Synthesis of novel 2,5-bis(substituted thio)-1,3,4-thiadiazoles by acid catalyzed intermolecular cyclization reactions of substituted dithiocarbazates as a possible 2019-nCoV main protease inhibitor

A convenient and facile synthesis of a privileged pharmaceutical scaffolds, 2,5-bis(substituted thio)-1,3,4-thiadiazoles is accomplished. The reaction of hydrazine hydrate with carbon disulfide and substituted alkyl/aryl chloride in basic medium yielded S-substituted alkyl/aryl dithiocarbazates in high yield. These dithiocarbazates on reaction with tetrafluoro acetic acid underwent a unique acid catalyzed intermolecular cyclization reaction to afford a novel 2,5-bis(substituted thio)-1,3,4-thiadiazoles. A simple procedure and high yields are the characteristic features of these reactions. These compounds are characterized on the basis of physico-chemical and spectral (FT-IR, ESI Mass, 1H, 13C and DEPT 135° 13C {1H} NMR) studies. Compound 2b crystallizes in orthorhombic system with point group P bca. Using the DFT/B3LYP/6–311 G (d,p) level of theory, HOMO-LUMO energy gap and molecular electrostatic potential (MEP) analyses were carried out. The HOMO-LUMO energy gap allowed the calculation of chemical hardness, chemical inertness, electronegativity and the electrophilicity index of the molecule, which depicted their potential kinetic stability and reactivity. The molecular docking studies of 2b-2e with 2019-nCoV main protease(7BRO) revealed binding free energies of (ΔGb) = -6.22, -5.38, -4.43 and -4.25 kcal mol−1 respectively. Docking study revealed that the aromatic congeners exhibit appreciable therapeutic efficiency to be used as 2019-nCoV main protease inhibitors. © 2021 Elsevier B.V.

Ectopic ACTH Syndrome Secondary to Small Cell Lung Cancer Presenting as Acute Anxiety

Small cell lung cancer (SCLC) can be complicated by paraneoplastic syndromes including ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Early recognition is vital, given the poor prognosis noted in this subset of patients. We present a case of EAS due to SCLC manifesting as acute anxiety. A 55-year-old male former smoker with a history of recently diagnosed diabetes mellitus, hypertension, and anxiety presented with complaints of worsening anxiety and confusion, which he attributed to the ongoing COVID-19 pandemic. Initial examination revealed hypertension (177/73 mmHg), anxious affect, and mild confusion. Laboratory work-up was notable for leukocytosis (18,510/mm3), hypokalemia (2.4 mg/dL, and metabolic alkalosis (33 mmol/L). Workup for refractory hypokalemia revealed elevated serum cortisol level (91.3 μ g/dL), elevated 24-hour urinary free cortisol level of (18,965 mcg/hour), and elevated serum adrenocorticotropic hormone (ACTH) (294 pg/mL). Magnetic resonance imaging (MRI) of the brain was unremarkable. Computed tomography (CT) scan of the chest, abdomen, and pelvis revealed a 2.8 cm soft tissue mass in the right paratracheal mediastinum with lymphadenopathy, suggestive of malignancy. Bronchoscopy with transbronchial needle aspiration of a mediastinal lymph node was performed, and histopathology confirmed the diagnosis of small cell carcinoma complicated by ectopic ACTH production. Progressive hyperactive delirium and metabolic derangements prompted the initiation of ketoconazole and continuous infusion of etomidate in the intensive care setting, with improvement in symptoms. Concurrent radiotherapy and a chemotherapy regimen of etoposide and cisplatin was initiated. Mitotane was administered given persistently elevated cortisol levels. His subsequent hospital course was complicated by septic shock, diverticulitis, and multi-organ failure, leading to a change in goals of care to comfort measures only. EAS is an uncommon manifestation of SCLC, affecting about 1% of these patients. EAS is typified by high levels of cortisol and ACTH which are not suppressed by high dose dexamethasone. EAS portends a poor prognosis in patients with SCLC, with a median survival ranging from 3.5 to 5.5 months. Given the broad range of symptomatology of hypercortisolism, the identification of EAS is often delayed, with a mean duration of 14 months from symptom onset to diagnosis. Our case uniquely presented with the deceptively benign symptom of acute anxiety without any associated respiratory symptoms that would suggest lung cancer. Hormonal suppression was challenging, requiring concurrent use of etomidate, ketoconazole, and mitotane, apart from chemotherapy.