The UV-vis spectra of isocorydine 1, norisocorydine 2 and boldine 3 were studied in 2% v/v acetonitrile, at constant ionic strength (0.1 M NaCl, 35 degree Celsius). The pK(a) values of isocorydine 1 and norisocorydine 2 were 11.75 and 12.07, respectively. Boldine 3 gave a pK(a) value of 9.16 and 10.44. All of the alkaloids 1-3 were stable at physiological pH; thereby all of them will not ionize, thus permitting the basic nitrogen to be protonated and accumulated within the acidic food vacuole of Plasmodium via pH trapping. Subsequently, acidic food vacuoles that have been neutralized by alkaloids would result in enhancement of the antiplasmodial activity. The alkaloids showed antiplasmodial activity against Plasmodium falciparum and antioxidant activities; DPPH radical scavenging, metal chelating and ferric reducing power. The antioxidant properties of the alkaloids under investigation revealed that in addition to the antiplasmodial activity, the alkaloids can also prevent oxidative damage. It can be prevented by binding free heme and neutralizing the electrons produced during the Plasmodium falciparum mediated haemoglobin destruction in the host. Slightly basic properties of the aforementioned alkaloids, along with their antioxidant activities, are advantageous in improving the suppression of malaria infection that cause less damage to the host.
A semi empirical kinetic (SEK) method has been used to determine the ratio of cetyltrimethylammonium bromide (CTABr) micellar binding constants of counterion X⁻ and Br⁻ (a reference counterion), i.e. K(X)/K(Br) (=R(X)(Br)). The values of K(X) and K(Br) have been derived from the kinetic parameters obtained in the presence spherical/non-spherical and spherical micelles, respectively. This rather new method gives the respective mean values of R(X)(Br) as 45±2, 25±3, 4.7±0.6 and 119±10 for X=2,4-, 2,5-, 2,6- and 3,4-Cl₂C₆H₃CO₂⁻ (Cl₂Bz'Na). Literature lacks the report on the values of R(X)(Br) for all X except for X=2,6-Cl₂C₆H₃CO₂⁻ (2,6-Cl2Bz'⁻) for which the reported value is 5.0. Rheological properties, such as shear thinning behavior, reveal indirectly the presence of wormlike micelles (WM) in the CTABr micellar solutions containing MX for all X except X=2,6-Cl₂Bz'⁻. The micelles remain spherical within [2,6-Cl₂Bz'⁻] range 0.01-0.34 M at 0.015 M CTABr. The maxima of the plots of zero shear viscosity, η₀, (obtained from the initial plateau region of flow curves, i.e. η vs. γ curve) vs. [MX] (MX=2,4-, 2,5- and 3,4-Cl₂Bz'Na) at 0.015 M CTABr also support indirectly the presence of linear, entangled and branched WM.
The fascinating and serendipitous discovery, in 1976, of the characteristic viscoelastic behavior of wormlike micelles of cetyltrimethylammonium salicylate (CTASa) surfactant solution at ~2×10(-4) M CTASa became a catalyst for an increasing interest in both industrial application and mechanism of the origin of micellar growth of this and related wormlike micellar systems. It has been perceived for more than three decades, based upon qualitative evidence, that the extent of the strength of the counterion (X) binding to ionic micelles determines the counterion-induced micellar structural transition from spherical-to-small rodlike-to-linear long stiff/flexible rodlike/wormlike-to-entangled wormlike micelles. This perception predicts the presence of a possible quantitative correlation of counterionic micellar binding constants (KX) with counterion-induced micellar growth. The quantitative estimation of counterion binding affinity to cationic micelles, in terms of the values of the degree of counterion binding (βX), is concluded to be either inefficient or unreliable for moderately hydrophobic counterions (such as substituted benzoate ions). The values of KX, measured in terms of conventional ion exchange constants (KX(Y)), can provide a quantitative correlation between KX or KX(Y) (with a reference counterion Y=Cl(-) or Br(-)) and counterion-induced ionic micellar growth. A recent new semi-empirical kinetic (SEK) method provides the estimation of KX(Y) for Y=Br as well as ratio of counterionic micellar binding constants KX/KBr (= RX(Br)) where the values of KBr and KX have been derived from the kinetic parameters in the presence of cationic spherical and nonspherical micelles, respectively. The SEK method has been used to determine the values of KX(Br) or RX(Br) for X=2-, 3- and 4-ClC6H4CO2(-). Rheometric measurements on aqueous CTABr/MX (MX=2-,3- and 4-ClBzNa) solutions containing 0.015 M CTABr and varying values of [MX] reveal the presence of spherical micelles for MX=2-ClBzNa and long linear as well as entangled wormlike micelles for MX=3- and 4-ClBzNa. The respective values of KX(Br) or RX(Br) of 5.7, 50 and 48 for X=2-, 3- and 4-ClBz(-) give a quantitative correlation with the rheometric measurements of the structural features of micelles of 0.015 M CTABr solutions containing 2-, 3- and 4 ClBzNa.
