasis on pathogenesis, signs and symptoms, clinical presentation, various diagnostic modalities including histopathology, radiology like CT and MRI, serology, tissue culture, various laboratory investigations, treatment protocols, management with prognosis, and so on. Any suspected case of mucormycosis needs quick detection and treatment since it progresses quickly due to the destructive course of infection. Long-term follow-up along with proper care is a must to detect any kind of recurrence.

Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy.

Cathepsin C plays a key role in the activation of several degradative enzymes linked to tissue destruction in chronic inflammatory and autoimmune diseases. Therefore, Cathepsin C inhibitors could potentially be effective therapeutics for the treatment of diseases such as chronic obstructive pulmonary disease (COPD) or acute respiratory distress syndrome (ARDS). In our efforts towards the development of a novel series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of aortic binding liability.

Phenoxo-bridged dinuclear mixed valence cobalt(III/II) complexes with reduced Schiff base ligands: synthesis, characterization, band gap measurements and fabrication of Schottky barrier diodes.

Two homometallic class-I dinuclear mixed valence cobalt complexes, [(N3)CoIIIL1(µ-C6H4(NO2)CO2)CoII(N3)] (1) and [(N3)CoIIIL2(µ-C6H4(NO2)CO2)CoII(N3)] (2), have been synthesized using multisite N2O4 coordination ligands, H2L1 {where H2L1 = (2,2-dimethyl-1,3-propanediyl)bis(iminomethylene)bis(6-methoxyphenol) and H2L2 = (2,2-dimethyl-1,3-propanediyl)bis(iminomethylene)bis(6-ethoxyphenol)}. Each complex has been structurally characterized by single crystal X-ray diffraction and spectral analysis. Both the cobalt centers in these dinuclear complexes adopt a distorted-octahedral geometry, where the cobalt(iii) center resides at the inner N2O2 cavity and the cobalt(ii) center resides at the outer O4 cavity of the reduced Schiff base. Both of them show good electrical conductivity, which has been rationalized by band gap measurements. The band gap in the solid state has been determined by experimental and DFT calculations and it confirms that each of the two complexes behaves as a semiconductor. The space-charge-limited current (SCLC) theory is employed to evaluate the charge transport parameters such as effective carrier mobility and transit time for both complexes. The difference in the conductivity values of the complexes may be correlated with the strengths of extended supramolecular interactions in the complexes. Bader's quantum theory of atoms-in-molecules (QTAIM) is applied extensively to get quantitative and qualitative insights into the physical nature of weak non-covalent interactions. In addition, the non-covalent interaction reduced density gradient (NCI-RDG) methods well support the presence of such non-covalent intermolecular interactions.

Field-induced single molecule magnet behavior of a dinuclear cobalt(II) complex: a combined experimental and theoretical study.

Two dinuclear cobalt(ii) complexes, [(dmso)CoIIL1(µ-(m-NO2)C6H4COO)CoII(NCS)] (1) and [(dmso)CoIIL2(µ-(m-NO2)C6H4COO)CoII(NCS)] (2) [dmso = dimethylsulfoxide, H2L1 = (2,2-dimethyl-1,3-propanediyl)bis(iminomethylene)bis(6-methoxyphenol) and H2L2 = (2,2-dimethyl-1,3-propanediyl)bis(iminomethylene)bis(6-ethoxyphenol)] have been synthesized and structurally characterized by single-crystal X-ray diffraction, magnetic-susceptibility measurements and various spectroscopic techniques. Each complex contains a cobalt(ii) center with a slightly distorted octahedral geometry and a second cobalt(ii) center with a distorted trigonal prismatic one. To obtain insight into the physical nature of weak non-covalent interactions, we have extensively used the Bader's quantum theory of atoms-in-molecules (QTAIM). In addition, the non-covalent interaction reduced density gradient (NCI-RDG) methods established the presence of such non-covalent intermolecular interactions. Variable temperature magnetic susceptibility measurements show that both cobalt centers in each complex are in the high spin state (S = 3/2) and both complexes show weak ferromagnetic couplings through the double phenoxido bridges (J = 3.36(3) cm-1 in 1 and 4.56(2) cm-1 in 2). The magnetic properties of both complexes can be fitted to a Co(ii) dimer model including similar orbital reduction factors (α = -0.94(1) for 1 and -0.85(1) for 2) although different zero field splitting parameters D(1) = 11.0(4) cm-1 and D(2) = 19.5(4) cm-1 in 1 and D(1) = 8.2(4) cm-1 and D(2) = -1.3(4) cm-1 in 2. AC magnetic measurements reveal that the CoII2 unit in complex 2 exhibits field-induced slow relaxation of the magnetization at low temperatures and high frequencies.

Emission Characteristics of Heat Recirculating Porous Burners With High Temperature Energy Extraction.

