Synthesis, Antimicrobial Activities of New Sulfonamidobenzoxazoles and Molecular Docking Studies on Escherichia coli TEM-1 β-Lactamase

β-Lactam antibiotics are frequently used for treatment of multi-drug resistant microbial infections and the most common mechanism of resistance against these antibiotics is bacterial β-lactamase production. Herein, we reported the design, synthesis and in vitro antimicrobial activities of some new 2-substituted-5-(2,4-dinitrophenylsulfonamido)benzoxazole derivatives. Compounds TN1, TN2, and TN3 were found to be significantly active against E. coli isolate which contains extended spectrum β-lactamase enzyme at the MIC value of 8 µg mL–1 and that is 4-fold higher than the reference drug ampicillin. We performed molecular docking studies into active site of Escherichia coli TEM-1 β-lactamase enzyme in order to predict the protein-ligand interactions. According to the docking results, compounds TN1, TN2, and TN3 showed strong interactions between the important active site residues which are responsible for the catalytic mechanism of TEM-1 β-lactamase enzyme and a good correlation is found with the experimental data. This work is licensed under a Creative Commons Attribution 4.0 International License

Synthesis and In vitro Antimicrobial Activity of Novel 2-(4-(Substituted-carboxamido)benzyl / phenyl)benzothiazoles

A new series of 2-[4-(4-substitutedbenzamido / phenylacetamido / phenylpropionamido) benzyl / phenyl]benzothiazole derivatives (6a−6w) were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli with their drug-resistant isolates and a yeast Candida albicans. Microbiological results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 200 and 6.25 μg/ml. Compounds 6e and 6j exhibited the greatest activity with MIC values of 6.25 μg/ml against Pseudomonas aeruginosa, and Staphylococcus aureus isolate, respectively.(doi: 10.5562/cca2064

Benzothiazole derivatives as human DNA topoisomerase IIα inhibitors

Abstract Benzothiazole derivatives resembling the structure of DNA purine bases were tested to determine their topoisomerase inhibition activities. Based on DNA topoisomerase I and II relaxation assay results, all 12 derivatives acted as human topoisomerase IIa inhibitors, whereas only two compounds inhibited Calf thymus topoisomerase I. 3-amino-2-(2-bromobenzyl)-1,3-benzothiazol-3-ium 4-methylbenzensulfonate (BM3) was observed to be the most effective human topoisomerase IIa inhibitor with the lowest IC 50 value of 39 nM. The mechanistic studies suggested that BM3 was neither a DNA intercalator nor a topoisomerase poison, it was only a DNA minor groovebinding agent. BM3 initially bound to the DNA topoisomerase IIa enzyme, then to DNA. As a result, the tested benzothiazole derivatives were obtained as strong topoisomerase IIa inhibitors. The benzothiazole tosylated salt form BM3 was found as the most effective topoisomerase IIa inhibitor. BM3's mechanisms of action might be its direct interaction with the enzyme. BM3's minor groove-binding property might also contribute to this action. Hence, BM3 could be a good candidate as a new anticancer agent

Digital Health Technologies to Improve Medication Adherence and Treatment Outcomes in Patients With Tuberculosis:Systematic Review of Randomized Controlled Trials

BACKGROUND: Nonadherence to medication in tuberculosis (TB) hampers optimal treatment outcomes. Digital health technology (DHT) seems to be a promising approach to managing problems of nonadherence to medication and improving treatment outcomes. OBJECTIVE: This paper systematically reviews the effect of DHT in improving medication adherence and treatment outcomes in patients with TB. METHODS: A literature search in PubMed and Cochrane databases was conducted. Randomized controlled trials (RCTs) that analyzed the effect of DHT interventions on medication adherence outcomes (treatment completion, treatment adherence, missed doses, and noncompleted rate) and treatment outcomes (cure rate and smear conversion) were included. Adult patients with either active or latent TB infection were included. The Jadad score was used for evaluating the study quality. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline was followed to report study findings. RESULTS: In all, 16 RCTs were selected from 552 studies found, and 6 types of DHT interventions for TB were identified: 3 RCTs examined video directly observed therapy (VDOT), 1 examined video-observed therapy (VOT), 1 examined an ingestible sensor, 1 examined phone call reminders, 2 examined medication monitor boxes, and 8 examined SMS text message reminders. The outcomes used were treatment adherence, including treatment completion, treatment adherence, missed dose, and noncompleted rate, as well as clinical outcomes, including cure rate and smear conversion. In treatment completion, 4 RCTs (VDOT, VOT, ingestible sensor, SMS reminder) found significant effects, with odds ratios and relative risks (RRs) ranging from 1.10 to 7.69. Treatment adherence was increased in 1 study by SMS reminders (RR 1.05; 95% CI 1.04-1.06), and missed dose was reduced in 1 study by a medication monitor box (mean ratio 0.58; 95% CI 0.42-0.79). In contrast, 3 RCTs of VDOT and 3 RCTs of SMS reminders did not find significant effects for treatment completion. Moreover, no improvement was found in treatment adherence in 1 RCT of VDOT, missed dose in 1 RCT of SMS reminder, and noncompleted rate in 1 RCT of a monitor box, and 2 RCTs of SMS reminders. For clinical outcomes such as cure rate, 2 RCTs reported that phone calls (RR 1.30; 95% CI 1.07-1.59) and SMS reminders (OR 2.47; 95% CI 1.13-5.43) significantly affected cure rates. However, 3 RCTs found that SMS reminders did not have a significant impact on cure rate or smear conversion. CONCLUSIONS: It was found that DHT interventions can be a promising approach. However, the interventions exhibited variable effects regarding effect direction and the extent of improving TB medication adherence and clinical outcomes. Developing DHT interventions with personalized feedback is required to have a consistent and beneficial effect on medication adherence and outcomes among patients with TB

