Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs).

AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.

Hydroxytriazenes incorporating sulphonamide derivatives: evaluation of antidiabetic, antioxidant, anti-inflammatory activities, and computational study.

The existent investigation deals with synthesis, characterization, computational analysis, and biological activities of some hydroxytriazene derivatives containing sulphonamide moiety. The compounds were screened for antidiabetic, antioxidant, and anti-inflammatory activities. The antidiabetic activity was assessed using α-glucosidase and α-amylase inhibition assays with IC50 values ranging from 32.0 to 759.13 µg/mL and 157.77 to 340.47 µg/mL while standard drug acarbose showed IC50 values 12.21 and 69.74 µg/mL, respectively. The antioxidant activity was evaluated using DPPH and ABTS radical scavenging assays with IC50 value ranging from 54.01 to 912.66 µg/mL and 33.22 to 128.11 µg/mL, and standard drug ascorbic acid showed IC50 values 29.12 µg/mL and 69.13 µg/mL, respectively. Anti-inflammatory activity was investigated using the carrageenan-induced paw edema method, where percentage inhibition was up to 93.0 and 98.57 for 2 h and 4 h, respectively, and all the compounds were found to exhibit excellent anti-inflammatory activity. Moreover, prediction of activity spectra for substance and molecular docking were also performed. The PASS prediction hypothesized the potential of the compounds for anti-inflammatory activity, and docking results suggested the best binding pose for compounds 1b and 2b with the least energy value from which compounds can be considered as potent COX-2 inhibitors. Furthermore, possible interactions between hydroxytriazene analogues and the targets of antioxidant NADPH oxidase and antidiabetic human maltase-glucoamylase enzyme have been identified. The HOMO and LUMO analysis revealed charge transfer within the compounds. These findings suggested that the synthesized compounds can be potential agents for the treatment of diabetes and inflammation.

Repurposing drugs targeting epidemic viruses.

For emerging and re-emerging epidemic infections, researchers face challenges to develop broad-spectrum antivirals as well as reducing development time and costs, and drug resistance. Drug repurposing is a reliable strategy for rapidly discovering potent new antiviral agents, reducing the need for clinical trials. In this review, we outline antiviral drug candidates identified using the drug repurposing approach, with their potential modes of action and biological responses against various epidemic viral infectious diseases.

Novel naphthyl based 1,2,4-trioxanes: Synthesis and in vivo efficacy in the Plasmodium yoelii nigeriensis in Swiss mice.

A new series of 1,2,4-trioxanes 9a1-a4, 9b1-b4, 10-13 and 9c1-c4 were synthesized and evaluated against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral and intramuscular (i.m.) routes. Adamantane-based trioxane 9b4, the most active compound of the series, provided 100% protection to the infected mice at the dose 48 mg/kg × 4 days and 100% clearance of parasitemia at the dose 24 mg/kg × 4 days via oral route. Adamantane-based trioxane 9b4, is twice active than artemisinin. We have also studied the photooxygenation behaviour of allylic alcohols 6a-b (3-(4-alkoxynaphthyl)-but-2-ene-1-ols) and 6c (3-[4-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-but-2-en-1-ol). Being behaving as dienes, they furnished corresponding endoperoxides, while behaving as allylic alcohols, they yielded ß-hydroxyhydroperoxides. All the endoperoxides (7a-c) and ß-hydroxyhydroperoxides (8a-c) have been separately elaborated to the corresponding 1,2,4-trioxanes, except from endoperoxide 7c. It is worthy to note that TBDMS protected naphthoyl endoperoxide 7c unable to deliver 1,2,4-trioxane, which demonstrated the strength of the O-Si bond is not easy to cleave under acidic condition.

Structural Insights to Human Immunodeficiency Virus (HIV-1) Targets and Their Inhibition.

Human immunodeficiency virus (HIV) is a deadly virus that attacks the body's immune system, subsequently leading to AIDS (acquired immunodeficiency syndrome) and ultimately death. Currently, there is no vaccine or effective cure for this infection; however, antiretrovirals that act at various phases of the virus life cycle have been useful to control the viral load in patients. One of the major problems with antiretroviral therapies involves drug resistance. The three-dimensional structure from crystallography studies are instrumental in understanding the structural basis of drug binding to various targets. This chapter provides key insights into different targets and drugs used in the treatment from a structural perspective. Specifically, an insight into the binding characteristics of drugs at the active and allosteric sites of different targets and the importance of targeting allosteric sites for design of new-generation antiretrovirals to overcome complex and resistant forms of the virus has been reviewed.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): a brief overview of clinically approved drugs and combination regimens.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of HIV-1 reverse transcriptase and are classified into generations depending on their discovery and resistance profiles. The NNRTIs are used in combination regimens with antiretroviral agents that target two or more enzymes in the viral life cycle. The combination regimens usually include a backbone of two nucleoside or nucleotide reverse transcriptase inhibitors and a third core agent among the NNRTIs or protease inhibitors. The combination regimens are maintained over long durations and consequently lead to long-term problems, including toxicity, drug-drug interactions, and increasing costs. This brief overview summarizes the pharmacokinetic profiles for NNRTIs and NNRTI-based combination regimens.

