Triblock Conjugates: Identification of a Highly Potent Antiinflammatory Agent

Rationally designed conjugates of chrysin, indole, and barbituric acid were synthesized and screened for their antiinflammatory activities through in vitro and in vivo experiments. Improved over the previously reported chrysin–indole–pyrazole conjugates and also in comparison to the chrysin, indole, and barbituric acid based COX-2 inhibitors, the new compounds have displayed significantly better IC₅₀ for COX-2 and some of them also exhibited inhibition of 5-LOX enzyme. For one of the test compounds, IC₅₀ for COX-2 and 5-LOX was 1 and 1.5 nM, respectively. Investigations of Swiss Albino mice through capsaicin induced paw lickings and dextran induced inflammation showed that these compounds possess appreciable analgesic and antiinflammatory activities. <i>K</i>_i, <i>K</i>_a, and Δ<i>G</i> for the enzyme–compound interaction were calculated and found to be in agreement with the biological data. The experimental results were supported by the molecular docking studies of the compounds in the active site of COX-2 and 5-LOX. Overall, a highly promising antiinflammatory agent was identified

Design and Synthesis of Aza-/Oxa Heterocycle-Based Conjugates as Novel Anti-Inflammatory Agents Targeting Cyclooxygenase‑2

A library of hybrid molecules was procured by the combination of triazine–indole adduct with morpholine/piperidine/pyrrolidine and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound <b>6</b> having an IC₅₀ value of 20 nM for COX-2 and 3000 nM for COX-1. The significant reduction in the formation of prostaglandin E₂ in the lipopolysaccharide-treated (COX-2-activated) human whole blood, almost no change in the production of thromboxane B₂ in the calcium ionophore-treated (COX-1-activated) sample of human whole blood, and the mechanistic studies on Swiss albino mice ensured that compound <b>6</b> is selective for COX-2. The association constant (<i>K</i>_a) of compound <b>6</b> with COX-2 was found to be of the order of 0.48 × 10⁶ M^–1. The diffusion spectroscopy experiments and relaxation time (<i>T</i>₁) calculations of compound <b>6</b> in the presence of COX-2 assisted in identifying the site-specific interactions of <b>6</b> with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure–activity relationship studies. With maximum tolerable dose >2000 mg kg^–1, compound <b>6</b> made 68 and 32% reduction in formalin-induced analgesia and carrageenan-induced inflammation in Swiss albino mice

Design and Synthesis of Aza-/Oxa Heterocycle-Based Conjugates as Novel Anti-Inflammatory Agents Targeting Cyclooxygenase‑2

A library of hybrid molecules was procured by the combination of triazine–indole adduct with morpholine/piperidine/pyrrolidine and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound <b>6</b> having an IC₅₀ value of 20 nM for COX-2 and 3000 nM for COX-1. The significant reduction in the formation of prostaglandin E₂ in the lipopolysaccharide-treated (COX-2-activated) human whole blood, almost no change in the production of thromboxane B₂ in the calcium ionophore-treated (COX-1-activated) sample of human whole blood, and the mechanistic studies on Swiss albino mice ensured that compound <b>6</b> is selective for COX-2. The association constant (<i>K</i>_a) of compound <b>6</b> with COX-2 was found to be of the order of 0.48 × 10⁶ M^–1. The diffusion spectroscopy experiments and relaxation time (<i>T</i>₁) calculations of compound <b>6</b> in the presence of COX-2 assisted in identifying the site-specific interactions of <b>6</b> with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure–activity relationship studies. With maximum tolerable dose >2000 mg kg^–1, compound <b>6</b> made 68 and 32% reduction in formalin-induced analgesia and carrageenan-induced inflammation in Swiss albino mice

Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent

Among the small peptides <b>2</b>–<b>31</b>, (H)­Gly-Gly-Phe-Leu­(OMe) (<b>30</b>) reduced prostaglandin production of COX-2 with an IC₅₀ of 60 nM relative to 6000 nM for COX-1. The 5 mg kg^–1 dose of compound <b>30</b> rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound <b>30</b> for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of <b>30</b> with COX-2 were supported by isothermal calorimetry experiments showing a <i>K</i>_a of 6.10 ± 1.10 × 10⁴ M^–1 and Δ<i>G</i> of −100.3 kJ mol^–1 in comparison to a <i>K</i>_a 0.41 × 10³ ± 0.09 M^–1 and Δ<i>G</i> of −19.2 ± 0.06 kJ mol^–1 for COX-1. Moreover, compound <b>30</b> did not show toxicity up to a 2000 mg kg^–1 dose. Hence, we suggest peptide <b>30</b> as a highly potent and promising candidate for further development into an anti-inflammatory drug

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundAccurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios.MethodsTo estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline.FindingsDuring the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction.InterpretationFertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world.</p