Abstract
Tuberculosis causes more than 1.2 million deaths each year. Worldwide, it is the first cause of death by a single infectious agent. The emergence of drug-resistant strains has limited pharmacological treatment of the disease and today, new drugs are urgently needed. Semi-synthetic mulinanes have previously shown important activity against multidrug-resistant (MDR) Mycobacterium tuberculosis. In this investigation, a new set of semi-synthetic mulinanes were synthetized, characterized, and evaluated for their in vitro activity against three drug-resistant clinical isolates of M. tuberculosis: MDR, pre-extensively Drug-Resistant (pre-XDR), and extensively Drug-Resistant (XDR), and against the drug-susceptible laboratory reference strain H37Rv. Derivative 1a showed the best anti-TB activity (minimum inhibitory concentration [MIC] = 5.4 µM) against the susceptible strain and was twice as potent (MIC = 2.7 µM) on the MDR, pre-XDR, and XDR strains and also possessed a bactericidal effect. Derivative 1a was also tested for its anti-TB activity in mice infected with the MDR strain. In this case, 1a produced a significant reduction of pulmonary bacilli loads, six times lower than the control, when tested at 0.2536 mg/Kg. In addition, 1a demonstrated an adjuvant effect by shortening second-line chemotherapy. Finally, the selectivity index of >15.64 shown by 1a when tested on Vero cells makes this derivative an important candidate for future studies in the development of novel antitubercular agents.
Highlights
Introduction conditions of the Creative CommonsTuberculosis (TB) is a communicable disease caused by the Mycobacterium tuberculosis complex that is a major cause of illness
The chemical structure of the semi-synthetic mulinanes was confirmed by their 1 H13 and C-NMR, IR, and MS data
The complete set of natural and semi-synthetic mulinanes were tested in vitro for anti-TB and cytotoxic activity, and the most active semi-synthetic mulinane was further evaluated in an anti-TB murine model
Summary
Introduction conditions of the Creative CommonsTuberculosis (TB) is a communicable disease caused by the Mycobacterium tuberculosis complex that is a major cause of illness. Estimated 10 million people fell ill with TB worldwide and there were 1.2 million TB deaths among HIV-negative individuals, with the addition of 208,000 deaths among HIV-positive patients [1]. M. tuberculosis, including multidrug-resistant (MDR; mycobacteria resistant to the firstline anti-TB pharmaceuticals Isoniazid and Rifampicin), pre-eXtensively Drug-Resistant (pre-XDR; MDR strains, which are resistant to any fluoroquinolone), and eXtensively. Drug-Resistant (XDR; MDR and that are resistant to any fluoroquinolone and at least one drug from Group A (that includes some of the most potent pharmaceuticals for the treatment of drug-resistant forms of TB, e.g., Levofloxacin, Moxifloxacin, Bedaquiline, and Linezolid) [2,3]. Drug-resistant TB continues to be a public health threat, with nearly half a million patients developing Rifampicin resistance, and with 78% of these individuals showing MDR-TB [1]. By the end of 2018, at least one case of XDR-TB was reported by each of the 131 World Health Organization (WHO) Member States, and data suggest that about 6.2% of MDR-TB cases worldwide have XDR-TB [4]
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