Anti-inflammatory effect of 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole derivatives as p38α inhibitors.

In the present work, the anti-inflammatory effect of 30 compounds containing 3-fluorophenyl pyrimidinylimidazo[2,1-b]thiazole was investigated. All final target compounds showed significant Inhibitory effect on p38α. P38α is considered one of the key kinases in the inflammatory process due to its regulatory effect on pro-inflammatory mediators. The final target compounds divided into four group based on the type of terminal moiety (amide and sulfonamide) and the linker between pyrimidine ring and terminal moiety (ethyl and propyl). Most compounds with terminal sulfonamide moiety and propyl linker between the sulfonamide and pyrimidine ring were the most potent among all synthesized final target compounds with sub-micromolar IC50s. Compound 24g (with p-Cl benzene sulfonamide and propyl linker) exhibited the highest activity over P38α with IC50 0.68 µM. All final target compounds were tested for their ability to inhibit nitric oxide release and prostaglandin E2 production. Compounds having amide terminal moiety with ethyl linker showed higher inhibitory activity for nitric oxide release and compound 21d exhibited the highest activity for nitric oxide release with IC50 1.21 µM. Compounds with terminal sulfonamide moiety and propyl linker showed the highest activity for inhibiting PGE2 production and compounds 24i and 24g had the lowest IC50s with value 0.87 and 0.89 µM, respectively. Compounds 21d, 22d and 24g were tested for their ability to inhibit over expression of iNOS, COX1, and COX2. In addition the ability of compounds 21d, 22d and 24g to inhibit inflammatory cytokines were determined. Finally molecular docking of the three compounds were performed on P38α crystal structure to expect their mode of binding.

Design, synthesis, and biological investigation of oxadiazolyl, thiadiazolyl, and pyrimidinyl linked antipyrine derivatives as potential non-acidic anti-inflammatory agents.

A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations.

New benzothiazole hybrids as potential VEGFR-2 inhibitors: design, synthesis, anticancer evaluation, and in silico study.

A new series of 2-aminobenzothiazole hybrids linked to thiazolidine-2,4-dione 4a-e, 1,3,4-thiadiazole aryl urea 6a-d, and cyanothiouracil moieties 8a-d was synthesised. The in vitro antitumor effect of the new hybrids was assessed against three cancer cell lines, namely, HCT-116, HEPG-2, and MCF-7 using Sorafenib (SOR) as a standard drug. Among the tested compounds, 4a was the most potent showing IC50 of 5.61, 7.92, and 3.84 µM, respectively. Furthermore, compounds 4e and 8a proved to have strong impact on breast cancer cell line with IC50 of 6.11 and 10.86 µM, respectively. The three compounds showed a good safety profile towards normal WI-38 cells. Flow cytometric analysis of the three compounds in MCF-7 cells revealed that compounds 4a and 4c inhibited cell population in the S phase, whereas 8a inhibited the population in the G1/S phase. The most promising compounds were subjected to a VEGFR-2 inhibitory assay where 4a emerged as the best active inhibitor of VEGFR-2 with IC50 91 nM, compared to 53 nM for SOR. In silico analysis showed that the three new hybrids succeeded to link to the active site like the co-crystallized inhibitor SOR.

A Review on Benzimidazole Scaffolds as Inhibitors of Mycobacterium tuberculosis Mycolyl-arabinogalactan-peptidoglycan Complex Biosynthesis.

