Drug resistance patterns of Mycobacterium tuberculosis complex and risk factors associated with multidrug-resistant tuberculosis in the upper southern part of Thailand

Background: this study aimed to assess the drug resistant pattern of Mycobacterium tuberculosis complex (MTBC) and the risk factors associated to multidrug-resistant tuberculosis cases (MDR-TB) in upper part of southern Thailand.  Methods: a total of 3238 TB cases was retrieved from a database of the office of prevention and control disease region 11. Only 1008 cases were confirmed by culture growth for Mycobacterium tuberculosis and drug-susceptibility testing (DST) during a period of 4 years (January 2013 to December 2016). The risk factors, including gender, age group, residence place, and history of treatment were analysed using multivariate logistic regression to predict the MDR-TB cases.  Results: among 1008 TB cases included in study, 77.4% of them were males, 31.5% lived in rural area with median age of 45.0 years (IQR = 23.0), 27.6% were retreatment for tuberculosis, 25.9%, 10.8%, 3.0%, 10.7% and 9.1 were determined to be resistant to isoniazid, rifampicin, ethambutol, streptomycin and MDR-TB, respectively. Adjusted odds ratios (95% confidence interval) of MDR-TB were 5.4 (2.68-11.03), and 4.2 (2.10, 8.45) for retreatment patients, and on treatment patients, respectively.  Conclusions: drug resistance tuberculosis is considerable problem in upper part of southern Thailand. Major risk factors involved previous history of TB treatment. Thus, it emphasizes on patients who had a history of previous TB treatment.&nbsp

Intramolecular substitutions of secondary and tertiary alcohols with chirality transfer by an iron (III) catalyst

Optically pure alcohols are abundant in nature and attractive as feedstock for organic synthesis but challenging for further transformation using atom efficient and sustainable methodologies, particularly when there is a desire to conserve the chirality. Usually, substitution of the OH group of stereogenic alcohols with conservation of chirality requires derivatization as part of a complex, stoichiometric procedure. We herein demonstrate that a simple, inexpensive, and environmentally benign iron(III) catalyst promotes the direct intramolecular substitution of enantiomerically enriched secondary and tertiary alcohols with O-, N-, and S-centered nucleophiles to generate valuable 5-membered, 6-membered and aryl-fused 6-membered heterocyclic compounds with chirality transfer and water as the only byproduct. The power of the methodology is demonstrated in the total synthesis of (+)-lentiginosine from D-glucose where iron-catalysis is used in a key step. Adoption of this methodology will contribute towards the transition to sustainable and bio-based processes in the pharmaceutical and agrochemical industries.Peer reviewe

Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols

This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems. The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate unsymmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields. The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioenriched alcohols by Lewis acid and Brønsted acid/base catalysis. In Chapter 3, the direct intramolecular substitution of non-derivatized alcohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N-centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the substrate. Competition and catalyst-substrate interaction experiments demonstrated that this transformation proceeds via an SN2-type reaction pathway. In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phosphinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.</p