The semiempirical kinetic method has been used to determine the ratio of cetyltrimethylammonium bromide, CTABr, micellar binding constants of counterions X (K(X)) and Br (K(Br)), i.e., K(X)/K(Br) (= R(X)(Br)) for X = dianionic 5-methyl- and 5-methoxysalicylate ions. The values of K(X) and K(Br) have been derived from the kinetic parameters obtained in the presence of spherical/nonspherical and spherical micelles, respectively. The values of R(X)(Br) remain essentially independent of [CTABr] within its range 0.005-0.015 M for both dianionic 5-methyl- and 5-methoxysalicylate ions. The increase in temperature from 35 to 55 °C decreases the values of R(X)(Br) from 796 to 53 for 5-methylsalicylate ions and from 89 to 7.0 for 5-methoxysalicylate ions. Rheological properties of 0.015 M CTABr solutions containing ≥0.01 M counterionic salt, M(2)X, show indirectly the presence of unilamellar vesicles, ULV, and long linear, entangled, and branched wormlike micelles, WM, at, respectively, 35 and 55 °C for X = dianionic 5-methylsalicylate ion. However, such studies show WM and probable spherical micelles, SM, at, respectively, 35 and 55 °C for X = dianionic 5-methoxysalicylate ions. It has been shown that, at a constant [CTABr], the micellar structural transitions from SM-to-WM-to-vesicles may be correlated quantitatively with the values of R(X)(Br) regardless of whether such micellar structural transitions occur due to variation in the values of [M(2)X] at a constant temperature or due to variation in temperature at a constant [M(2)X].
Pseudo-first-order rate constants (k(obs)) for the nucleophilic substitution reaction of piperidine (Pip) with ionized phenyl salicylate (PS(-)), obtained at a constant [Pip](T) (= 0.1 M), [PS(-)](T) (= 2 x 10(-4) M), [CTABr](T) (cetyltrimethylammonium bromide), < or = 0.06 M NaOH, and a varying concentration of MX (= 3-FC(6)H(4)CO(2)Na, 3-FBzNa and 4-FC(6)H(4)CO(2)Na, 4-FBzNa), follow the kinetic relationship k(obs) = (k(0) + thetaK(X/S)[MX])/(1 + K(X/S)[MX]) which is derived by the use of the pseudophase micellar (PM) model coupled with an empirical equation. The empirical equation explains the effects of [MX] on CTABr micellar binding constant (K(S)) of PS(-) that occur through X(-)/PS(-) ion exchange. Empirical constants theta and K(X/S) give the parameters F(X/S) and K(X/S), respectively. The magnitude of F(X/S) gives the measure of the fraction of micellized PS(-) transferred to the aqueous phase by the limiting concentration of X(-) through X(-)/PS(-) ion exchange. The values of F(X/S) and K(X/S) have been used to determine the usual thermodynamic ion exchange constant (K(X)(Y)) for ion exchange process X(-)/Y(-) on the CTABr micellar surface. The values of K(X)(Br) (where Br = Y) have been calculated for X = 3-FBzNa and 4-FBzNa. The mean values of K(X)(Br) are 12.8 +/- 0.9 and 13.4 +/- 0.6 for X(-) = 3-FBz(-) and 4-FBz(-), respectively. Nearly 3-fold-larger values of K(X)(Br) for X = 3-FBz(-) and 4-FBz(-) than those for X = Bz(-), 2-ClBz(-), 2-CH(3)Bz(-), and the 2,6-dichlorobenzoate ion (2,6-Cl(2)Bz(-)) are attributed to the presence of wormlike micelles in the presence of > 50 mM 3-FBz(-) and 4-FBz(-) in the [CTABr](T) range of 5-15 mM. Rheological properties such as shear thinning behavior of plots of shear viscosity versus the shear rate at a constant [3-FBz(-)] or [4-FBz(-)] as well as shear viscosity (at a constant shear rate) maxima as a function of the concentrations of 3-FBz(-) and 4-FBz(-) support the conclusion, derived from the values of K(X)(Br), for the probable presence of wormlike/viscoelastic micellar solutions under the conditions of the present study.
