Novel Benzotriazole-ß-lactam Derivatives as Antimalarial Agents: Design, Synthesis, Biological Evaluation and Molecular Docking Studies.

Many people around the world suffer from malaria, especially in tropical or subtropical regions. While malaria medications have shown success in treating malaria, there is still a problem with resistance to these drugs. Herein, we designed and synthesized some structurally novel benzotriazole-ß-lactams using 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid as a key intermediate. To synthesize the target molecules, the ketene-imine cycloaddition reaction was employed. First, The reaction of 1H-benzo[d][1,2,3]triazole with 2-bromoacetic acid in aqueous sodium hydroxide yielded 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid. Then, the treatment of 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid with tosyl chloride, triethyl amine, and Schiff base provided new ß-lactams in good to moderate yields.The formation of all cycloadducts was confirmed by elemental analysis, FT-IR, NMR and mass spectral data. Moreover, X-ray crystallography was used to determine the relative stereochemistry of 4a compound. The in vitro antimalarial activity test was conducted for each compound against P. falciparum K1. The IC50 values ranged from 5.56 to 25.65 µM. A cytotoxicity profile of the compounds at 200 µM final concentration revealed suitable selectivity of the compounds for malaria treatment. Furthermore, the docking study was carried out for each compound into the P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site to analyze their possible binding orientation in the active site.

Investigations of antiproliferative and antioxidant activity of ß-lactam morpholino-1,3,5-triazine hybrids.

This article reports for the first time the synthesis of some novel ß-lactam morpholino-1,3,5-triazine hybrids by a [2+2]-cycloaddition reaction of imines 7a-c, 9a-c and 11 with ketenes derived from substituted acetic acids. The reaction was totally diastereoselective, leading exclusively to the formation of cis-ß-lactams 8a-l, 10a-f and 12a-c. The synthesized compounds were tested for activity towards SW1116, MCF-7 and HepG2 cancer cell lines and non-cancerous HEK-293 cell line by MTT assay. None of the compounds exert an observable effect on HepG2, MCF-7 and HEK-293 cells, but compounds 7b, 8f, 8g, 8l, 10c, and 10e exhibited excellent growth inhibitory activity (IC50 < 5 µM) against SW 1116 cells, comparable to that of doxorubicin (IC50 = 6.9 µM). An evaluation of the antioxidant potential of each of the compounds, performed by diphenylpicrylhydrazyl (DPPH) assay, indicated that 7b, 9a, 9b and 9c have strong free radical scavenging activity. UV absorption titration studies reveal that 7b, 8l, 8g and 8f interact strongly with calf-thymus DNA (CT-DNA) in the order of 8l > 7b > 8f > 8g. Collectively, the in vitro capabilities of some of these morpholino-triazine imines and ß-lactams suggest possible applications to development of new antioxidants and DNA binding therapeutics.

The Utility of Feticide Procedure to Shorten the Induction-to-Abortion Interval in Medical Abortion.

AIM: To evaluate the effect of intracardiac potassium chloride feticide procedure (FP) on the induction-to-abortion (I-to-A) interval for various indications in the termination of pregnancy. METHOD: Medically indicated abortions between 17 and 28 weeks' gestation were retrospectively evaluated and allocated into 2 groups: Cases with (group 1, n = 58) or without an FP (group 2, n = 60). I-to-A intervals were compared across the groups, considering different baseline parameters and fetal abnormality categories. RESULTS: There were no differences among the groups except in gestational age (GA; mean, 21.2 vs. 19.6 weeks, p = 0.01) in group 1. Overall, the I-to-A interval was shorter (900 ± 233 vs. 1,198 ± 375 min, p = 0.001) and prolonged medical abortion (I-to-A interval > 48 h) was less common (2% vs. 6%, p = 0.03) in group 1. The facilitating effect of FP persisted when indications were categorized as central nervous system, chromosomal, other structural abnormalities, and unclassified conditions. Logistic regression analyses demonstrated the following features to be associated with expulsion of fetus after 24-h: (1) advanced GA (> 24 week; aOR 6.9, 95% CI 3.24-14.72), (2) central nervous system abnormalities (aOR 5.3, 95% CI 2.6-11.4), (3) lack of feticide (aOR 3.67, 95% CI 2.24-10.72). CONCLUSION: FPs seem to shorten the I-to-A interval and decrease prolonged I-to-A interval rates. This facilitating effect remains unchanged for various medical indications.

