Design, Synthesis, Pharmacodynamic and In Silico Pharmacokinetic Evaluation of Some Novel Biginelli-Derived Pyrimidines and Fused Pyrimidines as Calcium Channel Blockers.

Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds 2, 3a, 3b, 4, 11 and 13 showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds 2 and 11 were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, 2 and 11 displayed drug-like in silico ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds 2, 3a, 3b, 4, 11 and 13. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers.

New thieno[3,2-d]pyrimidine-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents, EGFR and ARO inhibitors inducing apoptosis in breast cancer cells.

An array of newly synthesized thieno[3,2-d]pyrimidine-based derivatives and thienotriazolopyrimidines hybridized with some pharmacophoric anticancer fragments were designed, synthesized and assessed for their in vitro antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using erlotinib and pictilisib as reference standards in the MTT assay. In general, many compounds were endowed with considerable antiproliferative activity (IC50 = 0.43-1.31 µM). Some of the tested compounds, namely 3c, 5b, 5c, 9d, 10, 11b and 13 displayed remarkable antiproliferative activity against both cell lines. Meanwhile, compounds 2c-e, 3b, 4a, 5a, 9c and 15b showed noticeable selectivity against MCF-7 cells while compounds 2b, 3a, 4b, 6a-c, 7, 8, 9b and 12 exhibited considerable selectivity against MDA-MB-231 cells. Further mechanistic evidences for their anticancer activities were provided by screening the most potent compounds against MCF-7 and/or MDA-MB-231 cells for EGFR and ARO inhibitory activities using erlotinib and letrozole as reference standards respectively. Results proved that, in general, tested compounds were better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed for all tested compounds with the 4-fluorophenylhydrazone derivative 2d exhibiting the highest activation. In treated MDA-MB-231 breast cell line samples, 11b was found to highly induce caspase-9 level thereby inducing apoptosis. Cell cycle analysis and Annexin V-FITC/PI assay were also assessed for active compounds where results indicated that all tested compounds induced preG1 apoptosis and cell cycle arrest at G2/M phase. Compound 9d, as an inhibitor of ARO, was observed to downregulate the downstream signaling proteins HSP27 and p-ERK in MCF-7 cells. Furthermore, compound 11b downregulated EGFR expression as well as the downstream signaling protein p-AKT. Docking experiments on EGFR and ARO enzymes supported their in vitro results. Thus, the thienotriazolopyrimidines 11b and 12 showing good EGFR inhibition and the thieno[3,2-d]-pyrimidine derivatives 3b and 9d, eliciting the best ARO inhibition activity, can be considered as new candidates as anti-breast cancer agents that necessitate further development.

Synthesis, biological evaluation and molecular modeling of novel thienopyrimidinone and triazolothienopyrimidinone derivatives as dual anti-inflammatory antimicrobial agents.

New thienopyrimidinone and triazolothienopyrimidinone derivatives have been synthesized. These compounds were subjected to anti-inflammatory and antimicrobial activity screening aiming to identify new candidates that have dual anti-inflammatory and antimicrobial activities. Compounds 5, 7 and 10a showed minimal ulcerogenic effect and high selectivity towards human recombinant COX-2 over COX-1 enzyme. Their docking outcome correlated with their biological activity and assured the high selectivity binding towards COX-2. In addition, they could act safely up to 80 mg/kg orally or 40 mg/kg parentrally. The antimicrobial screening showed that compound 10a displayed distinctive inhibitory effect on the growth of Escherichia coli comparable to that of ampicillin. Moreover, compounds 5, 7, 9 and 12a possessed 50% of the inhibitory activity of ampicillin against E. coli. Thus, compounds 5, 7 and 10a represent promising dual acting anti-inflammatory and antimicrobial agents. This work provides rewarding template enriching the chemical space for dual anti-inflammatory anti-microbial activities.

Synthesis and biological evaluation of novel N3-substituted dihydropyrimidine derivatives as T-type calcium channel blockers and their efficacy as analgesics in mouse models of inflammatory pain.

Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinson's disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the CaV3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of CaV3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated CaV3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in CaV3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40-fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Cav3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity.

Ethyl 5-methyl-7-phenyl-1,2,4-triazolo[4,3-a]pyrimidine-6-carboxyl-ate.