Emission characteristics of heat recirculating porous burners with high temperature heat extraction are studied numerically. Two types of burners are considered: counterflow porous burner (CFB) and reciprocal counterflow porous burner (RCFB). The combustion of methane-air mixtures flowing through the porous media is modeled by solving steady state governing equations to obtain the flame temperature and species profiles. Formation of CO, NO, NO2, and NOx is studied in CFB and RCFB in a range of equivalence ratios from 0.3 to 1.0 and heat extraction temperatures from 300 to 1,300 K. The contribution of various NO formation mechanisms is comparatively analyzed and related to the NO generation predicted by a detailed chemistry mechanism. The effect of high temperature heat extraction on the formation of CO and NOx is analyzed. Numerical predictions indicate a constant monotonic decrease of NOx concentration with increasing temperature of energy extraction. The formation of CO is observed to follow the similar trend. For heat extraction at 1,300 K, simulations predicted 3.6 ppm of NOx and 3.9 ppm of CO for CFB and 4.1 ppm of NOx and 3.5 ppm of CO for RCFB when these burners are operated at an equivalence ratio of 0.7.

Magnetic Properties of End-to-End Azide-Bridged Tetranuclear Mixed-Valence Cobalt(III)/Cobalt(II) Complexes with Reduced Schiff Base Blocking Ligands and DFT Study.

Two tetranuclear mixed-valence cobalt(III/II) complexes having the general formula [(µ1,3-N3){CoII(L n )(µ-O2CC6H4NO2)CoIII(N3)}2]PF6 (where H2L1 and H2L2 are two reduced Schiff base ligands) have been synthesized and characterized. The structures of both complexes show cobalt(II) and cobalt(III) centers with a distorted octahedral geometry with cobalt(III) and cobalt(II) centers located at the inner N2O2 and outer O4 cavities of the reduced Schiff base ligands, respectively. The oxidation states of both cobalt centers have been confirmed by bond valence sum (BVS) calculations. The magnetic properties show that both compounds behave as cobalt(II) dimers connected through an end-to-end azido bridging ligand and show moderate antiferromagnetic Co(II)-Co(II) couplings of -11.0 and -14.4 cm-1 for 1 and 2, respectively, as also corroborated by DFT calculations, J theo = -13.07 cm-1 for 1 and -12.49 cm-1 for 2. The calculated spin densities of both complexes at the cobalt(II) centers are -2.75 and +2.75, respectively, clearly supporting that they are the magnetic centers.

Methylene spacer regulated variation in molecular and crystalline architectures of cobalt(iii) complexes with reduced Schiff base ligands: a combined experimental and theoretical study.

Two heteronuclear cobalt(iii)/sodium complexes, [(H2O)2Co(H2L1)Na(N3)2] (1) and (µ-N3)2[(N3)Co(H2L2)Na]2 (2) have been synthesized by the reaction of two compartmental reduced Schiff bases, H2L1 [(1,2-propanediyl)bis(iminomethylene)bis(6-ethoxyphenol)] and H2L2 [(2,2-dimethyl-1,3-propanediyl)bis(iminomethylene)bis(6-ethoxyphenol)], with cobalt(ii) nitrate hexahydrate in methanol. Structures of both the complexes have been confirmed by single crystal X-ray diffraction analysis. In each complex, cobalt(iii) is located in the inner N2O2 compartment and sodium is placed in the outer O2O'2 compartment of the respective ligands. In complex 1, the saturated five-membered chelate ring assumes a half-chair conformation, thereby facilitating the anti-orientations of two N-H bonds, which in turn favours the formation of very strong hydrogen bonds forming an infinite one-dimensional assembly. Formation of this one-dimensional chain is also supported by C-Hπ (arene) interactions. On the other hand, the best hydrogen bond donor NH groups are in syn disposition (as the saturated chelate ring is six-membered and assumes a chair conformation) and do not participate in the crystal packing in complex 2. However, very strong C-Hπ(N3) interactions have been established in complex 2, where the π-system of the bridging azide ligand participates as the π-donor. A search in the Cambridge structural database (CSD) has also been carried out to investigate the abundance and directionality of the interaction using different pseudohalides. Energies of all these supramolecular interactions were estimated by DFT calculations including Grimme's dispersion correction and characterized by the NCI plot index computational tool.

One pot synthesis of two cobalt(iii) Schiff base complexes with chelating pyridyltetrazolate and exploration of their bio-relevant catalytic activities.

Two new cobalt(iii) tetrazolato complexes [Co(L1)(PTZ)(N3)] (1) and [Co(L2)(PTZ)(N3)] (2) {where H2L1 = 2((3-(methylamino)propylimino)methyl)-6-methoxyphenol, H2L2 = 2((3-(dimethylamino)propylimino)methyl)-6-ethoxyphenol and HPTZ = 5-(2-pyridyl)tetrazole}, have been synthesized via in situ 1,3-dipolar cycloaddition reaction of 2-cyanopyridine and sodium azide in the presence of cobalt(ii) nitrate hexahydrate and respective Schiff bases in the open atmosphere. The structures of both complexes have been confirmed by single crystal X-ray diffraction studies. Features of noncovalent interactions in the solid state of both complexes have been studied by means of DFT and MEP calculations and characterized using Bader's theory of "atoms in molecules" (AIM). These complexes act as biomimetic catalysts promoting the aerobic oxidation of 3,5-di-tert-butylcatechol (3,5-DTBC) to the corresponding o-benzoquinone at room temperature. The reaction follows Michaelis-Menten enzymatic reaction kinetics with turnover numbers of ∼0.030 s-1 in an acetonitrile-methanol (2 : 1) mixture. Both complexes are also reactive towards aerobic oxidation of o-aminophenol in acetonitrile-methanol (2 : 1) with turnover numbers ∼0.095 s-1.

Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide.

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.

Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent I Kur Inhibitor.

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

Gelatin-carboxymethyl tamarind gum biocomposites: In vitro characterization & anti-inflammatory pharmacodynamics.

In this study, gelatin and carboxymethyl tamarind gum (CTG) were chemically cross-linked to control the delivery of aceclofenac from their interpenetrating network (IPNs). Infrared spectra, thermal and X-ray data supported that drug and polymer was compatible in the composite hydrogels. Irregularly shaped IPN microstructures were seen under field emission scanning electron microscope (FE-SEM). IPN system was capable of entrapping about 96% of the drug fed. CTG in IPN structures suppressed the drug release rate in HCl solution (pH1.2); however extended the same in phosphate buffer solution (pH6.8). The drug release was controlled by polymer chain relaxation/swelling and simple diffusion in vitro. The anti-inflammatory activity of drug-loaded biocomposites lasted over 7h in albino rats, thus suggesting their potential as an anti-inflammatory therapeutics.

Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E(2) synthase-1 inhibitors.

mPGES-1 is inducible terminal synthase acting downstream of COX enzymes in arachidonic acid pathway, regulates the biosynthesis of pro-inflammatory prostaglandin PGE2. Cardiovascular side effect of coxibs and NSAIDs, selective for COX-2 inhibition, stimulated interest in mPGES-1, a therapeutic target with potential to deliver safe and effective anti-inflammatory drugs. The synthesis and structure activity relationship of a series of compounds from 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds as mPGES-1 inhibitor are discussed. A set of analogs (28, 48, 49) were identified with <10nM potencies in the recombinant human mPGES-1 enzyme and in the A549 cellular assays. These analogs were also found to be potent in the human whole blood assay (<400 nM). Furthermore, the representative compound 48 was shown to be selective with other prostanoid synthases and was able to effectively regulate PGE2 biosynthesis in clinically relevant inflammatory settings, in comparison with celecoxib.

Discovery of benzo[d]imidazo[5,1-b]thiazole as a new class of phosphodiesterase 10A inhibitors.

The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.

Imidazopyridazinones as novel PDE7 inhibitors: SAR and in vivo studies in Parkinson's disease model.

The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway.

Isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors: SAR and pharmacokinetic evaluation.

The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease models, are disclosed.

Triple hybrids of steroids, spiroketals, and oligopeptides as new biomolecular chimeras.

An oxidative enol ether rearrangement was the key methodology in the construction of steroid-spiroketal-RGD peptides. Biological studies demonstrated potent integrin CD11b/CD18 antagonistic effects.

[4 + 2] cycloadditions of N-alkenyl iminium ions: structurally complex heterocycles from a three-component Diels-Alder reaction sequence.

N-Alkenyl iminium ions serve as conduits to three-component [4 + 2] cycloaddition reactions accessing structurally and stereochemically diverse piperidine derivatives. These cationic 2-azadienes participate in endo- or exo-selective [4 + 2] cycloadditions with electron-rich and neutral alkene dienophiles to generate a tetrahydropyridinium ion as the initial cycloadduct. In situ nucleophilic addition to the cycloaddition-derived iminium ion completes the three-component coupling sequence and affords a versatile synthesis of structurally complex piperidines.

Chemistry of the Hexahydropyrrolo[2,3-b]indoles: configuration, conformation, reactivity, and applications in synthesis.

The stereoselective formation of 2-endo-substituted hexahydropyrrolo[2,3-b]indoles from 2-substituted tryptamine derivatives, especially tryptophan, is discussed. Parallels are drawn with the formation of related heterocyclic systems, such as the hexahydrofurano[2,3-b]benzofurans, in which the thermodynamic preference of a substituent at the 2-position is also for the endo-configuration. Functionalization of tryptophan-derived hexahydropyrroloindoles at positions 2-, 3-, and 3a- is discussed with special emphasis on the 2-position, at which both radical and nucleophilic reactions take place preferentially on the endo-face of the diazabicyclo[3.3.0]octane system. The kinetic and thermodynamic preference for the 2-endo-position is considered in terms of the minimization of torsional strain, and parallels are drawn to the Woerpel model for the reactivity of analogous five-membered cyclic oxacarbenium ions. The use of the tryptophan-derived hexahydro[2,3-b]pyrroloindoles in the stereocontrolled synthesis of amino acids and alkaloids is presented.