Prenatal sonographic diagnosis of cephalopagus conjoined twins at 14 weeks of pregnancy.

Conjoined twins are extremely rare and are a type of monozygotic twins that occur due to an incomplete embryonic division on postconception day 13 to 15. Eight different types of conjoined twins have been described in the literature. Management of the condition depends on the site and extent of the union. We present a case of cephalopagus twins diagnosed at 14 weeks of gestation.

Increased fetal epicardial fat thickness: A novel ultrasound marker for altered fetal metabolism in diabetic pregnancies.

OBJECTIVE: To evaluate whether fetal epicardial fat thickness (EFT) differs in diabetic and nondiabetic pregnant women. METHODS: Retrospective case-control study of pregnancies between 24 and 36 weeks complicated by preexisting (PDM) or gestational (GDM) diabetes mellitus, matched one to one with controls for body mass index and gestational age (GA). Epicardial fat was identified as the hypoechogenic area between myocardium and visceral pericardium over the right ventricle and its thickness was measured by a single observer blinded to clinical condition and outcomes. A linear regression analysis was performed to assess the relationship between GA and EFT, and regression lines were compared between diabetics and controls. RESULTS: 53 PDM and 53 GDM pregnant women were matched with controls. With the exception of maternal age, the demographics were similar among groups. EFT increased significantly with advancing gestation in both diabetics and controls (P < 0.0001) and was significantly greater in diabetics than in controls (P < 0.0001). The best fit lines were different between diabetics (EFT = 0.05 × GA + 0.07 mm; R2 = 0.70) and controls (EFT = 0.07 × GA + 0.04 mm; R2 = 0.93) (P < 0.0001). CONCLUSION: Fetal EFT was greater in diabetics than in nondiabetics, and even greater in pregestational diabetics. EFT maybe an additional and/or earlier marker to identify early changes in fetal metabolism before accelerated fetal growth and polyhydramnios is apparent.

The impact of concurrent pelvic organ prolapse reconstructive surgery on midurethral sling procedure outcome.

OBJECTIVES: To evaluate the effect of concurrent pelvic organ prolapse (POP) reconstructive surgery on midurethral sling (MUS) procedure outcome. MATERIAL AND METHODS: The present retrospective study included 300 women with urodynamically diagnosed stress urinary incontinence that underwent MUS procedures with or without concurrent POP reconstructive surgery. Patients were divided into four groups according to the performed surgery; 1) transobturator tape (TOT), 2) TOT with POP surgery (anterior colporrhaphy, posterior colporrhaphy and vaginal hysterectomy), 3) tension free vaginal tape (TVT), 4) TVT with POP surgery. Outcomes of surgeries for each group were evaluated postoperatively at the end of the first and sixth month by performing a cough stress test and also using the Incontinence Impact Questionnaire-7 (IIQ-7) and Urogenital Distress Inventory (UDI-6) questionnaires. Presence of a negative cough stress test was defined as "Cure". Multivariate regression was used to identify the parameters for surgical failure. RESULTS: Forty-two, 70, 49 and 139 women underwent isolated TOT, concurrent TOT and POP, isolated TVT and concurrent TVT and POP surgery, respectively. Postoperative UDI-6 score and postoperative cure rate were significantly higher in the only TOT group as compared to the TOT + POP group. However, in multiple regression analysis, women's age, parity, body mass index, menopausal status, preoperative urodynamic parameters, MUS types and presence of any concomitant POP reconstructive surgery were found to have no significant effect on surgical outcome. CONCLUSIONS: Concurrent POP reconstructive surgery including anterior colporrhaphy, posterior colporrhaphy and vaginal hysterectomy have no affect MUS procedure outcomes.

Prenatal diagnosis of inverted duplication deletion 8p syndrome mimicking trisomy 18.