The threat of varying global climates has greatly driven the attention of scientists, as climate change increases the odds of worsening drought in many parts of Pakistan and the world in the decades ahead. Keeping in view the forthcoming climate change, the present study aimed to evaluate the influence of varying levels of induced drought stress on the physiological mechanism of drought resistance in selected maize cultivars. The sandy loam rhizospheric soil with moisture content 0.43-0.5 g g-1, organic matter (OM) 0.43-0.55 g/kg, N 0.022-0.027 g/kg, P 0.028-0.058 g/kg, and K 0.017-0.042 g/kg was used in the present experiment. The findings showed that a significant drop in the leaf water status, chlorophyll content, and carotenoid content was linked to an increase in sugar, proline, and antioxidant enzyme accumulation at p < 0.05 under induced drought stress, along with an increase in protein content as a dominant response for both cultivars. SVI-I & II, RSR, LAI, LAR, TB, CA, CB, CC, peroxidase (POD), and superoxide dismutase (SOD) content under drought stress were studied for variance analysis in terms of interactions between drought and NAA treatment and were found significant at p < 0.05 after 15 days. It has been found that the exogenous application of NAA alleviated the inhibitory effect of only short-term water stress, but yield loss due to long-term osmotic stress will not be faced employing growth regulators. Climate-smart agriculture is the only approach to reduce the detrimental impact of global fluctuations, such as drought stress, on crop adaptability before they have a significant influence on world crop production.
In search of potent α-amylase inhibitor we have synthesized eighteen indole analogs (1-18), characterized by NMR and HR-EIMS and screened for α-amylase inhibitory activity. All analogs exhibited a variable degree of α-amylase inhibition with IC50 values ranging between 2.031 ± 0.11 and 2.633 ± 0.05 μM when compared with standard acarbose having IC50 values 1.927 ± 0.17 μM. All compounds showed good α-amylase inhibition. Compound 14 was found to be the most potent analog among the series. Structure-activity relationship has been established for all compounds mainly based on bringing about the difference of substituents on phenyl ring. To understand the binding interaction of the most active analogs molecular docking study was performed.
Chromen-4-one substituted oxadiazole analogs 1-19 have been synthesized, characterized and evaluated for β-glucuronidase inhibition. All analogs exhibited a variable degree of β-glucuronidase inhibitory activity with IC50 values ranging in between 0.8 ± 0.1-42.3 ± 0.8 μM when compared with the standard d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.
Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.
Thirty-two (32) bis-indolylmethane-hydrazone hybrids 1-32 were synthesized and characterized by 1HNMR, 13CNNMR and HREI-MS. All compounds were evaluated in vitro for β-glucuronidase inhibitory potential. All analogs showed varying degree of β-glucuronidase inhibitory potential ranging from 0.10 ± 0.01 to 48.50 ± 1.10 μM when compared with the standard drug d-saccharic acid-1,4-lactone (IC50 value 48.30 ± 1.20 μM). Derivatives 1-32 showed the highest β-glucuronidase inhibitory potentials which is many folds better than the standard drug d-saccharic acid-1,4-lactone. Further molecular docking study validated the experimental results. It was proposed that bis-indolylmethane may interact with some amino acid residues located within the active site of β-glucuronidase enzyme. This study has culminated in the identification of a new class of potent β-glucuronidase inhibitors.