BACKGROUND: Tuberculosis is one of the oldest known infectious diseases to mankind, caused by Mycobacterium tuberculosis. Although current treatment using first-line anti-tubercular drugs is proven to be effective, an infection caused by resistant strains, as in multidrug-resistant and extensive drug- resistant tuberculosis is still an impending challenge to treat. OBJECTIVE: Our objective is to focus on reporting benzimidazole derivatives that are targeting mycobacterial membrane biosynthesis, particularly the mycobacterial mycolyl-arabinogalactanpeptidoglycan complexes. From the literature survey, it has been noted that targeting Mycobacterium tuberculosis cell membrane biosynthesis is an effective approach to fight against drug resistance in tuberculosis. METHODS: Articles on benzimidazole derivatives as inhibitors of proteins responsible for the biosynthesis of the mycobacterial mycolyl-arabinogalactan-peptidoglycan complex have been selected. RESULTS: By reviewing the anti-tubercular activity of the reported benzimidazole derivatives, we have concluded that a correlation between benzimidazole derivatives and their biological activity is found. It has been noted that benzimidazole derivatives with substitution at N1, C2, C5, and C6 positions have shown a greater affinity towards target proteins. CONCLUSION: Even though scientific advancement toward the prevention of tuberculosis has been quite significant in the past few decades, infection caused by resistant strains is a major concern. We have collected data on benzimidazole derivatives that inhibit the biosynthesis of mycolic acid, arabinogalactan and, peptidoglycan. From our observations, we conclude that majority of the molecules have given anti-tubercular activity in nanomolar range. Still there are few mycobacterial membrane biosynthesis proteins where benzimidazole as an inhibitor has yet to be explored.

Effect of Hydroaloholic Extract of Rotula Aquatica Lour on Gentamicin-Induced Nephrotoxicity in Wistar Albino Rats: An In Vitro and In Vivo Approach.

One-third of the world population suffer from kidney complications such as acute and chronic renal failure, renal calculi, kidney stones, Fanconi's syndrome and urethritis which doesn't have a proper effective treatment regimen. The current study explores the nephroprotective effect of herbal drug Rotula Aquatica by both In Vitro and In Vivo methods. MTT assay was applied In Vitro to evaluate the nephroprotective effect of R. aquatica leaves extract on HEK 293 cell line. The acute toxicity of the extract was evaluated as per the limit test under the protocol of OECD 423 at a concentration of 2000 mg/kg using 6 female rats. Further, an In Vivo study using the Gentamicin-instigated nephrotoxicity model was carried out for a period of 8 days. Biochemical markers of renal damage, endogenous antioxidants and histopathology were determined to assess the effect of treatment. The In Vitro study using HEK 293 cell line resulted in an EC50 value of 51.50 µg/ml for the extract in comparison to the standard drug Cytsone (12.26 µg/ml). Based on the limit test of OECD 423, doses of 200 and 400 mg/kg were chosen for the study. The results revealed a strong nephroprotective activity at 400 mg/kg in Gentamicin-induced nephrotoxicity against standard drug cystone by restoring the decrement in body weight, renal enzymatic and non-enzymatic antioxidants, creatinine and urea levels in urine and plasma. This indicated that hydroalcoholic extract of Rotula aquatica (HAERA) can prevent the Gentamicin toxicity due to the high content of antioxidant and anti-inflammatory secondary metabolites.

A meta-analysis showing the effect of surgical site wound infections and associated risk factors in neonatal surgeries.

A meta-analysis was performed to assess the effect of surgical site wound infections and risk factors in neonates undergoing surgery. A systematic literature search up to January 2022 incorporated 17 trials involving 645 neonates who underwent surgery at the beginning of the trial; 198 of them had surgical site wound infections, and 447 were control for neonates. The statistical tools like the dichotomous or continuous method used within a random or fixed-influence model to establish the odds ratio (OR) and mean difference (MD) with 95% confidence intervals (CIs) to evaluate the risk factors and influence of surgical site wound infections in neonates undergoing surgery. Surgical site wound infections had significantly higher mortality with OR value 2.03 at 95% CI 1.40-2.95 with P-value <0.001, the longer length of hospital stay (MD, 31.88; 95% CI, 18.17-45.59, P < 0.001), and lower birthweight of neonates (MD, -0.30; 95% CI, -0.53 to -0.07, P = 0.01) compared with neonates with no surgical site wound infections undergoing surgery. However, no remarkable change was observed with surgical site wound infections in the gestational age at birth of neonates (MD, -0.70; 95% CI, -1.46 to 0.05, P = 0.07), and the preoperative antibiotic prophylaxis (OR, 1.28; 95% CI, 0.57-2.87, P = 0.55) compared with no surgical site wound infections for neonates undergoing surgery. Surgical site wound infections had significantly higher mortality, a longer length of hospital stay, and lower birthweight of neonates. However, they had no statistically significant difference in the gestational age at birth of neonates and the preoperative antibiotic prophylaxis compared with no surgical site wound infections for neonates undergoing surgery. Furthermore, evidence is needed to confirm the outcomes.

