Recent synthetic approaches towards thienothiophenes: a potential template for biologically active compounds.

Heterocyclic compounds are attractive candidates because of their vast applications in natural and physical sciences. Thienothiophene (TT) is an annulated ring of two thiophene rings with a stable and electron-rich structure. Thienothiophenes (TTs) fully represent the planar system, which can drastically alter or improve the fundamental properties of organic, π-conjugated materials when included into a molecular architecture. These molecules possessed many applications including, pharmaceutical as well as optoelectronic properties. Different isomeric forms of thienothiophene showed various applications such as antiviral, antitumor, antiglaucoma, antimicrobial, and as semiconductors, solar cells, organic field effect transistors, electroluminiscents etc. A number of methodologies were adopted to synthesize thienothiophene derivatives. In this review, we have addressed different synthetic strategies of various isomeric forms of thienothiophene that have been reported during last seven years, i.e., 2016-2022.

Neuroimaging changes associated with vitamin D Deficiency - a narrative review.

ABSTRACTEmerging evidence suggests the role of vitamin D in brain health and its implication in the pathogenesis of cognitive impairment. The Aim of this review is to summarize current evidence on neuroimaging changes seen in vitamin D deficient individuals. Cross-sectional and longitudinal studies have consistently found an association between low serum 25 hydroxyvitamin D and cognitive impairment. Furthermore, investigating the association between serum 25 hydroxyvitamin D and neuroimaging abnormalities could provide an insight into the potential mechanisms underlying the association with cognitive impairment. Animal studies have demonstrated structural changes in the cerebral cortex and hippocampus of vitamin D deficient mice. Neuroimaging studies of the brain have shown increased white matter hyperintensities in periventricular, cortical, and juxtacortical areas and grey matter atrophy of the hippocampus, anterior cingulate cortex, and left calcarine sulcus in elderly with vitamin D deficiency.

Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19.

The COVID-19 pandemic is rapidly spreading, and health care systems are being overwhelmed with the huge number of cases, with a good number of cases requiring intensive care. It has become imperative to develop safe and effective treatment strategies to improve survival. In this regard, understanding the pathogenesis of COVID-19 is highly important. Many hypotheses have been proposed, including the ACE/angiotensin-II/angiotensin receptor 1 pathway, the complement pathway, and the angiotensin-converting enzyme 2/mitochondrial assembly receptor (ACE2/MasR) pathway. SARS-CoV-2 binds to the ACE2 on the cell surface, downregulating the ACE2, and thus impairs the inactivation of bradykinin and des-Arg9-bradykinin. Bradykinin, a linear nonapeptide, is extensively distributed in plasma and different tissues. Kininogens in plasma and tissue are the main sources of the two vasoactive peptides called bradykinin and kallidin. However, the role of the dysregulated bradykinin pathway is less explored in the pathogenesis of COVID-19. Understanding the pathogenesis of COVID-19 is crucial for the development of new effective treatment approaches which interfere with these pathways. In this review, we have tried to explore the interaction between SARS-CoV-2, ACE2, bradykinin, and its metabolite des-Arg9-bradykinin in the pathogenesis of COVID-19.

Discovery of Amide-Functionalized Benzimidazolium Salts as Potent α-Glucosidase Inhibitors.

α-Glucosidase inhibitors (AGIs) are used as medicines for the treatment of diabetes mellitus. The α-Glucosidase enzyme is present in the small intestine and is responsible for the breakdown of carbohydrates into sugars. The process results in an increase in blood sugar levels. AGIs slow down the digestion of carbohydrates that is helpful in controlling the sugar levels in the blood after meals. Among heterocyclic compounds, benzimidazole moiety is recognized as a potent bioactive scaffold for its wide range of biologically active derivatives. The aim of this study is to explore the α-glucosidase inhibition ability of benzimidazolium salts. In this study, two novel series of benzimidazolium salts, i.e., 1-benzyl-3-{2-(substituted) amino-2-oxoethyl}-1H-benzo[d]imidazol-3-ium bromide 9a-m and 1-benzyl-3-{2-substituted) amino-2-oxoethyl}-2-methyl-1H-benzo[d] imidazol-3-ium bromide 10a-m were screened for their in vitro α-glucosidase inhibitory potential. These compounds were synthesized through a multistep procedure and were characterized by 1H-NMR, 13C-NMR, and EI-MS techniques. Compound 10d was identified as the potent α-glucosidase inhibitor among the series with an IC50 value of 14 ± 0.013 µM, which is 4-fold higher than the standard drug, acarbose. In addition, compounds 10a, 10e, 10h, 10g, 10k, 10l, and 10m also exhibited pronounced potential for α-glucosidase inhibition with IC50 value ranging from 15 ± 0.037 to 32.27 ± 0.050 µM when compared with the reference drug acarbose (IC50 = 58.8 ± 0.12 µM). A molecular docking study was performed to rationalize the binding interactions of potent inhibitors with the active site of the α-glucosidase enzyme.

Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl]-N-arylacetamides: An In Silico and Biochemical Approach.

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 µM, respectively, which were better than the standard drug, acarbose (IC50 = 58.8 µM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.

Synthesis and α-glucosidase inhibition studies of norfloxacin-acetanilide hybrids.

α-Glucosidase inhibitors occupy a prominent position among the various treatments of type-2 diabetes mellitus (DM2). In this study, a series of new norfloxacin-acetanilide hybrid molecules were synthesized and screened for α-glucosidase inhibition activity. The synthetic methodology involves the synthesis of a series of α-bromoacetanilides by condensing bromoacetyl bromide with various substituted anilines. These α-bromoacetanilides were coupled with norfloxacin in DMF to get the titled hybrids. The structure elucidation of synthesized compounds were characterized by 1H NMR, 13C NMR and LC-MS. Finally, the compounds were screened for their α-glucosidase inhibition activity using acarbose as a reference drug (IC50 =58 µM). Among the tested compounds, 3i and 3j displayed potent α-glucosidase inhibition activity with IC50 values of 7.81±0.038 and 5.55±0.012 µM respectively. In-addition, 3m, 3f and 3k were demonstrated moderate alpha-glucosidase inhibition activities with IC50 values of 52.905±0.041, 23.79± 0.087 and 23.06±0.026 µM respectively. The structure-activity relationship was established with the help of molecular docking by using Molecular Operating Environment software (MOE 2014).

Synthesis, molecular docking and anti-diabetic studies of novel benzimidazole-pyrazoline hybrid molecules.

Pyrazoline and benzimidazoles derivatives have been widely studied due to their potential applications in the medicinal field. In this research project, we have hybridized these two heterocyclic systems in the same molecule. A new series of compounds, 2-((3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-1H-benzo[d]imidazole (5a-i) were synthesized through a multistep reaction. In the first step, chalcones 3a-i were prepared by coupling of various acetophenones and benzaldehydes under alkaline conditions. These chalcones were cyclized with hydrazine hydrate to form a series of pyrazolines which were finally coupled with 2-chloromethyl-1H-benzimidazole to get a new series of titled hybrid molecules. The structures of these compounds were elucidated by spectral (1H NMR and 13C NMR) analysis. The anti-diabetic potential of these compounds was studied by screening them for their α-glucosidase inhibition activity. The SAR was established through molecular docking analysis. Compound 5d appeared as effective inhibitor with IC50 = 50.06µM as compared to reference drug (acarbose) having IC50 = 58.8µM.

Synthesis, characterization and antimicrobial activity of norfloxacin based acetohydrazides.

The drug resistance phenomenon in microbes is resulting in the ineffectiveness of available drugs to treat the infections. Thus, there is a continued need to discover new molecules to combat the drug resistance phenomenon. Norfloxacin is a fluoroquinolone antibiotic that is used for the treatment of urinary tract infections. In this research work, norfloxacin is structurally modified by hybridizing with a range of substituted acetohydrazidic moieties through a multistep reaction. The first step involves the coupling of norfloxacin 1 with methyl chloroacetate followed by the treatment with hydrazine hydrate to result in corresponding acetohydrazide 3. A range of substituted benzaldehydes were reacted with the acetohydrazide to form the targeted series of norfloxacin derivatives 4a-i. The final compounds were screened for antimicrobial activity. Among the tested compounds, 4c, 4d, 4e and 4f displayed better antifungal activity against F.avenaceum, while compound 4c and 4e were active against F. bubigeum.

Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies.

In searchof the potenttherapeutic agent as an α-glucosidase inhibitor, we have synthesized twenty-five analogs (1-25) of quinoline-based Schiff bases as an inhibitoragainst α-glucosidase enzyme under positive control acarbose (IC50 = 38.45 ±â€¯0.80 µM). From the activity profile it was foundthat analogs 1, 2, 3, 4, 11, 12 and 20with IC50values 12.40 ±â€¯0.40, 9.40 ±â€¯0.30, 14.10 ±â€¯0.40, 6.20 ±â€¯0.30, 14.40 ±â€¯0.40, 7.40 ±â€¯0.20 and 13.20 ±â€¯0.40 µMrespectively showed most potent inhibition among the series even than standard drug acarbose (IC50 = 38.45 ±â€¯0.80 µM). Here in the present study analog 4 (IC50 = 6.20 ±â€¯0.30 µM) was found with many folds better α-glucosidase inhibitory activity than the reference drug. Eight analogs like 5, 7, 8, 16, 17, 22, 24 and 25 among the whole series displayed less than 50% inhibition. The substituents effects on phenyl ring thereby superficially established through SAR study. Binding interactions of analogs and the active site of ligands proteins were confirmed through molecular docking study. Spectroscopic techniques like 1H NMR, 13C NMR and ESIMS were used for characterization.

