The 4-aza-S-ribosyl-L-homocysteine derivatives and the related gamma-lactam and azahemiacetal analogs: Synthesis, inhibition and quorum sensing activity

Quorum sensing (QS) is a population-dependent signaling process bacteria use to control multiple processes including virulence, critical for establishing infection. There are two major pathways of QS systems. Type 1 is species specific or intra-species communication in which N-acylhomoserine lactones (Gram-negative bacteria) or oligopeptides (Gram-positive bacteria) are employed as signaling molecules (autoinducer one). Type 2 is inter-species communication in which S-4,5-dihydroxy-2,3-pentanedione (DPD) or its borate esters are used as signaling molecules. The DPD is biosynthesized by LuxS enzyme from S-ribosylhomocysteine (SRH). Recent increase in prevalence of bacterial strains resistant to antibiotics emphasizes the need for the development of new generation of antibacterial agents. Interruption of QS by small molecules is one of the viable options as it does not affect bacterial growth but only virulence, leading to less incidence of microbial resistance. Thus, in this work, inhibitors of both N-acylhomoserine lactone (AHL) mediated intra-species and LuxS enzyme, involved in inter-species QS are targeted. The γ-lactam and their reduced cyclic azahemiacetal analogs, bearing the additional alkylthiomethyl substituent, were designed and synthesized targeting AHL mediated QS systems in P. aeruginosa and Vibrio harveyi. The γ-lactams with nonylthio or dodecylthio chains acted as inhibitors of las signaling in P. aeruginosa with moderate potency. The cyclic azahemiacetal with shorter propylthio or hexylthio substituent were found to strongly inhibit both las and rhl signaling in P. aeruginosa at higher concentrations. However, lactam and their azahemiacetal analogs were found to be inactive in V. harveyi QS systems. The 4-aza-S-ribosyl-L-homocysteine (4-aza-SRH) analogs and 2-deoxy-2-substituted-S-ribosyl-L-homocysteine analogs were designed and synthesized targeting Bacillus subtilis LuxS enzyme. The 4-aza-SRH analogs in which oxygen in ribose ring is replaced by nitrogen were further modified at anomeric position to produce pyrrolidine, lactam, nitrone, imine and hemiaminal analogs. Pyrrolidine and lactam analogs which lack anomeric hydroxyl, acted as competitive inhibitors of LuxS enzyme with KI value of 49 and 37 µM respectively. The 2,3-dideoxy lactam analogs were devoid of activity. Such findings attested the significance of hydroxyl groups for LuxS binding and activity. Hemiaminal analog of SRH was found to be a time-dependent inhibitor with IC50 value of 60 µM.

The influence of neighbourhood formality status and socio-economic position on self-rated health among adult men and women: a multilevel, cross sectional, population study from Aleppo, Syria

Background There is substantial evidence from high income countries that neighbourhoods have an influence on health independent of individual characteristics. However, neighbourhood characteristics are rarely taken into account in the analysis of urban health studies from developing countries. Informal urban neighbourhoods are home to about half of the population in Aleppo, the second largest city in Syria (population>2.5 million). This study aimed to examine the influence of neighbourhood socioeconomic status (SES) and formality status on self-rated health (SRH) of adult men and women residing in formal and informal urban neighbourhoods in Aleppo. Methods The study used data from 2038 survey respondents to the Aleppo Household Survey, 2004 (age 18–65 years, 54.8% women, response rate 86%). Respondents were nested in 45 neighbourhoods. Five individual-level SES measures, namely education, employment, car ownership, item ownership and household density, were aggregated to the level of neighbourhood. Multilevel regression models were used to investigate associations. Results We did not find evidence of important SRH variation between neighbourhoods. Neighbourhood average of household item ownership was associated with a greater likelihood of reporting excellent SRH in women; odds ratio (OR) for an increase of one item on average was 2.3 (95% CI 1.3-4.4 (versus poor SRH)) and 1.7 (95% CI 1.1-2.5 (versus normal SRH)), adjusted for individual characteristics and neighbourhood formality. After controlling for individual and neighbourhood SES measures, women living in informal neighbourhoods were less likely to report poor SRH than women living in formal neighbourhoods (OR= 0.4; 95% CI (0.2- 0.8) (versus poor SRH) and OR=0.5; 95%; CI (0.3-0.9) (versus normal SRH). Conclusions Findings support evidence from high income countries that certain characteristic of neighbourhoods affect men and women in different ways. Further research from similar urban settings in developing countries is needed to understand the mechanisms by which informal neighbourhoods influence women’s health.