Inverted duplication deletion of 8p (invdupdel[8p]) is a well-described and uncommon chromosomal rearrangement. The majority of the reported cases have revealed no life-threatening malformations. Although the invdupdel[8p] syndrome in children with central nervous system abnormalities has been reported before, we present the first prenatal microarray diagnosis of invdupdel[8p] syndrome mimicking trisomy 18 due to similar sonographic features. Contrary to reported cases with invdupdel[8p] syndrome, the present case had severe polyvalvular dysplasia and the infant deceased at day 12 of life. In this case, we also emphasize the diagnostic power of microarray analysis in detecting the underlying genetic causes for fetuses with multiple congenital anomalies. © 2017 Wiley Periodicals, Inc.

Maternal and perinatal outcomes in pregnancies with multiple sclerosis: a case-control study.

OBJECTIVE: To assess whether maternal multiple sclerosis (MS) is associated with adverse pregnancy outcomes by determining the clinical course of disease during pregnancy and postpartum throughout a 10-year-period in a single tertiary center. METHODS: We conducted a case-control study that included pregnancies with a definitive diagnosis of MS (n=43), matched with 100 healthy pregnant women with similar characteristics. Maternal and perinatal data were retrieved from hospital files. Groups were compared with the Mann-Whitney and χ2 tests. Logistic regression models were constructed to determine independent effects. RESULTS: Maternal demographic and baseline laboratory data were similar across the groups. Rates of preterm delivery, fetal growth restriction, preeclampsia, gestational diabetes, stillbirth, cesarean delivery, congenital malformation, and 5-min Apgar score were comparable (P>0.05 for all). General anesthesia during cesarean delivery (96% vs. 39%, P=0.002), urinary tract infection (UTI) (12% vs. 3%, P=0.04), low 1-min Apgar score (21% vs. 9%, P=0.04), and nonbreastfeeding (33% vs. 2%, P=0.001) were more frequent in women with MS. The low 1-min Apgar score and breastfeeding rates were independent of general anesthesia and UTI in regression models. CONCLUSION: MS during pregnancy was not associated with adverse maternal and perinatal outcomes except UTI, low 1-min Apgar scores, and decreased breastfeeding rates.

Reliability of posterior-left atrium space index measurements during 20-24 weeks of gestation in structurally normal fetuses.

OBJECTIVE: We aimed to evaluate the correlation between clinical parameters and the post-left atrium (LA) space index, which is a candidate screening marker for total anomalous pulmonary venous connection (TAPVC). We also calculated the inter- and intra-observer variabilities of measurements for this parameter. METHODS: The LA-descending aorta distance/descending aorta diameter ratios (post-LA space index) were obtained from 165 fetuses between 20 and 24 weeks of gestation. Regression analyses were utilized to evaluate the correlations across clinical parameters and the post-LA space index. Intraclass correlations coefficients were calculated for the intra- and inter-observer agreements of three examiners with different sonographic experience. RESULTS: The mean (±SD) maternal and gestational age (GA) was 28.6±4.9 years and 21.7±0.9 weeks of gestation, respectively. In multivariate analyses, there was no correlation between post-LA space index and maternal age, fetal gender, or GA at cardiac scan. There were moderate to strong correlations across the measurements by different examiners, indicating good inter- and intra-observer agreements. CONCLUSION: The post-LA space index during 20-24 weeks of gestation is a simple and reliable marker that is not affected by GA. However, its potential as a screening tool for TAPVC warrants further clinical investigation.

Reduced Postoperative Functional Length Ratio Influences Patient Satisfaction in First Metatarsophalangeal Joint Replacement.

Complications of first metatarsophalangeal joint metallic arthroplasty are well known. However, the resulting shortening of the metatarsals can lead to transverse metatarsalgia or medial column pain at the metatarsophalangeal joints by creating Morton's toe/foot, which increases pressure on the second metatarsal head. The effect of the functional length ratio of the first and second metatarsals on pain and patient satisfaction has not been rigorously evaluated. We evaluated the effect of the first/second metatarsal ratio on patient satisfaction with first metatarsophalangeal joint metallic arthroplasty. From October 2008 to February 2010, 34 patients (median age 66.2, range 55 to 70 years) with hallux rigidus were treated surgically using the Toefit-Plus(™) prosthesis. At a mean follow-up period of 27.5 (range 17 to 35) months, 30 patients (88.24%) underwent re-evaluation. The functional length of the first and second metatarsals and the lucency around the prosthesis were evaluated. Statistically significant (p ≤ .05) improvements were found for the mean modified American Orthopaedic Foot and Ankle Society score (from 44 to 80), pain (from 7 to 3 on a 10-cm visual analog scale), and mean total range of motion (from 42.2° to 59.4°). Also, 20 patients (58.82%) were fully satisfied with the procedure (scores of 8 to 10 on a 3-point Likert scale). Shortening the first metatarsal reduced the functional length ratio (r = 0.95; p < .001) and was associated with lower patient satisfaction (r = 0.66, p = .007). Preoperative consideration of the first/second metatarsal functional length ratio could be useful in preventing medial column pain due to a relatively short first metatarsal to a long second metatarsal axis in the transverse plane.

Crystal structure of (E)-N-(3,4-di-meth-oxy-benzyl-idene)morpholin-4-amine.

In the title compound, C13H18N2O3, the benzene ring makes a dihedral angle of 17.19 (11)° with the least-squares plane formed by the four C atoms of the morpholine ring, which adopts a chair conformation. In the crystal, C-H⋯N hydrogen bonds link the mol-ecules into supramolecular chains running along a 21 screw axis parallel to the b-axis direction. Weak C-H⋯π inter-actions are also observed.

Crystal structure of 1H-imidazol-3-ium 2-(1,3-dioxoisoindolin-2-yl)acetate.

The title salt, C3H5N2 (+)·C10H6NO4 (-), was obtained during a study of the co-crystallization of N'-[bis-(1H-imidazol-1-yl)methyl-ene]isonicotinohydrazide with (1,3-dioxoisoindolin-2-yl)acetic acid under aqueous conditions. The 1,3-dioxoisoindolinyl ring system of the anion is essentially planar [maximum deviation = 0.023 (2) Å]. In the crystal, cations and anions are linked via classical N-H⋯O hydrogen bonds and weak C-H⋯O hydrogen bonds, forming a three-dimensional network. Weak C-H⋯π inter-actions and π-π stacking inter-actions [centroid-centroid distances = 3.4728 (13) and 3.7339 (13) Å] also occur in the crystal.

Crystal structure of (E)-1(anthracen-9-ylmethylidene)[2-(morpholin-4-yl)eth-yl]amine.

The title compound, C21H22N2O, crystallizes with two independent mol-ecules in the asymmetric unit. In both mol-ecules, the anthracene ring systems are almost planar, with maximum deviations of 0.071 (8) and 0.028 (7) Å, and make dihedral angles of 73.4 (2) and 73.3 (2)° with the least-squares planes formed by the four C atoms of the morpholine rings, which adopt a chair conformation. An intra-molecular C-H⋯π inter-action occurs. In the crystal, the packing is stabilized by weak C-H⋯O hydrogen bonds, which connect pairs of molecules into parallel to the c axis, and C-H⋯π inter-actions.

1-(Morpholin-4-yl)-4-(2-nitro-phen-yl)spiro-[azetidine-3,9'-xanthen]-2-one.

In the title compound, C22H21N3O5, the ß-lactam (azetidin-2-one) ring is nearly planar [maximum deviation = 0.010 (1) Å] and makes dihedral angles of 69.22 (5), 55.32 (5) and 89.42 (4)° with the least-squares planes formed by the four C atoms of the morpholine ring, which adopts a chair conformation, the benzene ring and the xanthene ring system, respectively. In the crystal, C-H⋯O hydrogen-bond contacts connect neighbouring mol-ecules into infinite zigzag chains running parallel to the b axis.

(E)-4-{[(Morpholin-4-yl)imino]-meth-yl}benzo-nitrile.

In the title compound, C12H13N3O, the morpholine ring adopts a chair conformation and its mean plane is inclined to that of the benzene ring by 16.78 (12)°. The N-N=C-C bridge, which has an E conformation, has a torsion angle of 173.80 (19)°. In the crystal, mol-ecules stack along the a axis but there are no significant inter-molecular inter-actions present.