Synthesis, molecular docking study and thymidine phosphorylase inhibitory activity of 3-formylcoumarin derivatives.

Thymidine phosphorylase (TP) over expression plays role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. The inhibitor of this enzyme plays an important role in preventing the serious threat due to over expression of TP. In this regard, a series of seventeenanalogs of 3-formylcoumarin (1-17) were synthesized, characterized by 1HNMR and EI-MS and screened for thymidine phosphorylaseinhibitory activity. All analogs showed a variable degree of thymidine phosphorylase inhibition with IC50 values ranging between 0.90 ±â€¯0.01 and 53.50 ±â€¯1.20 µM when compared with the standard inhibitor 7-Deazaxanthine having IC50 value 38.68 ±â€¯1.12 µM. Among the series, fifteenanalogs such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16 and 17 showed excellent inhibition which is many folds better than the standard 7-Deazaxanthine whiletwo analogs 13 and 14 showed good inhibition. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl ring. Molecular docking study was carried out to understand the binding interaction of the most active analogs.

Synthesis, α-glucosidase inhibition and molecular docking study of coumarin based derivatives.

We have synthesized seventeen Coumarin based derivatives (1-17), characterized by 1HNMR, 13CNMR and EI-MS and evaluated for α-glucosidase inhibitory potential. Among the series, all derivatives exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 1.10 ±â€¯0.01 and 36.46 ±â€¯0.70 µM when compared with the standard inhibitor acarbose having IC50 value 39.45 ±â€¯0.10 µM. The most potent derivative among the series is derivative 3 having IC50 value 1.10 ±â€¯0.01 µM, which are many folds better than the standard acarbose. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituent's on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.

Synthesis, characterization, monoamine oxidase inhibition, molecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivatives.

In this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues.

Ectopic Pregnancy With Tubal Rupture: An Analysis Of 80 Cases.

BACKGROUND: Ectopic pregnancy (EP) is a major problem in obstetrics as there is evidence of increasing incidence throughout the world. It is an important cause of maternal morbidity and mortality. In Pakistan, the care seeking behaviour among female is limited that makes female vulnerable to die due to complication of ectopic pregnancy. The aim of this study is to determine the frequency of tubal rupture in ectopic pregnancy in Pakistani patients. METHODS: In this crosssectional study data pertaining to age, gestational age, parity and duration of presenting symptoms were collected and analysed. RESULTS: 80 patients were diagnosed to have ectopic pregnancy. The frequency of tubal rupture was 91.25%. It is encountered significantly more often in women with age of 26 years. More tubal rupture is found in patient with low parity, in which the frequency of tubal rupture is up to 100% and decrease up to 78.6% with increasing parity up to four. Furthermore, it is noted that increase in gestational age from 8 weeks to 10 weeks caused an increase in frequency of tubal rupture from 80 to 100% respectively. It is also noted that earlier the patient presents the lesser is the frequency of tubal rupture, as compared to late presentation beyond 3-4 days which make frequency up to 95%. CONCLUSIONS: Tubal rupture is still common cause of maternal morbidity and mortality, and is still a major challenge in gynaecological practice. Creating awareness amongst midwives and GPs regarding early diagnosis can contribute to decrease the mortality, morbidity and fertility loss related to EP.

Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent ß-glucuronidase inhibitors.

Thirty N-arylidenequinoline-3-carbohydrazides (1-30) have been synthesized and evaluated against ß-glucuronidase inhibitory potential. Twenty four analogs showed outstanding ß-glucuronidase activity having IC50 values ranging between 2.11±0.05 and 46.14±0.95 than standard d-saccharic acid 1,4 lactone (IC50=48.4±1.25µM). Six analogs showed good ß-glucuronidase activity having IC50 values ranging between 49.38±0.90 and 80.10±1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent ß-glucuronidase inhibitors for further investigation.

Serum fasting lipid profile in children and adolescents with ß-thalassaemia major in southern Pakistan.

