Structure-based design, optimization of lead, synthesis, and biological evaluation of compounds active against Trypanosoma cruzi.

Chagas' disease affects approximately eight million people throughout the world, especially the poorest individuals. The protozoan that causes this disease-Trypanosoma cruzi-has the enzyme cruzipain, which is the main therapeutic target. As no available medications have satisfactory effectiveness and safety, it is of fundamental importance to design and synthesize novel analogues that are more active and selective. In the present study, molecular docking and the in silico prediction of ADMET properties were used as strategies to optimize the trypanocidal activity of the pyrimidine compound ZN3F based on interactions with the target site in cruzipain. From the computational results, eight 4-amino-5-carbonitrile-pyrimidine analogues were proposed, synthesized (5a-f and 7g-h) and, tested in vitro on the trypomastigote form of the Tulahuen strain of T. cruzi. The in silico study showed that the designed analogues bond favorably to important amino acid residues of the active site in cruzipain. An in vitro evaluation of cytotoxicity was performed on L929 mammal cell lines. All derivatives inhibited the Tulahuen strain of T. cruzi and also exhibited lower toxicity to L929 cells. The 5e product, in particular, proved to be a potent, selective (IC50 = 2.79 ± 0.00 µM, selectivity index = 31.3) inhibitor of T. cruzi. The present results indicated the effectiveness of drugs based on the structure of the receptor, revealing the potential trypanocidal of pyrimidines. This study also provides information on molecular aspects for the inhibition of cruzipain.

Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process.

BACKGROUND: Globally, medical cannabis legalization has increased in recent years and medical cannabis is commonly used to treat chronic pain. However, there are few randomized control trials studying medical cannabis indicating expert guidance on how to dose and administer medical cannabis safely and effectively is needed. METHODS: Using a multistage modified Delphi process, twenty global experts across nine countries developed consensus-based recommendations on how to dose and administer medical cannabis in patients with chronic pain. RESULTS: There was consensus that medical cannabis may be considered for patients experiencing neuropathic, inflammatory, nociplastic, and mixed pain. Three treatment protocols were developed. A routine protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg CBD twice daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 2.5 mg and titrate by 2.5 mg every 2 to 7 days until a maximum daily dose of 40 mg/day of THC. A conservative protocol where the clinician initiates the patient on a CBD-predominant variety at a dose of 5 mg once daily and titrates the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day, clinicians may consider adding THC at 1 mg/day and titrate by 1 mg every 7 days until a maximum daily dose of 40 mg/day of THC. A rapid protocol where the clinician initiates the patient on a balanced THC:CBD variety at 2.5-5 mg of each cannabinoid once or twice daily and titrates by 2.5-5 mg of each cannabinoid every 2 to 3 days until the patient reaches his/her goals or to a maximum THC dose of 40 mg/day. CONCLUSIONS: In summary, using a modified Delphi process, expert consensus-based recommendations were developed on how to dose and administer medical cannabis for the treatment of patients with chronic pain.

The new supramolecular nano-aggregate curcumin-cucurbit[7]uril: synthesis, photophysical properties and biocompatibility evaluation.

The supramolecular nano-aggregate CUR-CB[7] (CUR = curcumin and CB[7] = cucurbit[7]uril) was efficiently prepared by mixing CUR and CB[7] at a molar ratio of 1 : 1 in ethanol at room temperature. The supramolecular aggregate formation was evidenced by mainly FTIR, 1H NMR, DOSY and spectroscopy experiments. The supramolecular arrangement promotes the increase in the solubility and stability of CUR without affecting the biological properties of the A549 cells. The luminescence properties of CUR and CUR-CB[7] show anti-Kasha's rule fluorescence, and their remarkable NIR emission enables this material to be used as a luminescent probe and marker for in vivo tracking and structural integrity monitoring of the supramolecular complex.