The rate of conversion of 1 to N-(2-methoxyphenyl)phthalimide (2) within [HCl] range 5.0x10(-3)-1.0 M at 1.0M ionic strength (by NaCl) reveals the presence of both uncatalyzed and specific acid-catalyzed kinetic terms in the rate law. Intramolecular carboxamide group-assisted cleavage of amide bond of 1 reveals rate enhancement of much larger than 10(6)-fold compared to the expected rate of analogous intermolecular reaction.
The apparent second-order rate constant (k OH) for hydroxide-ion-catalyzed conversion of 1 to N-(2'-methoxyphenyl)phthalamate (4) is approximately 10(3)-fold larger than k OH for alkaline hydrolysis of N-morpholinobenzamide (2). These results are explained in terms of the reaction scheme 1 --> k(1obs) 3 --> k(2obs) 4 where 3 represents N-(2'-methoxyphenyl)phthalimide and the values of k(2obs)/k(1obs) vary from 6.0 x 10(2) to 17 x 10(2) within [NaOH] range of 5.0 x 10(-3) to 2.0 M. Pseudo-first-order rate constants (k(obs)) for alkaline hydrolysis of 1 decrease from 21.7 x 10(-3) to 15.6 x 10(-3) s(-1) with an increase in ionic strength (by NaCl) from 0.5 to 2.5 M at 0.5 M NaOH and 35 degrees C. The values of k obs, obtained for alkaline hydrolysis of 2 within [NaOH] range 1.0 x 10(-2) to 2.0 M at 35 degrees C, follow the relationship k(obs) = kOH[HO(-)] + kOH'[HO (-)] (2) with least-squares calculated values of kOH and kOH' as (6.38 +/- 0.15) x 10(-5) and (4.59 +/- 0.09) x 10(-5) M (-2) s(-1), respectively. A few kinetic runs for aqueous cleavage of 1, N'-morpholino-N-(2'-methoxyphenyl)-5-nitrophthalamide (5) and N'-morpholino-N-(2'-methoxyphenyl)-4-nitrophthalamide (6) at 35 degrees C and 0.05 M NaOH as well as 0.05 M NaOD reveal the solvent deuterium kinetic isotope effect (= k(obs) (H 2) (O)/ k(obs) (D 2 ) (O)) as 1.6 for 1, 1.9 for 5, and 1.8 for 6. Product characterization study on the cleavage of 5, 6, and N-(2'-methoxyphenyl)-4-nitrophthalimide (7) at 0.5 M NaOD in D2O solvent shows the imide-intermediate mechanism as the exclusive mechanism.
A kinetic study on the aqueous cleavage of N-(2-methoxyphenyl)phthalimide (1) and N-(2-hydroxyphenyl)phthalimide (2), under the buffers of N-methylmorpholine, reveals the equilibrium presence of monocationic amide (Ctam) formed due to nucleophilic reactions of N-methylmorpholine with 1 and 2. Pseudo-first-order rate constants for the reactions of water and HO- with Ctam (formed through nucleophilic reaction of N-methylmorpholine with 1) are 4.60 x 10(-5) s-1 and 47.9 M-1 s-1, respectively. But the cleavage of Ctam, formed through nucleophilic reaction of N-methylmorpholine with 2, involves intramolecular general base (2'-O- group of Ctam)-assisted water attack at carbonyl carbon of cationic amide group of Ctam in or before the rate-determining step.
The rates of the hydrolyses of N-(o-hydroxyphenyl)phthalimide (1) and N-(o-methoxyphenyl)phthalimide (2), studied at different pH, show that the hydrolysis of 1 involves intramolecular general base (IGB) assistance where the o-O- group of ionized 1 acts as IGB and H2O as the reactant. The rate enhancement due to the IGB-assisted reaction of H2O with ionized 1 is>8x10(4)-fold. Pseudo-first-order rate constant for the reaction of water with 2 is approximately 2x10(3)-fold smaller than the first-order rate constant (0.10 s-1) for pH-independent hydrolysis of 1 within the pH range of 9.60-10.10. Second-order rate constants (kOH) for hydroxide ion-assisted hydrolysis of ionized 1 and 2 are 3.0 and 29.1 M-1 s-1, respectively. The solvent deuterium kinetic isotope effect (dKIE) on the rate of alkaline hydrolysis of 1 and 2 reveals that the respective values of kOH/kOD are 0.84 and 0.78, where kOD represents the second-order rate constant for DO--assisted cleavage of these imides (1 and 2). The value of kwH2O/kdD2O is 2.04, with kwH2O and kdD2O representing pseudo-first-order rate constants for the reactions of ionized 1 with H2O and D2O, respectively.
