Focusing on C-4 position of Hantzsch 1,4-dihydropyridines: Molecular modifications, enantioseparation, and binding mechanism to L- and T-type calcium channels.

1,4-Dihydropyridines (DHPs) represent the blockbuster class of L-type calcium channel blockers that have tremendous therapeutic value against cardiovascular conditions. Due to their abilities to additionally target other subtypes of calcium channels, DHPs are also considered promising molecules for the treatment of neurological and psychiatric disorders. Having been in the market for more than forty years, DHP is one of the most modified scaffolds for the development of novel molecules acting on calcium channels. Taking the chemical structures of approved DHPs into account, it is noteworthy that C-4 position is the least modified part of the ring system. Therefore, in the present study, we focused on this location and carried out various molecular modifications to obtain twelve potential calcium channel blockers with a DHP-based hexahydroquinoline scaffold (DA1-DA12). The whole-cell patch clamp technique applied to analyze the blocking ability of the synthesized compounds on both L- (Cav1.2) and T- (Cav3.2) type calcium channels revealed five blockers with different selectivity profiles. Introducing naphthyl moiety onto the C-4 position of the main scaffold led to the identification of a selective blocker of Cav1.2 (DA8). The benzodioxole-substituted derivative (DA1) was the most potent and selective Cav3.2 inhibitor, therefore, its enantiomers were separated using HPLC on a chiral stationary phase. Retesting single isomers on Cav3.2 revealed that S-enantiomer was mainly responsible for the block. Finally, DA compounds were docked into two generated homology models of L- and T-type calcium channels. Molecular dynamics (MD) simulations and 3D pharmacophore modeling provided further insights into the detailed binding mechanism of DHPs to Cav1.2 as well as to Cav3.2.

Acute Limb Ischemia in Hospitalized COVID-19 Patients.

BACKGROUND: COVID-19 is a multisystemic disorder. Hematologic and cardiovascular involvement of COVID-19 causes thromboembolic events across multiple organs which mainly manifest as venous thromboembolism, and rarely, peripheral arterial thromboembolic events. In-situ thrombosis of a healthy, non-atherosclerotic native artery is rare, and COVID-19 has been reported to be a cause of this phenomenon. We aimed to report our institutional experience with COVID-19 patients who developed acute limb ischemia (ALI) during hospitalization or after discharge. METHODS: This was a single-center cross-sectional study. Records of all patients ≥18 years of age admitted to a tertiary center with a confirmed diagnosis of COVID-19 infection between September 1 and December 31, 2020 were retrospectively examined. Data regarding patient demographics, co-morbidities and outcomes were collected. Patients were followed-up during index hospitalization and for 30 days postdischarge. Acute limb ischemia was diagnosed by means of duplex ultrasound and computed tomography angiography in the presence of a clinical suspicion. RESULTS: A total of 681 consecutive patients (38.5% women) were hospitalized with a confirmed diagnosis of COVID-19 during the study period. Median age was 63 years (IQR, 52-74). In-hospital mortality occurred in 94 (13.8%) patients. Ninety (13.2%) patients required intensive care unit admission at some point of their hospital stay. Six (0.9%) patients (one woman) with a median age of 62 years experienced ALI (IQR, 59-64.3). All patients were receiving low molecular weight heparin when they developed ALI. The median of duration between COVID-19 diagnosis and ALI symptom onset was 13 days (IQR, 11.3-14). Three patients underwent emergent surgical thrombectomy combined with systemic anticoagulation, and 3 received systemic anticoagulation alone. Two patients with ALI did not survive to hospital discharge. Among survivors, 1 patient underwent bilateral major amputations, and another underwent a minor amputation within 1 month of hospital discharge. Symptoms of ALI completely resolved in 2 patients without sequelae. CONCLUSIONS: COVID-19 is a multisystemic disorder with involvement of hematologic and cardiovascular systems. Despite widespread use of thromboprophylaxis, hospitalized patients with COVID-19 are at increased risk of ALI, and subsequent limb loss or even death.