Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a-h), and hydrazine monohydrate (NH2NH2•H2O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a-h). After synthesis and characterization of the mentioned cinnolines (3a-h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3ß, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, and hDHODH, which have confirmed their functions and roles in the neurodegenerative diseases (NDs), based on molecular docking studies, and the obtained results were compared with a wide range of approved drugs and well-known (with IC50, EC50, etc.) compounds. In addition, in silico ADMET prediction analysis was performed to examine the prospective drug properties of the synthesized heterocyclic compounds (3a-h). The obtained results from the molecular docking studies and ADMET-related data demonstrated that these series of 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines (3a-h), especially hit ones, can really be turned into the potent core of new drugs for the treatment of neurodegenerative diseases (NDs), and/or due to the having some reactionable locations, they are able to have further organic reactions (such as cross-coupling reactions), and expansion of these compounds (for example, with using other types of aryl(or heteroaryl)glyoxal monohydrates) makes a new avenue for designing novel and efficient drugs for this purpose.

Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3-d]pyrimidines as potential active site inhibitors and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro.

In this paper, an environmentally benign, convenient, and efficient one-pot three-component reaction has been developed for the regioselective synthesis of novel 5-aroyl(or heteroaroyl)-6-(alkylamino)-1,3-dimethylfuro[2,3-d]pyrimidine-2,4(1H,3H)-diones (4a‒n) through the sequential condensation of aryl(or heteroaryl)glyoxal monohydrates (1a‒g), 1,3-dimethylbarbituric acid (2), and alkyl(viz. cyclohexyl or tert-butyl)isocyanides (3a or 3b) catalyzed by ultra-low loading ZrOCl2•8H2O (just 2 mol%) in water at 50 ˚C. After synthesis and characterization of the mentioned furo[2,3-d]pyrimidines (4a‒n), their multi-targeting inhibitory properties were investigated against the active site and putative allosteric hotspots of both SARS-CoV-2 main protease (MPro) and papain-like protease (PLPro) based on molecular docking studies and compare the attained results with various medicinal compounds which approximately in three past years were used, introduced, and or repurposed to fight against COVID-19. Furthermore, drug-likeness properties of the mentioned small heterocyclic frameworks (4a‒n) have been explored using in silico ADMET analyses. Interestingly, the molecular docking studies and ADMET-related data revealed that the novel series of furo[2,3-d]pyrimidines (4a‒n), especially 5-(3,4-methylendioxybenzoyl)-6-(cyclohexylamino)-1,3-dimethylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (4g) as hit one is potential COVID-19 drug candidate, can subject to further in vitro and in vivo studies. It is worthwhile to note that the protein-ligand-type molecular docking studies on the human body temperature-dependent MPro protein that surprisingly contains zincII (ZnII) ion between His41/Cys145 catalytic dyad in the active site, which undoubtedly can make new plans for designing novel SARS-CoV-2 MPro inhibitors, is performed for the first time in this paper, to the best of our knowledge.

Pharmacological actions of oximino-propofol analogues at GABA(B) autoreceptors.

1. GABA(B) autoreceptors are a subclass of GABA(B) receptors that inhibit the release of [(3) H]GABA from GABAergic nerve terminals. Baclofen is an agonist that reduces [(3)H]GABA, whilst the antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) enhances [(3)H]GABA release in electrically-stimulated rat neocortical brain slices preloaded with [(3)H]GABA. Here, the pharmacological actions of a series of compounds derived from the positive allosteric modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930), were examined on GABA(B) autoreceptors. 2. The compound, 3-(3,5-ditbutyl-4-hydroxyphenyl)-2,2-dimethyl-1-oximinopropane (compound 2), at 10 µmol/L had little effect on the stimulation-induced overflow of [(3)H]GABA when superfused alone, but when superfused in the presence of baclofen (2 µmol/L) inhibited the overflow of [(3)H]GABA. These effects were reversed by Sch 50911 (10 µmol/L). Although compounds 1-(4-chlorophenyl)-3-(4-hydroxy-3,5-diisopropylphenyl)-2-methyl-1-oximinopropane (compound 1), 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1-oximinomethylcyclohexane (compound 3), 3-(3,5-ditbutyl-4-hydroxyphenyl)-1,2-diphenyl-1-oximinopropane (compound 4) and 4-(3,5-ditbutyl-4-hydroxyphenyl)-3-methyl-2-oximinobutane (compound 5) (each at 10 µmol/L) tended to reduce the stimulation-induced overflow in the presence of baclofen, an effect reversed by Sch 50911, their status as modulators is not confirmed in the present study. 3. Another derivative, 3-(3,5-ditbutyl-4-hydroxyphenyl)-1-(4-chlorophenyl)-2-methyl-1-oximinopropane (compound 6) (10 µmol/L), acted as an agonist as it inhibited the release of [(3)H]GABA by 32% (EC(50) of 3.3 µmol/L), an effect reversed by Sch 50911 (10 µmol/L). The other compounds, 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1-methyl-2-oximinocyclohexane (compound 7), 4-(3,5-ditbutyl-4-hydroxyphenyl)-3,3-dimethyl-2-oximinobutane (compound 8) and 4-(4-hydroxy-3,5-diisopropylphenyl)-3,3-dimethyl-2-oximinobutane (compound 9) (each at 10 µmol/L), were inactive. 4. These findings indicate that this series of compounds show different modes of activity at GABA(B) autoreceptors.

Tautomerism and isotopic multiplets in the 13C NMR spectra of partially deuterated 3-arylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and their sulfur analogs--evidence for elucidation of the structure backbone and tautomeric forms.

The tautomerism of the synthesized 3-arylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones (1a-d) and 3-aryl-7-thioxo-7,8-dihydro-6H-pyrimido[4,5-c]pyridazine-5-ones (2a-d) was studied in dimethyl sulfoxide (DMSO)-d(6). (1)H NMR spectra of 1a-d showed a clustered water molecule in the structure backbone that is attached by strong intermolecular H bonding. The relation between the temperature and H bonding of the clustered water molecule with 1a was also studied as representative. The relation between the electronegativity (chi) of the substituent on phenyl ring and the chemical shifts of clustered water protons in 1a-d was also studied. All of 1a-d and also 2d compounds existed in lactam (I) form, whereas 2a-c compounds have two distinguished tautomers in DMSO-d(6) [lactam (I) and lactim (II) forms]. The solvent-substrate proton exchange was examined in compounds 1a-d and 2a-d by adding one drop of D(2)O. All compounds (except 1d) showed proton/deuterium exchange of the clustered water protons in DMSO by adding one drop of D(2)O. Some compounds (but not all of them) that are easily soluble in DMSO-d(6) containing D(2)O showed isotopic splitting (beta-isotope effect) in their (13)C NMR spectra. Among them, compound 1a was the best evidence to help the spectral assignments and structure determination of predominant tautomer by carbon-13 splitting (beta-isotope effect).