Synthesis of sulpha drug based hydroxytriazene derivatives: Anti-diabetic, antioxidant, anti-inflammatory activity and their molecular docking studies.

Herein, we report synthesis, characterization, anti-diabetic, anti-inflammatory and anti-oxidant activities of hydroxytriazenes derived from sulpha drugs, namely sulphanilamide, sulphadiazine, sulphapyridine and sulphamethazine. Before biological screening of the compounds, theoretical prediction using PASS was done which indicates probable activities ranging from Pa (probable activity) values 65-98% for anti-inflammatory activity. As per the predication, experimental validation of some of the predicted activities particularly anti-diabetic, anti-inflammatory and anti-oxidant was done. Anti-diabetic activities have been screened using two methods namely α-amylase and α-glucosidase inhibition method and IC50 values were ranging from 66 to 260 and 148 to 401 µg/mL, while for standard drug acarbose the values were 12 µg/mL and 70 µg/mL, respectively. Docking studies have also been done for antidiabetic target pancreatic alpha amylase. The molecular docking studies in α-amylase enzyme reveal that the middle phenyl ring of all the compounds mainly occupies in the small hydrophobic pocket formed by the Ala198, Trp58, Leu162, Leu165 and Ile235 residues and sulphonamide moiety establish H-bond interaction by two water molecules. Further, anti-inflammatory activity has been evaluated using carrageenan induced paw-edema method and results indicate excellent anti-inflammatory activity by hydroxytriazenes (71 to 97%) and standard drug diclofenac 94% after 4 h of treatment. Moreover, antioxidant effect of the compounds was tested using DPPH and ABTS methods. All the compounds displayed good results (24-488 µg/mL) against ABTS radical and many compounds are more active than ascorbic acid (69 µg/mL) while all other compounds showed moderate activity against DPPH radical (292-774 µg/mL) and ascorbic acid (29 µg/mL). Thus, the studies reveal potential of sulfa drug based hydroxytriazenes as candidates for antidiabetic, anti-inflammatory and antioxidant activities which have been experimentally validated.

Catalyst- and Solvent-Free Coupling of 2-Methyl Quinazolinones and Isatins: An Environmentally Benign Access of Diastereoselective Schizocommunin Analogues.

An environmentally benign highly atom-economic protocol for the construction of the C-C bond has been developed under catalyst- and solvent-free conditions. This protocol involves the efficient coupling of 2-methyl quinazolinones with isatin for the highly diastereoselective access of schizocommunin derivatives in excellent yields (up to 97%). Furthermore, the preliminary cytotoxicity screening of selected schizocommunin analogues displayed promising anticancer activity against human cancer cell lines, and the cytotoxic potential of active compound 12ac was also validated by in silico molecular docking simulation studies.

The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic.

Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clinical requirements for drugs.

HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: SAR and Lead Optimization Using CoMFA and CoMSIA Studies (1995-2016).

BACKGROUND: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising and clinically approved drugs. However, the efficiency of many of these drugs has been reduced by the drug-resistant variants of HIV-1 RT. The aim of the current review is to provide a summary of lead optimization strategies from the 3D-QSARs studies on NNRTI class from the past 21 years (1995 to 2016). METHODS: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine, formimidoester disulfides, thiocarbamate, thiazolidinone derivatives, etc. have been discussed in detail. In addition, we explore the position of the functional groups that drive the protein-ligand interaction. RESULTS: The structure-activity relationship (SAR) revealed from CoMFA and CoMSIA studies of these drug classes is not only in agreement with the structure-based method but also provides an efficient way of lead optimization. In addition to molecular docking experiments, protein-ligand interaction fingerprints were calculated in order to understand the common binding mode of NNRTI compounds. CONCLUSION: Overall, this review enlightens the protein-ligand interactions with a detailed SAR discussion for chemotypes. Such discussion will help medicinal chemist to gain a better understanding for the design of novel and promising NNRTI candidates.