Synthesis, molecular modeling and bio-evaluation of cycloalkyl fused 2-aminopyrimidines as antitubercular and antidiabetic agents

An economical and efficient one step synthesis of a series of 8-(arylidene)-4-(aryl)-5,6,7,8-tetrahydro-quinazolin-2-ylamines and 9-(arylidene)-4-(aryl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-2-ylamines by the reaction of bis-benzylidene cycloalkanones and guanidine hydrochloride in presence of NaH has been developed. All the synthesized compounds were evaluated against Mycobacterium tuberculosis H₃₇Rv strain and the α-glucosidase and glycogen phosphorylase enzymes. Few of the compounds have shown interesting in vitro activity with MIC up to 3.12 μg/mL against M. tuberculosis and very good inhibition of α-glucosidase and glycogen phosphorylase enzymes. The most potent non toxic compound 40 exhibited about 58% ex vivo activity at MIC of 3.12 μg/mL. The present study opens a new gate to synthesize antitubercular agents for diabetic TB patients. In silico docking studies indicate that mycobacterial dihydrofolate reductase is the possible target of these compounds.     

TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome

Purpose

Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9.

Methods and Materials

Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4–10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study.

Results

Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001).

Conclusions

TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies.     

Correlation of epiphyllous bud differentiation with foliar senescence in crassulacean succulent Kalanchoe pinnata as revealed by thidiazuron and ethrel application

Leaves of Kalanchoe pinnata have crenate margins with each notch bearing a dormant bud competent to develop into a healthy plantlet. Leaf detachment is a common signal for inducing two contrastingly different leaf-based processes, i.e. epiphyllous bud development into plantlet and foliar senescence. To investigate differentiation of bud and its correlation, if any, with foliar senescence, thidiazuron (TDZ), having cytokinin activity and ethrel (ETH), an ethylene releasing compound, were employed. The experimental system was comprised of marginal leaf discs, each harbouring an epiphyllous bud. Most of the growth characteristics of plantlet developing from the epiphyllous bud were significantly inhibited by TDZ but promoted by ETH. The two regulators modulated senescence in a manner different for leaf discs and plantlet leaves. Thus, TDZ caused a complete retention whereas ETH a complete loss of chlorophyll in the leaf discs. In contrast, the former resulted in a complete depletion of chlorophyll from the plantlet leaves producing an albino effect, while the latter reduced it by 50% only. In combined dispensation of the two regulators, the effect of TDZ was expressed in majority of responses studied. The results presented in this investigation clearly show that the foliar processes of epiphyllous bud differentiation and senescence are interlinked as TDZ that delayed senescence inhibited epiphyllous bud differentiation and ETH that hastened senescence promoted it. A working hypothesis to interpret responsiveness of the disc-bud composite on lines of a source-sink duo, has been proposed.     

Ecological significance and some biotechnological application of an organic solvent stable alkaline serine protease from Bacillus subtilis strain DM-04

An organic solvent stable, alkaline serine protease (Bsubap-I) with molecular mass of 33.1 kDa, purified from Bacillus subtilis DM-04 showed optimum activity at temperature and pH range of 37–45 °C and 10.0–10.5, respectively. The enzyme activity of Bsubap-I was significantly enhanced in presence of Fe²⁺. The thermal resistance and stability and of Bsubap-I in presence of surfactants, detergents, and organic solvents, and its dehairing activity supported its candidature for application in laundry detergent formulations, ultrafiltration membrane cleaning, peptide synthesis and in leather industry. The broad substrate specificity and differential antibacterial property of Bsubap-I suggested the natural ecological role of this enzyme for the producing bacterium.     

Enantioselective synthesis of 1-methoxy- and 1-deoxy-2'-methyl-delta8-tetrahydrocannabinols: new selective ligands for the CB2 receptor

Two new series of cannabinoids were prepared and their affinities for the CB1 and CB2 receptors were determined. These series are the (2'R)- and (2'S)-1-methoxy- and 1-deoxy-3-(2'-methylalkyl)-delta8-tetrahydrocannabinols, with alkyl side chains of three to seven carbon atoms. These compounds were prepared by a route that employed the enantioselective synthesis of the resorcinol precursors to the cannabinoid ring system. All of these compounds have greater affinity for the CB2 receptor than the CB1 receptor and four of them, (2'R)-1-methoxy-3-(2'-methylbutyl)-delta8-THC (JWH-359), (2'S)-1-deoxy-3-(2'-methylbutyl)-delta8-THC (JWH-352), (2'S)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), and (2'R)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), have good affinity (K(i) = 13-47 nM) for the CB2 receptor and little affinity (K(i) = 1493 to >10,000 nM) for the CB1 receptor. In the 1-deoxy-3-(2'-methylalkyl)-delta8-THC series, the 2'S-methyl compounds in general have greater affinity for the CB2 receptor than the corresponding 2'R isomers.     

Site-related differences in the localization of the monoclonal antibody OX7 in SL2 and SL1 lymphomas

Summary The uptake of a monoclonal antibody (OX7) by murine lymphomas (SL1, SL2) growing in two sites in the mouse were compared. SL2 tumors grown in the subrenal site showed greater specific antibody uptake than did the same tumor grown in the subcutaneous site. Major differences in membrane bound antibody, in vitro antibody binding patterns, and gamma scintillation camera imaging were also observed between the two sites. These differences may be due to the greater blood flow measured in tumors growing in the subrenal capsule than those growing at the subcutaneous site. The differences observed in antibody uptake of the same tumor growing in two different sites raises questions concerning the choice of animal model systems that can be used to predict clinical utility.     

Fisher information matrix of the Dirichlet-multinomial distribution

In this paper we derive explicit expressions for the elements of the exact Fisher information matrix of the Dirichlet-multinomial distribution. We show that exact calculation is based on the beta-binomial probability function rather than that of the Dirichlet-multinomial and this makes the exact calculation quite easy. The exact results are expected to be useful for the calculation of standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters for data that arise in practice in toxicology and other similar fields. Standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters, based on the exact and the asymptotic Fisher information matrix based on the Dirichlet distribution, are obtained for a set of data from Haseman and Soares (1976), a dataset from Mosimann (1962) and a more recent dataset from Chen, Kodell, Howe and Gaylor (1991). There is substantial difference between the standard errors of the estimates based on the exact Fisher information matrix and those based on the asymptotic Fisher information matrix.     

Statistical optimization of <Emphasis Type="Italic">Bacillus alcalophilus</Emphasis> α-amylase immobilization on iron-oxide magnetic nanoparticles

We report the statistical optimization of the immobilization of alkaline α-amylase [E.C. 3.2.1.1] from Bacillus alcalophilus onto nano-sized supermagnetic ironoxide nanoparticles (MNPs) for augmenting the cost effective industrial application of MNP-bound α-amylase. Both Plackett-Burman factorial design and response surface methodology (RSM) were employed to screen the influence of different parameters and the central effect of response on the α-amylase-iron oxide MNP binding process. The high coefficient of determination (R2) and analysis of variance (ANOVA) of the quadratic model indicated the competence of the proposed model. The size of the MNPs was confirmed by X-ray diffraction and scanning electron microscope analyses in which Fourier transform infrared spectroscopy suggested immobilization of the enzyme on iron-oxide MNPs. A significant improvement (∼ 26-fold) in specific activity, thermal and storage stability, and reusability of α-amylase after binding with iron-oxide MNP reinforced the improved biotechnological potential of the α-amylase iron-oxide MNP bioconjugate compared to free α-amylase. These results open new avenues for applying this MNP immobilized enzyme in different industrial sectors, notably in the paper and brewing industries.