The values of the relative counterion (X) binding constant R(X)(Br) (=K(X)/K(Br), where K(X) and K(Br) represent cetyltrimethylammonium bromide, CTABr, micellar binding constants of X(v-) (in non-spherical micelles), v = 1,2, and Br(-) (in spherical micelles)) are 58, 68, 127, and 125 for X(v-) = 1(-), 1(2-), 2(-), and 2(2-), respectively. The values of 15 mM CTABr/[Na(v)X] nanoparticles-catalyzed apparent second-order rate constants for piperidinolysis of ionized phenyl salicylate at 35 °C are 0.417, 0.488, 0.926, and 0.891 M(-1) s(-1) for Na(v)X = Na1, Na2 1, Na2, and Na2 2, respectively. Almost entire catalytic effect of nanoparticles catalyst is due to the ability of nonreactive counterions, X(v-), to expel reactive counterions, 3(-), from nanoparticles to the bulk water phase.
In the current research work, a facile synthesis of a series of novel thiophene-based derivatives of 5-bromothiophene-2-carboxylic acid ( 1 ) have been synthesized. All analogs ( 5a - 5e , 10a - 10f ) were obtained from the coupling reaction of 5-bromothiophene-2-carboxylic acid ( 1 ) and different arylboronic acids with moderate-to-good yields under controlled and optimal conditions. The structures of the newly synthesized compounds were characterized through spectral analysis and their spasmolytic activity, and most of the compounds exhibited potentially good spasmolytic effect. Among the synthesized analogs, compound phenethyl 5-(3,4-dichlorophenyl)thiophene-2-carboxylate ( 10d ) particular showed an excellent spasmolytic effect with an EC 50 value of 1.26. All of the compounds were also studied for their structural and electronic properties by density functional theory (DFT) calculations. Through detailed insight into frontier molecular orbitals of the compounds and their different reactivity descriptors, it was found that the compounds 10c and 5c are the most reactive, while 10a is the most stable in the series. Furthermore, compounds 10c and 5c showed a very good NLO response with the highest β values.
A series of thiazole derivatives 1-21 were prepared, characterized by EI-MS and (1)H NMR and evaluated for α-glucosidase inhibitory potential. All twenty one derivatives showed good α-glucosidase inhibitory activity with IC50 value ranging between 18.23±0.03 and 424.41±0.94μM when compared with the standard acarbose (IC50, 38.25±0.12μM). Compound (8) (IC50, 18.23±0.03μM) and compound (7) (IC50=36.75±0.05μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC50, 38.25±0.12μM). All other analogs also showed good to moderate enzyme inhibition. Molecular docking studies were carried out in order to find the binding affinity of thiazole derivatives with enzyme. Studies showed these thiazole analogs as a new class of α-glucosidase inhibitors.
To discover multifunctional agents for the treatment of Alzheimer's disease, a series of hydrazide based Schiff bases were designed and synthesized based on multitarget-directed strategy. We have synthesized twenty-eight analogs of hydrazide based Schiff bases, characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase and butyrylcholinesterase inhibition. All compounds showed varied degree of acetylcholinesterase and butyrylcholinesterase inhibition when compared with standard Eserine. Among the series, compounds 10, 3 and 24 having IC50 values 4.12±0.01, 8.12±0.01 and 8.41±0.06μM respectively showed potent acetylcholinesterase inhibition when compared with Eserine (IC50=0.85±0.0001μM). Three compounds 13, 24 and 3 having IC50 values 6.51±0.01, 9.22±0.07 and 37.82±0.14μM respectively showed potent butyrylcholinesterase inhibition by comparing with eserine (IC50=0.04±0.0001μM). The remaining compounds also exhibited moderate to weak inhibitory potential. Structure activity relationship has been established. Through molecular docking studies the binding interaction was confirmed.