Identification of Suitable Agents against Adenine Phosphoribosyl Transferase for the Management of Leishmaniasis: Synthesis, Characterization and Computational Studies

A leishmaniasis is a group of diseases attributable to protozoan parasites of the genus Leishmania. It is a potential disease mostly occurring in developing nations. Various quinoline substituted derivatives (11a-f, 12a-f, and 13a-f) were synthesized by refluxing amino quinolines with an equivalent number of different alkylaminoethyl chlorides and evaluated for their in vitro antileishmanial activity against promastigotes forms of Leishmania donovani by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] reduction assay. Compounds 11f (IC50 = 13.61μg/mL), 12f (IC50 = 11.92 μg/mL) and 13f (IC50 =10.41 μg/mL) have shown significant antileishmanial activity when compared with standard sitamaquine (IC50= 10.09 μg/mL). Furthermore, the molecular docking analysis targeting adenine phosphoribosyltransferase of Leishmania donovani exhibits significant binding interactions. In silico, ADMET predictions revealed that these compounds, i.e., 11f, 12f, and 13f, demonstrated good absorption as well as solubility characteristics with good drug-likeness and drug score values compared to the standard drug.

Expanding the scope of prenylated 1,2,3-triazoles as new antiparasitic drug candidates

We have previously shown that prenyl and aliphatic triazoles are interesting motifs to prepare new chemical entities for antiparasitic and antituberculosis drug development. In this opportunity a new series of prenyl-1,2,3-triazoles were prepared from isoprenyl azides and different alkynes looking for new antimalarial drug candidates. The compounds were prepared by copper(I) catalyzed dipolar cycloaddition of the isoprenyl azide equilibrium mixture providing exclusively 1,4-disubstituted 1,2,3-triazols in a regiospecific fashion. The complete collection of 64 compounds was tested on chloroquine -sensitive, Sierra Leone (D6), and the chloroquine-resistant, Indochina (W2), strains of Plasmodium falciparum and those compounds which were not previously reported were also tested against Leishmania donovani , the causative agent for visceral leishmaniasis. Thirteen analogs displayed antimalarial activity with IC50 below 10 uM, while the antileishmanial activity was less potent than the previously reported analogs. The cytotoxicity assay against Vero cells revealed that none of the compounds was cytotoxic up to concentrations of 4.75 ug/mL. Compounds 1o and 1r were identified as the most promising antimalarial drug leads with IC50 below 3.0 uM for both CQ-sensitive and resistant P. falciparum strains. Finally, a chemoinformatic in silico analysis was performed to evaluate physicochemical parameters, cytotoxicity risk and drug score. The validation of a bifunctional farnesyl/geranylgeranyl diphosphate synthase PfFPPS/GGPPS as the potential target of the antimalarial activity of selected analogs should be further investigated.

The beneficial impact of filtration surgery on antiviral therapy cessation in patients with cytomegalovirus-related secondary glaucoma

Purpose Cytomegalovirus (CMV)-related keratouveitis elevates intraocular pressure (IOP). Antiviral therapy does not always control IOP and some patients do not tolerate systemic antiviral therapy because of the side effects. The purpose of this study is to evaluate the clinical characteristics of patients with CMV-related keratouveitis and determine the impact of glaucoma surgeries on the postoperative antiviral therapy regimen. Methods We enrolled twenty-two patients with CMV-DNA-positive keratouveitis between June 2012 and July 2019 in Kobe University Hospital. The following clinical parameters were collected: gender, age, history of previous intraocular surgery, antiviral medications, visual acuity, IOP, glaucoma drug score, corneal endothelial cells density, and the mean deviation of a Humphrey visual field test at the first visit and before and 1 year after glaucoma surgery. Results All twenty-two patients started on oral and/or topical antiviral therapy. Eighteen patients needed glaucoma surgery despite their antiviral medications. Nine patients underwent trabeculotomy (TLO) and nine underwent trabeculectomy (TLE) as the first surgical intervention. Six of patients who initially underwent TLO and two of the patients who initially underwent TLE required additional TLE within 1 year. Each of the 15 patients who underwent at least 1 TLE showed a reduction in the magnitude and variation of IOP and glaucoma drug scores and 13 patients were able to discontinue antiviral therapy. For the remaining 4 patients, IOP and inflammation were controlled but with antiviral medications. Conclusions In patients with CMV-related keratouveitis, TLE decreases and stabilizes IOP and contributes to withdrawal from antiviral medications.

Autologous Scleral Pocket Technique for Ahmed Glaucoma Valve Implantation with Pars Plana Tube Insertion for Neovascular Glaucoma

Specific postoperative complications, such as tube exposure and conjunctival erosion, have occurred despite the favorable surgical outcomes of tube shunt surgeries for refractory glaucoma. The new autologous scleral pocket technique is performed by inserting the tube into the vitreous cavity without using a donor scleral patch. The purpose of this study was to evaluate the surgical results of Ahmed glaucoma valve (AGV) implantation using this technique for neovascular glaucoma (NVG), which is one of the representative refractory types of glaucoma. This observational retrospective case series included 15 consecutive eyes of 15 patients with NVG who had undergone AGV implantation at Kobe University between January 2018 and December 2019. The mean preoperative intraocular pressure (IOP) was 37.2 ± 13.8 mmHg and the glaucoma drug score was 4.2 ± 2.2. The mean IOP and glaucoma drug score at 1 year postoperatively decreased to 15.0 ± 4.6 mmHg and 1.3 ± 2.0, respectively (p < 0.001). No significant change in the corneal endothelial cell density following surgery was observed (p = 0.09); however, one patient required an additional trabeculectomy at 7 months postoperatively. No cases of tube exposure or conjunctival erosion were observed at 1 year postoperatively. These results indicated the effectiveness and safety of this technique in patients with NVG.

