Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities

Funding Information: We acknowledge Diogo Vila Vi?osa for valuable discussions. We acknowledge financial support from Funda??o para a Ci?ncia e a Tecnologia, Portugal through projects PTDC/MED-QUI/29036/2017, PTDC/BIA-MIC-30692/2017, UIDB/00100/2020, UIDP/00100/2020, UIDB/04046/2020, UIDP/04046/2020, and UID/Multi/04413/2020, and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017. Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation, USA (MCB 1616059). Funding Information: We acknowledge Diogo Vila Viçosa for valuable discussions. We acknowledge financial support from Fundação para a Ciência e a Tecnologia , Portugal through projects PTDC/MED-QUI/29036/2017 , PTDC/BIA-MIC-30692/2017 , UIDB/00100/2020 , UIDP/00100/2020 , UIDB/04046/2020 , UIDP/04046/2020 , and UID/Multi/04413/2020 , and Grants CEECIND/02300/2017 and DL57/CEECIND/0256/2017 . Contributions from JRK, CMB, and DCG supported in part by a grant from the National Science Foundation , USA ( MCB 1616059 ). Publisher Copyright: © 2021 The AuthorsIsoniazid (INH) is one of the two most effective first-line antitubercular drugs and is still used at the present time as a scaffold for developing new compounds to fight TB. In a previous study, we have observed that an INH derivative, an hydrazide N′-substituted with a C10acyl chain, was able to counterbalance its smaller reactivity with a higher membrane permeability. This resulted in an improved performance against the most prevalent Mycobacterium tuberculosis (Mtb) resistant strain (S315T), compared to INH. In this work, we have designed two new series of INH derivatives (alkyl hydrazides and hydrazones) with promising in silico properties, namely membrane permeabilities and spontaneous IN* radical formation. The kinetics, cytotoxicity, and biological activity evaluations confirmed the in silico predictions regarding the very high reactivity of the alkyl hydrazides. The hydrazones, on the other hand, showed very similar behavior compared to INH, particularly in biological tests that take longer to complete, indicating that these compounds are being hydrolyzed back to INH. Despite their improved membrane permeabilities, the reactivities of these two series are too high, impairing their overall performance. Nevertheless, the systematic data gathered about these compounds have showed us the need to find a balance between lipophilicity and reactivity, which is paramount to devise better INH-based derivatives aimed at circumventing Mtb resistance.publishersversionpublishe

In vitro Evaluation of Isoniazid Derivatives as Potential Agents Against Drug-Resistant Tuberculosis

Funding Information: Financed by Fundação para a Ciência e a Tecnologia, I.P./MCTES through national funds (PIDDAC, PT2020) under projects PTDC/MED-QUI/29036/2017, PTDC/BIA-MIC-30692/2017, EXPL/BIA-BFS/1034/2021, UIDB/00100/2020, UIDP/00100/2020, LA/P/0056/2020, UID/Multi/04413/2020, CEECIND/03247/2018 and DL57/CEECIND/0256/2017. Publisher Copyright: Copyright © 2022 Marquês, Frazão De Faria, Reis, Machado, Santos, Santos, Viveiros, Martins and De Almeida.The upsurge of multidrug-resistant tuberculosis has toughened the challenge to put an end to this epidemic by 2030. In 2020 the number of deaths attributed to tuberculosis increased as compared to 2019 and newly identified multidrug-resistant tuberculosis cases have been stably close to 3%. Such a context stimulated the search for new and more efficient antitubercular compounds, which culminated in the QSAR-oriented design and synthesis of a series of isoniazid derivatives active against Mycobacterium tuberculosis. From these, some prospective isonicotinoyl hydrazones and isonicotinoyl hydrazides are studied in this work. To evaluate if the chemical derivatizations are generating compounds with a good performance concerning several in vitro assays, their cytotoxicity against human liver HepG2 cells was determined and their ability to bind human serum albumin was thoroughly investigated. For the two new derivatives presented in this study, we also determined their lipophilicity and activity against both the wild type and an isoniazid-resistant strain of Mycobacterium tuberculosis carrying the most prevalent mutation on the katG gene, S315T. All compounds were less cytotoxic than many drugs in clinical use with IC50 values after a 72 h challenge always higher than 25 µM. Additionally, all isoniazid derivatives studied exhibited stronger binding to human serum albumin than isoniazid itself, with dissociation constants in the order of 10−4–10−5 M as opposed to 10−3 M, respectively. This suggests that their transport and half-life in the blood stream are likely improved when compared to the parent compound. Furthermore, our results are a strong indication that the N′ = C bond of the hydrazone derivatives of INH tested is essential for their enhanced activity against the mutant strain of M. tuberculosis in comparison to both their reduced counterparts and INH.publishersversionpublishe