OBJECTIVE: Serum fasting lipid profile has been studied in various clinical spectrum of Beta (ß)-thalassaemia syndrome. Premature cardiac impairment in thalassaemia major appears primarily due to iron accumulation and oxidative injury; however it might be a sequel of abnormal lipoprotein concentrations. The rational of this study is to analyse the serum fasting lipid profile in cardiovascular disease free ß-thalassaemia major (ß-TM) patients. Relationships with age, gender, haematological parameters, liver enzymes and serum ferritin were observed. METHOD: Fasting serum lipid levels, liver function test (LFT), complete blood count (CBC) and serum ferritin were measured in 36 patients with homozygous ß-TM from March 2012 to March 2014. Patients were stratified into two groups, age≤15 and >15 years, to determine the possible lipid profile distinction in relation to age. RESULTS: 17 were males and 19 were females, with median age of 12.0 years. The mean total cholesterol (TC) and triglyceride (TG) were 5.01±1.32 and 8.36±5.28 mmol/L respectively. High TG was detected in 36.1%, while high density lipoprotein cholesterol (HDL) and low density lipoprotein cholesterol (LDL) were markedly low, 0.98±0.51 and 2.35±1.22 mmol/L respectively. No statistically significant difference was noted between the two age groups. The median TC to HDL ratio (TC:HDL) was elevated, 5.7 (4.0). We established significant correlation of total bilirubin with TC (r=-0.4), HDL (r=-0.5) and LDL (r=-0.4) (P<0.05). CONCLUSION: Dyslipidaemia in ß-TM patients is irrespective of age and gender including low HDL and high TC:HDL, whilst high TC:HDL may contribute as a significant risk marker for future cardiac events in these patients.

Effect of iron chelator desferrioxamine on serum zinc levels in patients with beta thalassemia major.

UNLABELLED: ß-thalassemia is the most common genetic disorder worldwide with an increased prevalence around the Mediterranean, Indian subcontinent and in South-East Asia. Various siderotic and non-siderotic complications significantly impact the quality of life. Thalassemic patients are also at risk of zinc deficiency due to diverse causes including desferrioxamine chelation. This study sought to investigate the prevalence of zinc deficiency in beta thalassemia major patients on desferrioxamine for iron chelation. STUDY DESIGN: This was a descriptive, prospective, cross-sectional study over a 6-month period. 63 cases of beta thalassemia major within the age group of 5-15 years on desferrioxamine for at least 1 year, were included. Basic patient demographics such as age, gender and duration of disease were recorded. Serum zinc levels were determined by atomic absorption spectrophotometry. RESULTS: The mean age of patients was 10.84±3.47 (5 to 15) years. There were 35 (55.6%) males and 28(44.4%) females. The prevalence of zinc deficiency (zinc levels>50 µg/dl) was 22.2%. Proportions of deficiency were higher in males with a duration of disease beyond 10 years. CONCLUSIONS: Zinc deficiency is not uncommon in beta thalassemia patients on desferrioxamine. We suggest that zinc levels be regularly monitored in these patients.

Microbial-catalyzed biotransformation of multifunctional triterpenoids derived from phytonutrients.

Microbial-catalyzed biotransformations have considerable potential for the generation of an enormous variety of structurally diversified organic compounds, especially natural products with complex structures like triterpenoids. They offer efficient and economical ways to produce semi-synthetic analogues and novel lead molecules. Microorganisms such as bacteria and fungi could catalyze chemo-, regio- and stereospecific hydroxylations of diverse triterpenoid substrates that are extremely difficult to produce by chemical routes. During recent years, considerable research has been performed on the microbial transformation of bioactive triterpenoids, in order to obtain biologically active molecules with diverse structures features. This article reviews the microbial modifications of tetranortriterpenoids, tetracyclic triterpenoids and pentacyclic triterpenoids.

Structure and absolute configuration of 20ß-Hydroxyprednisolone, a biotransformed product of predinisolone by the marine endophytic fungus Penicilium lapidosum.

The anti-inflammatory drug predinisolone (1) was reduced to 20ß-hydroxyprednisolone (2) by the marine endophytic fungus Penicilium lapidosum isolated from an alga. The structural elucidation of 2 was achieved by 1D- and 2D-NMR, MS, IR data. Although, 2 is a known compound previously obtained through microbial transformation, the data provided failed to prove the C20 stereochemistry. To solve this issue, DFT and TD-DFT calculations have been carried out at the B3LYP/6-31+G (d,p) level of theory in gas and solvent phase. The absolute configuration of C20 was eventually assigned by combining experimental and calculated electronic circular dichroism spectra and 3JHH chemical coupling constants.

(E)-3-Chloro-N'-(2-fluoro-benzyl-idene)thio-phene-2-carbohydrazide.

The title compound, C12H8ClFN2OS, is a hydrazide derivative adopting an E conformation with an azomethine N=C double bond length of 1.272 (2) Å. The mol-ecular skeleton is approximately planar; the terminal five- and six-membered rings form a dihedral angle of 5.47 (9)°. In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds into zigzag chains propagating in [100].

2-{[2-(2-Hy-droxy-5-meth-oxy-benzyl-idene)hydrazin-1-yl-idene]meth-yl}-4-meth-oxy-phenol.

The title phenyl-hydrazine derivative, C16H16N2O4, has a crystallographically imposed centre of symmetry. Except for the methyl group, all non-H atoms are almost coplanar (r.m.s. deviation = 0.0095 Å). Intra-molecular O-H⋯N hydrogen bonds are observed, generating S(6) graph-set ring motifs.