Синтез и антидепрессивная активность 4-алкил-5-бром-2,4-дигидро-2-(тиетан-3-ил)-1,2,4-триазол-3-онов

Реакциями 5-бром-2,4-дигидро-2-(тиетан-3-ил)-1,2,4-триазол-3-она (I) с алкилгалогенидами и диметилсульфатом синтезированы 4-алкил-5-бром-2,4-дигидро-2-(тиетан-3-ил)-1,2,4-триазол-3-оны (IIa-g), структура которых подтверждена данными ИК-, а также 1H и 13C ЯМР-спектров. Антидепрессивная активность синтезированных соединений исследована в тестах подвешивания за хвост и принудительного плавания на неинбредных мышах-самцах. При однократном внутрибрюшинном введении соединения I, IIa,c,f,g оказывали антидепрессивное действие в скрининговых тестах и не вызывали седативного и/или психостимулирующего эффекта в тесте «Открытое поле». Сопоставимый с флуоксетином антидепрессивный эффект выявлен у соединения I, которое характеризовалось низкой токсичностью (IV класс токсичности) и превосходило флуоксетин по терапевтическому индексу и выраженности антидепрессивного эффекта при курсовом введении. Расчет физико-химических свойств и токсических рисков показал, что все синтезированные соединения удовлетворяют «Правилу пяти» Липинского. Расчетный показатель «drug score» и отсутствие прогнозируемых токсических рисков у наиболее активного соединения I позволяют сделать вывод о перспективности создания на его основе новой фармацевтической субстанции c антидепрессивной активностью.

Effects of Sublingual Duster Mite Drops on Lung Function and Exhaled Nitric Oxide in Children with Multiple and Single Allergic Respiratory Diseases

Objective. To evaluate the efficiency of sublingual immunotherapy with Dermatophagoides Farinae Drops in children with single and multiple respiratory allergic diseases. Methods. Seventy-one children with allergic respiratory diseases who had been treated with Dermatophagoides Farinae Drops for one year or more were divided into a single allergic group (12 cases) and multiple allergic group (59 cases). The rhinitis score, daytime and night symptom score of asthma, VAS score, drug score, pulmonary function, and FeNO level before and after treatment were evaluated and compared between the two groups. Results. The rhinitis score, night symptom score, VAS score, and drug score in the single allergic group after treatment were significantly lower than those before treatment ( p < 0.05 ), but there was no significant difference in the daytime symptom score before and after treatment ( p > 0.05 ). The rhinitis score, VAS score, and drug score in the multiple allergic group after treatment were significantly lower than those before treatment ( p < 0.05 ), but there was no significant difference in the scores of daytime symptoms and nighttime symptoms before and after treatment ( p > 0.05 ). In both the single allergic group and multiple allergic group, the pulmonary function indexes of the patients were significantly improved after treatment, and the FeNO after treatment was significantly lower than that before treatment ( p < 0.05 ). There was no significant difference in scores, pulmonary function, and FeNO between the two groups ( p > 0.05 ). Conclusion. Sublingual specific immunotherapy is effective in treating multiple and single allergic respiratory diseases in children.

Synthesis, in vitro and in silico Studies of Naphthalene Pyrazoline Prop-2-en-1-one Derivatives

The synthesized new naphthalene pyrazoline prop-2-en-1-one derivatives (NDPP 1-8) were obtained by the Michael addition reaction of ethyl propanoate, hydrazine hydrate with NPD as a multicomponent scaffold. (E)-1-(naphthalen-3-yl)-3-phenylprop-2-en-1-one (NPD) was formed from 2-acetyl naphthalene and substituted aldehyde via Claisen-Schmidt condensation reaction. The NDPP skeleton structures were confirmed by infrared, 1H & 13C NMR spectral data and elemental analysis. The structure of NDPP compounds was subjected to molecular docking and ADME studies. The result of ADME prediction, compound NDPP 2, which contains electron withdrawing -Cl group has high drug-likeness value 4.21 than the compounds NDPP 4 and 7 which had electron donating CH3 and OCH3 group shows the drug-likeness value 2.62. The NDPP 2 also has high drug score 0.63 than NDPP 4 and NDPP 7 have drug score 0.60 and 0.69, respectively. Docking studies shows that compound NDPP 5 which also contain electron withdrawing NO2 group has good binding affinity value -8.8 Kcal/mol were docked with 1UAG protein. These compounds showed good drug-likeness value 2.25 and drug score 0.65. in vitro Studies have a high inhibition value for the same NO2 substituted derivative. All the compounds have higher binding affinity value than standards binding affinity value.

Antifungal Activity of Synthesized Benzothiazole Derivatives using Structure Activity Relationship

In the field of drug discovery the benzothiazole is found to be a magical compound. Computational tools were used to predict their molecular property, drug likeness, overall drug score and toxicity risks which are essential parameter for a chemical to be qualified as a drug. As good results were observed by computational tools then novel series of 2-amino-6-substituted benzothiazoles with halo ketone have been synthesized by conventional method. All the synthesized compounds have been characterized by elemental analysis and IR, 1H NMR data in full accordance with their expected (depicted) structures. The synthesized compounds were screened for their antifungal activity using standard drug ampicillin.