Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

Radical Releasing Anti-Tuberculosis Agents and the Treatment of Mycobacterial Tuberculosis Infections – An Overview

: The treatment and management of tuberculosis (TB) is a major global concern. Approved drugs for the treatment of TB to date displayed various modes of action which can be grouped into radical releasing and non-radical releasing anti TB agents. Radical releasing agents are of special interest because they diffuse directly into the mycobacterium cell wall, interact with the host cell DNA causing DNA strand breakages and fatal destabilization of the DNA helix inhibiting nucleic acid synthase. As a therapeutic agent with aforementioned activity, nitroimidazoles and most especially bicyclic nitroimidazoles are currently in clinical use for the treatment of tuberculosis. However, the approved drugs, pretomanid (PR) and delamanid (DE) are limited in their nitric oxide radical (NO•) releasing abilities to cause effective bactericidity. It is believed that their bactericidal activity can be improved by harnessing alternative strategies to increase NO• release. The last decade has witness the strategic inclusion of NO-donors into native drugs to improve their activities and/or reverse resistance. The rationale behind this strategy is the targeting of NO• release at specific therapeutic sites. This review therefore aims to highlight various radical releasing agents that may be effective in the treatment of TB. The review also investigates various structural modification to PR and DE and suggests alternative strategies to improve NO• release as well as some applications where NO-donor hybrid drugs have been used with good therapeutic effect.

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach.

Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment

Background: Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. Methods: We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. Results: Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors’ role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. Conclusion: These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.

Hybrid Molecules Development: A Versatile Landscape for the Control of Antifungal Drug Resistance: A Review

Hybrid molecule approach of drug design has become popular due to advantages such as delayed resistance, reduced toxicity, ease of treatment of co-infection and lower cost of preclinical evaluation. Antifungal drugs currently available for the treatment of fungal diseases suffer a major side effect of drug resistance. Hybrid drugs development is one of the approaches that has been employed to control microbial resistance. Their antifungal activity is influenced by their design. This review is focused on hybrid molecules exhibiting antifungal properties to guide scientists in search of more efficient drugs for the treatment of fungal diseases.