1-[3-(Morpholin-4-yl)prop-yl]-3-[(naph-tha-len-2-yl)oxy]-4-(3-nitro-phen-yl)azeti-din-2-one.

In the title compound, C26H27N3O5, the ß-lactam (azetidin-2-one) ring is nearly planar [maximum deviation = 0.011 (3) Å]. The mean plane formed by the four C atoms of the morpholine ring, which adopts a chair conformation, the benzene ring and the naphthalene ring system form dihedral angles of 72.85 (17), 87.46 (15) and 65.96 (11)°, respectively, with the ß-lactam ring. In the crystal, molecules are linked via C-H⋯O hydrogen bonds, forming inversion dimers with R 2 (2)(8).

3-(2,4-Di-chloro-phen-oxy)-1-(4-meth-oxy-benz-yl)-4-(4-nitro-phen-yl)azetidin-2-one.

The ß-lactam ring of the title compound, C23H18Cl2N2O5, is nearly planar [maximum deviation = 0.019 (2) Šfor the N atom] and its mean plane makes dihedral angles of 56.86 (15), 68.83 (15) and 83.75 (15)° with the di-chloro-, nitro- and meth-oxy-substituted benzene rings, respectively. In the crystal, mol-ecules are linked by pairs of C-H⋯O hydrogen bonds, forming inversion dimers with R 2 (2)(10) loops. The dimers are linked by further C-H⋯O hydrogen bonds, forming sheets lying parallel to (001). The mol-ecular packing is further stabilized by C-H⋯π inter-actions.

(E)-Benz-yl(4-{[1-(prop-2-en-1-yl)-1H-1,2,3-triazol-4-yl]meth-oxy}benzyl-idene)amine.

The triazole ring of the title compound, C20H20N4O, is normal to the central benzene ring, making a dihedral angle of 90.0 (3)°, and forms a dihedral angle of 69.2 (3)° with the terminal phenyl ring. The dihedral angle between the phenyl and benzene rings is 88.2 (3)°. The atoms of the terminal propenyl group are disordered over two sets of sites, with a site-occupancy ratio of 0.663 (13):0.337 (13). In the crystal, C-H⋯N contacts lead to the formation of a layer structure extending parallel to (011). Two weak C-H⋯π inter-actions are also observed.

(E)-N-(4-{[1-(Prop-2-en-1-yl)-1H-1,2,3-triazol-4-yl]meth-oxy}benzyl-idene)morpholin-4-amine.

The asymmetric unit of the title compound, C17H21N5O2, contains two crystallographically independent mol-ecules, which are linked by a C-H⋯N hydrogen bond. The morpholine rings of both mol-ecules adopt distorted chair conformations. The dihedral angles between the triazole and benzene rings are 12.8 (3)° in the first independent molecule in which the -N=C- group between the morpholine and benzene rings is disordered [site-occupancy ratio = 0.576 (7):0.424 (7)] and 88.1 (2)° in the second independent mol-ecule. In the crystal, mol-ecules are linked by C-H⋯N hydrogen bonds along the [100] direction. In addition, one weak C-H⋯π inter-action and two weak π-π stacking inter-actions [centroid-centroid distances = 3.840 (3) and 3.823 (2) Å] between the triazole rings of adjacent mol-ecules are observed. The atoms of the terminal propenyl groups in both mol-ecules are disordered over two sets of sites [site-occupancy ratios = 0.691 (10):0.309 (10) and 0.705 (15):0.295 (15)].

1-[3-(Morpholin-4-yl)prop-yl]-4-(3-nitro-phen-yl)spiro-[azetidine-3,9'-xanthen]-2-one.

The ß-lactam (azetidin-2-one) ring of the title compound, C28H27N3O5, is nearly planar [maximum deviation = 0.010 (1) Å] and makes dihedral angles of 75.77 (5), 52.78 (9) and 88.72 (5)°, respectively, with the benzene ring, the least-squares plane formed by the four C atoms of the morpholine ring, which adopts a chair conformation, and the xanthene ring system. In the crystal, C-H⋯O hydrogen-bond contacts connect neighbouring mol-ecules into infinite zigzag chains running parallel to the b axis.