A meta-analysis comparing efficiency of limb-salvage surgery vs amputation on patients with osteosarcoma treated with neoadjuvant chemotherapy.

Osteogenic sarcoma is the central malignant bone neoplasm affecting the bones of arms and legs and rarely the soft tissues outside the bones. Historically, amputation was the chief surgical technique; currently, the popular standard is limb salvage surgery (LSS), although both procedures' effect on 5-year-event survival, 5-year disease-free survival rates (DFS) and the local recurrence is uncertain. Therefore, this meta-study aimed to establish the relationship between the effect of LSS and amputation in subjects with osteogenic carcinoma. A systematic survey till January 2021 to know the effect of LLS vs amputation with subjects treated with neoadjuvant chemotherapy was conducted. Clinical studies were identified with 9760 subjects with osteosarcoma of the extremities at the beginning of the trial; 7095 of them were managed with limb salvage surgery and 2611 with amputation. This study tried to compare the effects of LSS vs amputation in subjects with osteogenic sarcoma in the extremities. The dichotomous method in statistical analysis was used as a tool for establishing odds ratio (OR) at a confidence interval of 95% (CI) to assess the efficiency of LSS and amputees with osteosarcoma of the extremities with a fixed or random-effect model. Although patients with osteosarcoma of the extremities managed with LSS were significantly related to a higher local recurrence rate than those treated with amputation, they were also associated with higher 5-year overall survival (OS) than amputation. Patients showed no significant difference in a 5-year DFS rate between LSS vs amputation. The subjects who have undergone LSS for osteosarcoma of the extremities may have a higher risk of local recurrence than amputees. However, LSS may increase 5-year OS compared to amputees. These results depict that local recurrence of osteosarcoma does not influence survival rate. However, more studies are needed to validate this finding.

Novel Phenolic Compounds as Potential Dual EGFR and COX-2 Inhibitors: Design, Semisynthesis, in vitro Biological Evaluation and in silico Insights.

INTRODUCTION: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance. METHODS: Three semi-synthetic series of compounds (C1-4, P1-4, and G1-4) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. (p-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities. RESULTS: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC50: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC50: 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC50 values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites. DISCUSSION: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.

Fascinating Chemopreventive Story of Wogonin: A Chance to Hit on the Head in Cancer Treatment.

Cancer, global havoc, is a group of debilitating diseases that strikes family as well as society. Cancer cases are drastically increasing these days. Despite many therapies and surgical procedures available, cancer is still difficult to control due to limited effective therapies or targeted therapies. Natural products can produce lesser side effects to the normal cells, which are the major demerit of chemotherapies and radiation. Wogonin, a natural product extracted from the plant, Scutellaria baicalensis has been widely studied and found with a high caliber to tackle most of the cancers via several mechanisms that include intrinsic as well as extrinsic apoptosis signaling pathways, carcinogenesis diminution, telomerase activity inhibition, metastasis inhibition in the inflammatory microenvironment, anti-angiogenesis, cell growth inhibition and arrest of the cell cycle, increased generation of H2O2 and accumulation of Ca2+ and also as an adjuvant along with anticancer drugs. This article discusses the role of wogonin in various cancers, its synergism with various drugs, and the mechanism by which wogonin controls tumor growth.

Treatment of Parkinson's Disease by MAO-B Inhibitors, New Therapies and Future Challenges - A Mini-Review.