In the title compound, C15H14N4O2, the triazolo-pyrimidine ring system is almost planar (r.m.s. deviation = 0.02 Å) and the phenyl ring is inclined to its mean plane by 42.45 (9)°. The carboxyl group is inclined to the triazolo-pyrimidine ring mean plane by 57.8 (3)°. In the mol-ecule, there is a short C-H⋯O contact involving the carbonyl O atom and an H atom of the adjacent methyl substituent. In the crystal, neighbouring mol-ecules are linked by C-H⋯O hydrogen bonds, forming chains propagating along [010]. There are also weak π-π inter-actions present involving the pyridine and phenyl rings of neighbouring chains [inter-centroid distance = 3.8580 (16) Å].

Primary SARS-CoV-2 Pneumonia Screening in Adults: Analysis of the Correlation Between High-Resolution Computed Tomography Pulmonary Patterns and Initial Oxygen Saturation Levels.

BACKGROUND: Chest High-Resolution Computed Tomography (HRCT) is mandatory for patients with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and a high Respiratory Rate (RR) because sublobar consolidation is the likely pathological pattern in addition to Ground Glass Opacities (GGOs). OBJECTIVE: The present study determined the correlation between the percentage extent of typical pulmonary lesions on HRCT, as a representation of severity, and the RR and peripheral oxygen saturation level (SpO2), as measured through pulse oximetry, in patients with Reverse Transcriptase Polymerase Chain Reaction (RT-PCR)-confirmed primary (noncomplicated) SARS-CoV-2 pneumonia. METHODS: The present retrospective study was conducted in 332 adult patients who presented with dyspnea and hypoxemia and were admitted to Prince Mohammed bin Abdulaziz Hospital, Riyadh, Saudi Arabia between May 15, 2020 and December 15, 2020. All the patients underwent chest HRCT. Of the total, 198 patients with primary noncomplicated SARS-CoV-2 pneumonia were finally selected based on the typical chest HRCT patterns. The main CT patterns, GGO and sublobar consolidation, were individually quantified as a percentage of the total pulmonary involvement through algebraic summation of the percentage of the 19 pulmonary segments affected. Additionally, the statistical correlation strength between the total percentage pulmonary involvement and the age, initial RR, and percentage SpO2 of the patients was determined. RESULTS: The mean ± Standard Deviation (SD) age of the 198 patients was 48.9 ± 11.4 years. GGO magnitude alone exhibited a significant weak positive correlation with patients' age (r = 0.2; p = 0.04). Sublobar consolidation extent exhibited a relatively stronger positive correlation with RR than GGO magnitude (r = 0.23; p = 0.002). A relatively stronger negative correlation was observed between the GGO extent and SpO2 (r = - 0.38; p = 0.002) than that between sublobar consolidation and SpO2 (r = - 0.2; p = 0.04). An increase in the correlation strength was demonstrated with increased case segregation with GGO extent (r = - 0.34; p = 0.01). CONCLUSION: The correlation between the magnitudes of typical pulmonary lesion patterns, particularly GGO, which exhibited an incremental correlation pattern on chest HRCT, and the SpO2 percentage, may allow the establishment of an artificial intelligence program to differentiate primary SARS-CoV-2 pneumonia from other complications and associated pathology influencing SpO2.

Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities.

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.

Brain MRI in SARS-CoV-2 pneumonia patients with newly developed neurological manifestations suggestive of brain involvement.

The increased frequency of neurological manifestations, including central nervous system (CNS) manifestations, in patients with coronavirus disease 2019 (COVID-19) pandemic is consistent with the virus's neurotropic nature. In most patients, brain magnetic resonance imaging (MRI) is a sensitive imaging modality in the diagnosis of viral encephalitides in the brain. The purpose of this study was to determine the frequency of brain lesion patterns on brain MRI in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients who developed focal and non-focal neurological manifestations. In addition, it will compare the impact of the Glasgow Coma Scale (GCS) as an index of deteriorating cerebral function on positive brain MRIs in both neurological manifestations. This retrospective study included an examination of SARS-CoV-2 pneumonia patients with real-time reverse transcription polymerase chain reaction (RT-PCR) confirmation, admitted with clinicoradiologic evidence of COVID-19 pneumonia, and who were candidates for brain MRI due to neurological manifestations suggesting brain involvement. Brain imaging acquired on a 3.0 T MRI system (Skyra; Siemens, Erlangen, Germany) with a 20-channel receive head coil. Brain MRI revealed lesions in 38 (82.6%) of the total 46 patients for analysis and was negative in the remaining eight (17.4%) of all finally enclosed patients with RT-PCR confirmed SARS-CoV-2 pneumonia. Twenty-nine (63%) patients had focal neurological manifestations, while the remaining 17 (37%) patients had non-focal neurological manifestations. The patients had a highly significant difference (p = 0.0006) in GCS, but no significant difference (p = 0.4) in the number of comorbidities they had. Brain MRI is a feasible and important imaging modality in patients with SARS-CoV-2 pneumonia who develop neurological manifestations suggestive of brain involvement, particularly in patients with non-focal manifestations and a decline in GCS.