Design and synthesis of S-ribosylhomocysteine analogues

Bacteria are known to release a large variety of small molecules known as autoinducers (AI) which effect quorum sensing (QS) initiation. The interruption of QS effects bacterial communication, growth and virulence. ^ Three novel classes of S-ribosylhomocysteine (SRH) analogues as potential inhibitors of S-ribosylhomocysteinase (LuxS enzyme) and AI-2 modulators of QS were developed. The synthesis of 2-deoxy-2-bromo-SRH analogues was attempted by coupling of the corresponding 2-bromo-2-deoxypentafuranosyl precursors with the homocysteinate anion. The displacement of the bromide from C2 rather than the expected substitution of the mesylate from C5 was observed. The synthesis of 4-C-alkyl/aryl-S-ribosylhomocysteine analogues involved the following steps: (i) conversion of the D-ribose to the ribitol-4-ulose; (ii) diastereoselective addition of various alkyl or aryl or vinyl Grignard reagents to 4-ketone intermediate; (iii) oxidation of the primary hydroxyl group at C1 followed by the intramolecular ring closure to the corresponding 4-C-alkyl/aryl-substituted ribono-1,4-lactones; (iv) displacement of the activated 5-hydroxyl group with the protected homocysteinate. Treatment of the 4-C-alkyl/aryl-substituted SRH analogues with lithium triethylborohydride effected reduction of the ribonolactone to the ribose (hemiacetal) and subsequent global deprotection with trifluoroacetic acid provided 4-C-alkyl/aryl-SRHs. ^ The 4-[thia]-SRH were prepared from the 1-deoxy-4-thioribose through the coupling of the &agr;-fluoro thioethers (thioribosyl fluorides) with homocysteinate anion. The 4-[thia]-SRH analogues showed concentration dependent effect on the growth on las (50% inhibitory effect at 200 µg/mL). The most active was 1-deoxy-4-[thia]-SRH analogue with sufur atom in the ring oxidized to sulfoxide decreasing las gene activity to approximately 35% without affecting rhl gene. Neither of the tested compounds had effect on bioluminescence nor on total growth of V. harveyi, but had however slight inhibition of the QS.^

Lifestyle Behaviors and Self-Rated Health: The Living for Health Program

Background. Lack of adherence to dietary and physical activity guidelines has been linked to an increase in chronic diseases in the United States (US). The aim of this study was to assess the association of lifestyle behaviors with self-rated health (SRH). Methods. This cross-sectional study used self-reported data from Living for Health Program ( 1,701) which was conducted from 2008 to 2012 in 190 health fair events in South Florida, US. Results. Significantly higher percent of females as compared to males were classified as obese (35.4% versus 27.0%), reported poor/fair SRH (23.4% versus 15.0%), and were less physically active (33.9% versus 25.4%). Adjusted logistic regression models indicated that both females and males were more likely to report poor/fair SRH if they consumed 2 servings of fruits and vegetables per day (, 95% CI 1.30–3.54; , 95% CI 1.12–7.35, resp.) and consumed mostly high fat foods (, 95% CI 1.03–2.43; , 95% CI 1.67–2.43, resp.). The association of SRH with less physical activity was only significant in females (, 95% CI 1.17–2.35). Conclusion. Gender differences in health behaviors should be considered in designing and monitoring lifestyle interventions to prevent cardiovascular diseases.

Perceived Stress and Self‑rated Health of Haitian and African Americans with and without Type 2 Diabetes

Background: Blacks have a higher incidence of diabetes and its related complications. Self-rated health (SRH) and perceived stress indicators are associated with chronic diseases. The aim of this study was to examine the associations between SRH, perceived stress and diabetes status among two Black ethnicities. Materials and Methods: The cross-sectional study included 258 Haitian Americans and 249 African Americans with (n = 240) and without type 2 diabetes (n = 267) (N = 507). Recruitment was performed by community outreach. Results: Haitian-Americans were less likely to report ‘fair to poor’ health as compared to African Americans [OR=0.58 (95% CI: 0.35, 0.95), P = 0.032]; yet, Haitian Americans had greater perceived stress than African Americans (P = 0.002). Having diabetes was associated with ‘fair to poor’ SRH [OR=3.14 (95% CI: 2.09, 4.72),P < 0.001] but not perceived stress (P = 0.072). Haitian-Americans (P = 0.023), females (P = 0.003) and those participants having ‘poor or fair’ SRH (P < 0.001) were positively associated with perceived stress (Nagelkerke R2=0.151). Conclusion: Perceived stress associated with ‘poor or fair’ SRH suggests that screening for perceived stress should be considered part of routine medical care; albeit, further studies are required to confirm our results. The findings support the need for treatment plans that are patient-centered and culturally relevant and that address psychosocial issues.