Structure--activity relationship studies of novel arylsulfonylimidazolidinones for their anticancer activity

To define the SAR, a series of novel N-arylsulfonylimidazolidinone derivatives were evaluated for their in vitro anticancer activity against five human tumor cell lines, including A549, COLO205, KATO III, K562, SK-OV-3 and murine leukemia (P288D1) cell line. Among them, N-(2-chloroacetyl)-6-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)-3,4-dihydroquinoline-1(2H)-carboxamide (4m) and N-cyclohexyl-6-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)-3,4-dihydroquinoline-1(2H)-carboxamide (4n) exhibited comparable in vitro anticancer activity to doxorubicin against A549, KATO III and K562 cell lines and gave superior xenographic results against NCI-H23 and SW620 cancer cell lines. Regarding the structure-activity relationship, two critical points were discovered; the steric congestion at 4-position of N-arylsulfonylimidazolidinone scaffold abolishes the activity and the bulkiness or hydrophobicity of acyl groups at 3,4-dihydroquinoline of 4, especially with carbamoyl moiety, enormously enhances the activity.     

Exploration of imidazole and imidazopyridine dimers as anticancer agents: Design,synthesis, and structure–activity relationship study

Dimerization of proteins/receptors plays a critical role in various cellular processes, including cell proliferation and differentiation. Therefore, targeting such dimeric proteins/receptors by dimeric small molecules could be a potential therapeutic approach to treating various diseases, including inflammation‐associated diseases like cancer. A novel series of bis‐imidazoles ( 13–18 ) and bis‐imidazo[1,2‐a]pyridines ( 19–28 ) were designed and synthesized from Schiff base dimers ( 1–12 ) for their anticancer activities. All the synthesized compounds were screened for anticancer activities against three cancer cell lines, including cervical (HeLa), breast (MDA‐MB‐231), and renal cancer (ACHN). From structure–activity relationship studies, imidazo[1,2‐a]pyridines ( 19–28 ) showed remarkable cytotoxic activities, with compounds 19 and 24 showing the best inhibitory activities against all three cell lines. Especially, both 19 and 24 were very effective against the breast cancer cell line ( 19 , GI₅₀ = 0.43 µM; 24 , GI₅₀ = 0.3 µM), exceeding the activity of the control adriamycin (GI₅₀ = 0.51 µM). The in vivo anticancer activity results of compounds 19 and 24 were comparable with those of the animals treated with the standard drug tamoxifen. Therefore, the dimeric imidazo[1,2‐a]pyridine scaffold could serve as a potential lead for the development of novel anticancer agents.     

Evaluation of beam matching accuracy among six linacs from the same vendor

The purpose of this study was to evaluate the dosimetric variation among six non-beam-matched Varian linacs using different techniques for the same plans. Six non-beam-matched Varian machines, comprising two Clinac iX, two 600 C/D (Unique), and two True Beam Tx photon 6 MV X-ray devices were acquired. Sixty patients with of head and neck (H&N; 30) and pelvic (30) treatment sites were chosen. For all 60 patients, three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and volumetric-modulated radiotherapy (VMAT) plans were generated for the Clinac iX-1 device; all plans were migrated to the remaining machines, using the eclipse treatment planning system without any modification. The dosimetric variation among the six machines for each target volume and organ at risk was recorded and analyzed. In H&N cases, the maximum variation among the six machines with 3DCRT, IMRT, and VMAT was 2.57%, 2.6%, and 2.6%, respectively. In pelvic cases, the maximum variation among the six machines with 3DCRT, IMRT, and VMAT was 2.2%, 1.95%, and 2.05%, respectively. Our overall results show that dosimetric variation, while interchanging the plans among the six machines at phantom and patient levels, remains within the limits of clinical acceptability. The noted variation was not correlated with any of these treatment techniques: 3DCRT, IMRT, or VMAT.     

The recent outbreaks of human coronaviruses: A medicinal chemistry perspective

Coronaviruses (CoVs) infect both humans and animals. In humans, CoVs can cause respiratory, kidney, heart, brain, and intestinal infections that can range from mild to lethal. Since the start of the 21st century, three β‐coronaviruses have crossed the species barrier to infect humans: severe‐acute respiratory syndrome (SARS)‐CoV‐1, Middle East respiratory syndrome (MERS)‐CoV, and SARS‐CoV‐2 (2019‐nCoV). These viruses are dangerous and can easily be transmitted from human to human. Therefore, the development of anticoronaviral therapies is urgently needed. However, to date, no approved vaccines or drugs against CoV infections are available. In this review, we focus on the medicinal chemistry efforts toward the development of antiviral agents against SARS‐CoV‐1, MERS‐CoV, SARS‐CoV‐2, targeting biochemical events important for viral replication and its life cycle. These targets include the spike glycoprotein and its host‐receptors for viral entry, proteases that are essential for cleaving polyproteins to produce functional proteins, and RNA‐dependent RNA polymerase for viral RNA replication.     

Pharmacological evaluation of synthetic cannabinoids identified as constituents of spice

In recent years, many synthetic cannabinoid (CB) receptor agonists have appeared on the market as constituents of herbal incense mixtures known as “spice”. Contrary to the declared use, they are perorally consumed as a replacement for marijuana to get “high”. In many cases, detailed information on the physicochemical and pharmacological properties of the synthetic compounds found in spice preparations is lacking. We have now evaluated a large series of heterocyclic compounds, 1,3-disubstituted indole and 2-azaindole derivatives known or assumed to be CB₁ receptor agonists, many of which have previously been identified in forensic samples. The mainly observed structural variations to circumvent restriction by law were bioisosteric exchanges of functional groups in known CB₁ agonists. We analyzed the structure-activity relationships of compounds at human CB₁ and CB₂ receptors based on affinities obtained in radioligand binding studies, and determined their efficacy in cAMP accumulation assays. Moreover, we investigated the activities of the compounds at the orphan G protein-coupled receptors GPR18 and GPR55 both of which are known to interact with cannabinoids. Most of the investigated compounds behaved as potent full agonists of CB₁ and CB₂ receptors with affinities in the low nanomolar to subnanomolar concentration range. Some compounds were moderately potent GPR55 antagonists, while none interacted with GPR18. Most derivatives were predicted to cross the blood–brain barrier as determined by bioinformatics tools. These data are useful for assessing synthetic cannabinoids and will be helpful for predicting pharmacological properties of novel compounds that appear on the illicit drug market.