Synthesis of new N3-substituted dihydropyrimidine derivatives as L-/T- type calcium channel blockers.

Cardiovascular diseases (CVDs) are the main cause of deaths worldwide. Up-to-date, hypertension is the most significant contributing factor to CVDs. Recent clinical studies recommend calcium channel blockers (CCBs) as effective treatment alone or in combination with other medications. Being the most clinically useful CCBs, 1,4-dihydropyridines (DHPs) attracted great interest in improving potency and selectivity. However, the short plasma half-life which may be attributed to the metabolic oxidation to the pyridine-counterparts is considered as a major limitation for this class. Among the most efficient modifications of the DHP scaffold, is the introduction of biologically active N3-substituted dihydropyrimidine mimics (DHPMs). Again, some potent DHPMs showed only in vitro activity due to first pass effect through hydrolysis and removal of the N3-substitutions. Herein, the synthesis of new N3-substituted DHPMs with various functionalities linked to the DHPM core via two-carbon spacer to guard against possible metabolic inactivation is described. It was designed to keep close structural similarities to clinically efficient DHPs and the reported lead DHPMs analogues, while attempting to improve the pharmacokinetic properties through better metabolic stability. Applying whole batch clamp technique, five compounds showed promising L- and T- type calcium channel blocking activity and were identified as lead compounds. Structure requirements for selectivity against Cav1.2 as well against Cav3.2 are described.

Synthesis, evaluation and modeling of some triazolothienopyrimidinones as anti-inflammatory and antimicrobial agents.

AIM: New triazolotetrahydrobenzothienopyrimidinone derivatives were synthesized. EXPERIMENTAL: Their structures were confirmed, and their anti-inflammatory, antimicrobial activities and ulcerogenic potentials were evaluated. RESULTS: Compounds 7a, 10a and 11a showed minimal ulcerogenic effect and high selectivity toward human recombinant COX-2 over COX-1 enzyme with IC50 values of 1.39, 1.22 and 0.56 µM, respectively. Their docking outcome correlated with their biological activity and confirmed the high selectivity binding toward COX-2. Compound 12b displayed antimicrobial activity comparable to that of ampicillin against Escherichia coli while compounds 6 and 11c were similar to ampicillin against Staphylococcus aureus. In addition, compounds 7a, 9a, 10b and 11c showed dual anti-inflammatory/antimicrobial activities. CONCLUSION: This work represents a promising matrix for developing new potential anti-inflammatory, antimicrobial and dual antimicrobial/anti-inflammatory candidates. [Formula: see text].

Probing nano-scale adhesion force between AFM and acid demineralized intertubular dentin: Moist versus dry dentin.

OBJECTIVE: The aim of this study was to investigate the effect of dentin dryness on the variation in the probed nano-scale adhesion force between an AFM silicon nitride tip and demineralized intertubular dentin collagen fibrils network surface. METHODS: Dentin specimens were etched with 37% phosphoric acid for 15s and then divided into three groups. Specimens of the first two groups were air-dried for 5 or 10s (DH5s and DH10s), respectively, whereas specimens of the third group were left in the hydrated condition (H). For each group, Force curves were characterized by contact-mode AFM and the adhesion force (Fad) was calculated. The structure of the demineralized collagen fibrils network was characterized by tapping mode AFM. The tensile bond strength (TBS) to dentin was evaluated using one alcohol-based dentin self-priming adhesive. The dentin/resin interface was investigated by SEM. RESULTS: Dentin specimens in the wet-hydrated condition (H) showed significantly higher adhesion force and TBS values than dry-dehydrated specimens (DH5s and DH10s). AFM images showed open collagen fibrils network structure in wet-hydrated specimens (H), while the dry-dehydrated specimens (DH5s and DH10s) showed a collapsed appearance to varying degrees. SEM images revealed minimum resin infiltration in dry-dehydrated specimens. SIGNIFICANCE: The nano-scale adhesion force between the AFM probe and demineralized intertubular dentin surface was shown to be sensitive to surface air-drying. The decrease in the nano-scale adhesion force with the increase in the time of air-dryness is related to dehydration of the demineralized collagen fibrils network surface.