Recent biological applications of heterocyclic hybrids containing s-triazine scaffold.

s-Triazine possesses an auspicious status in the field of drug discovery and development owing to its presence in many naturally occurring compounds as well as commercially available drugs like enasidenib, gedatolisib, bimiralisib, atrazine, indaziflam, and triaziflam. Easy, cost-effective, and efficient access to its derivatives in addition to their splendid biological activities such as anticancer, anti-inflammatory, antiviral, anticonvulsant, anti-tubercular, antidiabetic, antimicrobial, makes it an attractive heterocyclic nucleus in the field of medicinal chemistry. Other than the direct access of its derivatives from simple commercially available starting materials like amidine, the s-triazine derivatives have also been obtained starting from an inexpensive commercially available 2,4,6-trichloro-1,3,5-triazine (TCT) commonly known as cyanuric chloride. Owing to the high reactivity and the possibility of sequential substitution of TCT, a variety of biologically active heterocyclic scaffolds have been installed on this nucleus in order to have more potent compounds. These s-triazine-based heterocyclic hybrids have been reported to show enhanced biological activities in recent years. Therefore, it is important to summarize and highlight recent examples of these hybrids which is imperative to attract the attention of the drug development community.

A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation.

OBJECTIVES: We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS: Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

Efficacy of newer modalities in the management of indirect hyperbilirubinaemia at a secondary care hospital: A prospective study from 2015-2018.

OBJECTIVE: To evaluate the efficacy of current practices and new modalities for the management of neonatal indirect hyperbilirubinaemia. METHODS: The prospective study was conducted at King Khalid Hospital, Al Majmaah, Saudi Arabia, from September 2015 to September 2018, and copmprised neonates with hyperbilirubinaemia who were managed using the National Institute for Health and Clinical Excellence 2010 guidelines. The outcomes were measured in terms of decrease in total serum bilirubin and clinical improvement. Data was analysed using SPSS 25. RESULTS: Of the 233 subjects, there were 119(51%) girls and 114(49%) boys. Phototherapy was used in 162(69.5%) cases, intensive phototherapy in 36(15.5%) and intravenous immunoglobulin in 35(15%). Exchange transfusion was done in 2(0.85%) patients. All the 233(100%) patients improved with the management and total serum bilirubin significantly reduced (p<0.05). CONCLUSIONS: Newer techniques were found to have a vital role in the management of neonatal hyperbilirubinaemia.

In vitro anti-oxidant potential of new metabolites from Hypericum oblongifolium (Guttiferae).

Phytochemical investigations on Hypericum oblongifolium led to the isolation of a flavone named folicitin (1) and a bicyclic conjugated lactone, folenolide (2) from the ethyl acetate fraction of methanolic extract. Both metabolites were characterised as new compounds based on detailed spectroscopic analyses. In vitro anti-oxidant potential of both the compounds was evaluated by the DPPH radical scavenging assay. Compound 1 exhibited significant antioxidant activity while compound 2 was found inactive.

Synthesis, evaluation of antioxidant activity and crystal structure of 2,4-dimethylbenzoylhydrazones.

2,4-Dimethylbenzoylhydrazones 1-30 were synthesized by condensation reactions of 2,4-dimethylbenzoylhydrazide with various aromatic aldehydes and characterized. The assigned structures of compounds 10, 15 and 22 were further supported by single-crystal X-ray diffraction data. The synthesized compounds were evaluated for their in vitro DPPH radical scavenging activity. They exerted varying degree of scavenging activity toward DPPH radical with IC50 values between 25.6-190 µM. Compounds 1, 4, 2, 3, 7, and 6 have IC50 values of 25.6, 28.1, 29.3, 29.8, 30.0 and 30.1 µM respectively, showing better activity than an n-propyl gallate standard (IC50 value = 30.30 µM). For super oxide anion scavenging activity compounds 1, 2 and 3 with IC50 values of 98.3, 102.6, and 105.6, respectively, also showed better activity than the n-propyl gallate standard (IC50 value = 106.34 µM).

Bioassay-guided isolation of urease and α-chymotrypsin inhibitory constituents from the stems of Lawsonia alba Lam. (Henna).

Seven constituents were isolated from the stems of Lawsonia alba Lam., following an activity-guided isolation, which include two new constituents, namely lawsorosemarinol (1) and lawsofructose (2), one known compound 2-(ß-d-glucopyranosyloxy)-1, 4-naphthoquinone (3) and four compounds, 4-hydroxy coumarine (4), 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate (5), 3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate (6) and 7-hydroxy-4-methyl coumarin (7) first time isolated from Lawsonia alba. Their structure elucidation was based on spectroscopic data analyses. Compounds 3 and 7 showed a moderate inhibition of urease activity, while rest of them showed less than 50% inhibition. These compounds did not show any significant inhibition against α-chymotrypsin.

Two new prenylflavanones from Erythrina sigmoidea.

Two new prenylflavanones named sigmone and sigmotriol have been isolated from the stem bark of Erythrina sigmoidea along with two known constituents 8-(3"-methylbut-2"-enyl)-7,3',4'-trihydroxyflavanone and 7,3',4'-trihydroxyflavanone. Their structures were elucidated by spectroscopic methods.

bis-Sigmodiol: a new prenylflavanone dimer from Erythrina sigmoidea Hua (Fabaceae) of Nigeria.

A new prenylflavanone dimer named bis-sigmodiol was isolated from Erythrina sigmoidea, along with six known constituents isobavachin, lupiwighteone, orientanol A, ergosta-4, 6, 8 (14), 22-tetraen-3-one, lupenyl acetate, and p-hydroxybenzoic acid. These known constituents have not been reported so far from E. sigmoidea. Their structures were elucidated by spectroscopic methods.

Two new aromatic acids from Clerodendrum formicarum Gurke (Lamiaceae) of Cameroon.

The ethanolic extract of the leaves of Clerodendrum formicarum, a Lameacious plant of Cameroon, afforded two new salicylic acid derivatives named formoic acids A and B along with four known constituents which have been obtained for the first time from this source. They include flemingipanic acid, martynoside, verbascoside, and seguinoside K. Structures of all the isolated constituents have been elucidated with the aid of 1D and 2D NMR spectroscopic techniques.

Flavonoids from Erythrina vogelii (Fabaceae) of Cameroon.

A new flavone, vogeol, and a new isoflavone, vogliiol, have been isolated from Erythrina vogelii, a Cameroonian medicinal plant, along with seven known constituents (salvigenin, carpachromene, euchrenone b10, scandenone, 5,4'-dihydroxy-8-(3"-methylbut-2"-enyl)-2'''-(4'''-hydroxy-4'''-methylethyl)-furano-[4''',5''':6,7] isoflavone, erythrivarone C, and 5,7,4'-trihydroxy-6-[3"-methylbut-3"-enyl]-flavone). Their structures were elucidated by spectroscopic methods.

Formadienoate-A and B: two new long chained feruloyl esters from Clerodendrum formicarum (Lamiaceae) of Cameroon.

The ethanol extract of the leaves of Clerodendrum formicarum Gürke, a Lameacious plant of Cameroon, afforded two new long-chained esters named formadienoate-A (1) and B (2) along with two known constituents which have been obtained for the first time from C. formicarum. They include: hexacosyl-(E)-ferulate (3) and 26-hydroxyhexacosyl-(E)-ferulate (4). Structures of all the isolated constituents have been elucidated with the aid of 1D and 2D NMR spectroscopic techniques.