BACKGROUND: One of the most prevalent neurodegenerative diseases with increasing age is Parkinson's disease (PD). Its pathogenesis is unclear and mainly confined to glutamate toxicity and oxidative stress. The dyskinesia and motor fluctuations and neuroprotective potential are the major concerns which are still unmet in PD therapy. OBJECTIVE: This article is a capsulization of the role of MAO-B in the treatment of PD, pharmacological properties, safety and efficiency, clinical evidence through random trials, future therapies and challenges. CONCLUSION: MAO-B inhibitors are well tolerated for the treatment of PD because of their pharmacokinetic properties and neuroprotective action. Rasagiline and selegiline were recommended molecules for early PD and proven safe and provide a modest to significant rise in motor function, delay the use of levodopa and used in early PD. Moreover, safinamide is antiglutamatergic in action. When added to Levodopa, these molecules significantly reduce the offtime with a considerable improvement of non-motor symptoms. This review also discusses the new approaches in therapy like the use of biomarkers, neurorestorative growth factors, gene therapy, neuroimaging, neural transplantation, and nanotechnology. Clinical evidence illustrated that MAOB inhibitors are recommended as monotherapy and added on therapy to levodopa. A large study and further evidence are required in the field of future therapies to unwind the complexity of the disease.

Emerging therapeutic potentials of dual-acting MAO and AChE inhibitors in Alzheimer's and Parkinson's diseases.

No drug has been approved to prevent neuronal cell loss in patients suffering from Parkinson's disease (PD) or Alzheimer's disease (AD); despite increased comprehension of the underlying molecular causes, therapies target cognitive functional improvement and motor fluctuation control. Drug design strategies that adopt the "one protein, one target" philosophy fail to address the multifactorial aetiologies of neurodegenerative disorders such as AD and PD optimally. On the contrary, restoring neurotransmitter levels by combined combinatorial inhibition of cholinesterases, monoamine oxidases, and adenosine A2A A receptors, in conjunction with strategies to counter oxidative stress and beta-amyloid plaque accumulation, would constitute a therapeutically robust, multitarget approach. This extensive review delineates the therapeutic advantages of combining dual-acting molecules that inhibit monoamine oxidases and cholinesterases and/or adenosine A2A A receptors, and describes the structure-activity relationships of compound classes that include, but are not limited to, alkaloids, coumarins, chalcones, donepezil-propargylamine conjugates, homoisoflavonoids, resveratrol analogs, hydrazones, and pyrazolines. In the wake of recent advances in network biology, in silico approaches, and omics, this review emphasizes the need to consider conceptually informed research strategies for drug discovery, in the context of the mounting burden posed by chronic neurodegenerative diseases with complex aetiologies and pathophysiologies involving multiple signalling pathways and numerous drug targets.

Fe3 O4 nanoparticles mediated synthesis of novel spirooxindole-dihydropyrimidinone molecules as Hsp90 inhibitors.

Heat shock protein 90 (Hsp90) is a validated molecular chaperone considered as the new key recipient for cancer intervention. The current study illustrates the synthesis of novel spirooxindole-dihydropyrimidinones (4a-j) by Fe3 O4 nanoparticles intervened synthesis and their Hsp90 ATPase inhibitory activity was investigated by the malachite green assay. All the compounds in the study demonstrated a moderate to potent ATPase inhibitory profile, with IC50 values ranging from 0.18 to 6.80 µM. Compounds 4j, 4h, 4f, and 4i exhibited maximum inhibitory potential with IC50 values of 0.18, 0.20, 0.35, and 0.55 µM, respectively. They were found to be better than the standard drug, geldanamycin (Hsp9 ATPase inhibition IC50 = 0.90 µM). Compounds 4h and 4j with IC50 values of 22.82 ± 0.532, 20.78 ± 0.234 and 21.32 ± 0.765, 28.43 ± 0.653 µM showed significantly greater potencies against the MCF-7 and HepG2 cell lines, respectively. Compound 4j showed good antioxidant activities in the DPPH test and H2 O2 assay (IC50 = 20.13.23 ± 0.32 and 23.27 ± 0.32 µg/mL) when compared with the standard ascorbic acid (IC50 = 19.16 ± 0.20 and 20.66 ± 1.09 µg/mL). A molecular docking study was performed to observe the binding efficiency and steric interactions of the lead moiety.

Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones.

BACKGROUND: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer's disease (AD). METHODS: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated. RESULTS: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively. CONCLUSION: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.