The 12(th) AFMC International Medicinal Chemistry Symposium (AIMECS 2019) in Istanbul, Turkey

AFMC-AIMECS meetings are internationally organized biannually by the Asian Federation for Medicinal Chemistry (AFMC) and are focused on recent studies in drug discovery and development both in academia and industry. Member organizations of the AFMC are the Pharmaceutical Society of Japan, the Chinese Pharmaceutical Association, the Royal Australian Chemical Institute, the Pharmaceutical Society of Korea, the Korean Chemical Society, the Chemical Society Located in Taipei, the Indonesian Society of Medicinal Chemistry, the Medicinal Chemistry Section of the Israel Chemical Society, and the Computer-Aided Drug Design \& Development Society in Turkey. Each time, the symposium is organized within these member countries. The AIMECS 2019 symposium was held in Turkey this year, as Prof. Dr. Esin Aki-Yalcin is the current president of the AFMC (2018-2020); the next AIMECS meeting will be organized in 2021 in Tokyo, Japan. In this report, we discuss key topics at the 12(th) AFMC International Medicinal Chemistry Symposium - New Avenues for Design and Development of Translational Medicine (AIMECS 2019) held in Istanbul, September 8-11, 2019

Benzoxazines as new human topoisomerase I inhibitors and potential poisons

Background The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. Objectives In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. Methods We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. Results While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC50:8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC50:0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC50:0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R-2 position were play a role for increasing of its poisonous effect. Conclusion As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs

Synthesis of novel 2-[4-(4-substitutedbenzamido/phenylacetamido) phenyl]benzothiazoles as antimicrobial agents

Abstract A new series of 2-[4-(4-substitutedbenzamido/ phenylacetamido)phenyl] benzothiazole derivatives (6a-k) were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli with their drug-resistant isolates and a yeast Candida albicans. Microbiological results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms at minimum inhibitory concentration (MIC) values between 100 and 6.25 lg/ml. Compounds 6d and 6k exhibited significant antibacterial activity showing 6.25 lg/ml MIC values against drugresistant S. aureus and P. aeruginosa isolates, respectively

Synthesis and antimicrobial activity of some novel 2,6,7-trisubstituted-2<i>H</i>-3,4- dihydro-1 ,4-benzoxazin-3-one derivatives

905-909The synthesis of a new series of 2H-3,4-dihydro-1,4-benzoxazin-3-one derivatives 1-8 is accomplished in order to determine their antimicrobial activities and study their structure-ac tivity relationships (SAR). The synthesized compounds have been tested in vitro against two Gram-positive, three Gram-negative bacteria and the fungus Candida albicans. The in vitro activity results show that the synthesized compounds exibit MIC values between 50- 12.5 μg/mL for the antimicrobial activity against the tested microorganisms. The antibacterial and antifungal activities or the compounds 1-8 are also compared to several standard drugs

Synthesis, biological evaluation and 2D-QSAR analysis of benzoxazoles as antimicrobial agents

Abstract A new series of 5(or 6)-nitro/amino-2-(substituted phenyl/benzyl)benzoxazole derivatives (1ae1m, 2ae2l) were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and their drug-resistant isolate. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between &gt;400 and 12.5 mg/ml. The results against B. subtilis, P. aeruginosa, drug-resistant B. subtilis, drug-resistant E. coli, and C. albicans isolate for these kinds of structures are quite encouraging. The 2D-QSAR analysis of a set of newly and previously synthesized benzoxazoles tested for growth inhibitory activity against B. subtilis ATCC 6633 was performed by using the multivariable regression analysis. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization