Alejandro Cruz

Type 2 diabetes (T2D) is a multifactorial metabolic disease in which hyperglycemia coexists with insulin resistance, β-cell dysfunction, dyslipidemia, and progressive microvascular and macrovascular complications. The structural versatility of the benzothiazole scaffold has enabled the development of a diverse array of preclinical compounds capable of modulating multiple diabetes-relevant targets. This review critically analyzes the available evidence on benzothiazole-derived compounds exhibiting antidiabetic or other diabetes-related pharmacological activities. No lower publication-date limit was imposed, and the literature included in the review ranged from 1997 to March 2026, encompassing in silico, in vitro, ex vivo, and in vivo evidence. The compounds are discussed according to their primary molecular targets, including α-glucosidase and α-amylase, dipeptidyl peptidase-4 (DPP-4), peroxisome proliferator-activated receptor -γ (PPAR-γ), protein tyrosine phosphatase 1B (PTP1B), glycogen phosphorylase, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), aldose reductase, AMPK, and other emerging metabolic targets. Structure–activity relationships (SAR) are highlighted, demonstrating that C-2 functionalization, substitution at the C-5 and C-6 positions, halogenation, the presence of electron-donating or electron-withdrawing groups, and hybridization with thiazolidinedione, rhodanine, triazole, oxadiazole, and other pharmacophores can markedly alter potency, selectivity, and metabolic effects. Various derivatives have matched or outperformed reference agents such as acarbose, glibenclamide, pioglitazone, or aldose reductase inhibitors in preclinical assays. However, a direct comparison between studies is limited by the heterogeneity of models, endpoints, units, and dosing regimens, and clinical efficacy for T2D has not yet been established for this chemical class. Overall, the benzothiazole scaffold emerges not as a universal antidiabetic pharmacophore, but as a highly adaptable platform for the rational design of multitarget compounds.

Type 2 diabetes is a multifactorial disease characterized by chronic hyperglycemia, insulin resistance, oxidative stress, inflammation, and dyslipidemia, factors that contribute to the development of long-term complications. In this context, the 2-aminobenzothiazole scaffold has emerged as a promising candidate due to its broad spectrum of biological properties. In this study, we performed a multidisciplinary evaluation of benzothiazole derivatives (5a–d, 8a–d, 11a–d, and 12c–d), starting with the in silico prediction of their properties, along with molecular docking against aldose reductase (ALR2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). All compounds complied with the main rules of pharmacological similarity and optimal affinity, highlighting 8d (ΔG = −8.39 kcal/mol for ALR2 and −7.77 kcal/mol for PPAR-γ). Selected compounds from families C and D were synthesized in moderate yields (~60%) and showed low acute oral toxicity (LD₅₀ > 1250 mg/Kg). Compounds 8c and 8d inhibited ALR2 at concentrations below 10 µM. In vivo studies using a streptozotocin-induced diabetic rat model with a high-fat diet revealed that compound 8d produced sustained antihyperglycemic effects and reduced insulin resistance, dyslipidemia, and polydipsia, without inducing hepatotoxicity or displaying intrinsic antioxidant or anti-inflammatory activity. These findings suggest that 8d is a promising candidate for further development in diabetes-related therapeutic strategies.

Several benzothiazole (BT) derivatives have recently been explored in medicinal chemistry, and they are frequently reported in the literature. The interest in this kind of heterocyclic compounds and their structural hybrids has been increasing, as shown by several reviews reported over the last decade. In this context, we found that about 70 articles related to the synthesis of BT derivatives that studied their biological activities were published in the last five years. From this, we prepared a review on the synthesis and biological activity studies about this topic. In this bibliographic review it was found that medicinal chemists also explore BT derivatives in search of anticancer and anti-Alzheimer’s candidates. This review comprehends 70 articles, published between 2020 and 2024, related to the synthesis of BT derivatives with the purpose of assessing their biological activities. On the other hand, BT derivatives have been explored as molecular species that perform two or more biological actions, called multifunctional drugs. Some accounts related to the structure–activity relationship which provide a framework for drug discovery and design are also discussed. The synthetic methods of BT synthesis include the use of biocatalysts, solvent-free conditions, photocatalysts, and catalysts supported on nanoparticles. Studies also explore renewable energy sources such as microwave, UV, and visible-light and mechanochemical sources.

The benzimidazole core (BI) plays a central role in biologically active molecules. The BI nucleus is widely used as a building block to generate a variety of bioactive heterocyclic compounds to be used as antihelmintics, antiprotozoal, antimalarials, anti-inflammatories, antivirals, antimicrobials, antiparasitics, and antimycobacterials. A versatile BI derivative is the 2-guanidinobenzimidazole (2GBI), which, together with its derivatives, is a very interesting poly-functional planar molecule having a delocalised 10 π electrons system conjugated with the guanidine group. The 2GBI molecule has five nitrogen atoms containing five labile N–H bonds, which interact with the out-ward-facing channel entrance, forming a labile complex with the biological receptor sites. In this work, 2GBI and their derivatives were analyzed as ligands to form host–guest, coordination and organometallic complexes. Synthesis methodology, metal geometries, hydrogen bonding (HB) interactions, and the biological activities of the complexes were discussed.

Currently, there are several drugs used for the treatment of type 2 diabetes (T2D); however, all of them have adverse effects. Benzothiazoles have a broad spectrum of biological activities such as antidiabetic. This study aimed to evaluate in silico and in vivo two series of 2-aminobenzothiazole derivatives linked to isothioureas (3a–w) or guanidines (4a–z) for the treatment of T2D. The ADMET properties were determined in silico, from which it was possible to select nine compounds (two isothioureas and seven guanidines), and, with molecular docking, it was shown that compounds methyl (E)-N′-(benzo[d]thiazol-2-yl)-N-methylcarbamimidothioate (3b) and 2-(benzo[d]thiazol-2-yl)-1,3-di-tert-butylguanidine (4y) showed a high affinity for PPARγ (ΔG = −7.8 and −8.4 kcal/mol, respectively). In vivo, the LD50 value was estimated in rats based on OECD Guideline 425, being >1750 mg/kg for both compounds. The pharmacological effect of 3b and 4y was evaluated in the T2D rat model, showing that after oral administration in an equimolar ratio to pioglitazone (15 mg/kg) for 4 weeks, both compounds were able to reduce blood glucose levels (<200 mg/dL) and improve the lipid profile. Therefore, 3b and 4y could be used in the future as antidiabetic agents.

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer’s disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified—some are involved with amyloid beta (Aβ) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aβ. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π–π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC₅₀ value in the μM range. Also, benzimidazoles and benzothiazoles can inhibit Aβ aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC₅₀ value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles’ activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.

Currently, there are several drugs used for the treatment of type 2 diabetes (T2D), however, all of them have adverse effects. Benzothiazoles have a broad spectrum of biological activities such as antidiabetic. This study aimed to evaluate in silico and in vivo two series of 2-aminobenzothiazole derivatives linked to isothioureas (3a-w) or guanidines (4a-z) for the treatment of T2D. The ADMET properties were determined in silico from which it was possible to select compounds 3a, 3b, 4a, 4b, 4c, 4r, 4s, 4x, and 4y and, with molecular docking, it was shown that 3b and 4y showed high affinity for PPAR gamma (ΔG = -7.8 and -8.4 kcal/mol, respectively). In vivo, the LD50 value was estimated in rat based on OECD Guideline 425, being > 1750 mg/kg for both compounds. The pharmaco-logical effect of 3b and 4y was evaluated in the T2D rat model, showing that after oral admin-istration in equimolar ratio to pioglitazone (15 mg/kg) for 4 weeks, both compounds were able to reduce blood glucose levels (< 200 mg/dL) and improve the lipid profile. Therefore, 3b and 4y could be used in the future as antidiabetic agents.

Benzazoles (Bz) and derivatives are interesting molecules in medicinal chemistry. Several of these compounds display diverse biological activities; some are still used in clinical applications. In this way, synthetic chemists are interested in developing new procedures to access compounds with the guanidine moiety as 2-aminobenzimidazole (2ABI), Astemizole (antihistaminic), Albendazole (anthelmintic) and Carbendazim (fungicide). The guanidine group, considered a super base bonded to a benzoxazole ring, results in the 2-guanidinobenzazoles (2GBZs), which could modify the biological activity of these heterocycles. On these bases, we prepared this review article, which covers chemical aspects of 2-guanidinobenzoazoles as potential therapeutic agents and summarizes the current knowledge on the mechanism of pharmacological activities such as cytotoxic, inhibition of cell proliferation via angiogenesis and apoptosis. Specifically, it highlights the most recent results of synthetic approaches to 2GBZs with variety of modifications and functionalization with aromatic, carbohydrate, and amino-acid moieties as illustrated on 28 schemes and is concluded with 141 references. Additionally, the format of this interesting review is exclusively designed on specifically classified category of chemical reactions with primary precursors such as o-substituted anilines and 2-aminobenzazoles (2ABZs). This will constitute the important goals and novelty of this paper to facilitate synthetic chemists in the investigation about development of new pharmacophores.

(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the 2-(thio)ureabenzothizoles [(T)UBTs] are formed, improving the physicochemical as well as the biological properties, making these compounds very interesting in medicinal chemistry. Frentizole, bentaluron and methabenzthiazuron are examples of UBTs used for treatment of rheumatoid arthritis and as wood preservatives and herbicides in winter corn crops, respectively. With this antecedent, we recently reported a bibliographic review about the synthesis of this class of compounds, from the reaction of substituted 2-aminobenzothiazoles (ABTs) with iso(thio)cyanates, (thio)phosgenes, (thio)carbamoyl chlorides, 1,1’-(thio)carbonyldiimidazoles, and carbon disulfide. Herein, we prepared a bibliographic review about those features of design, chemical synthesis, and biological activities relating to (T)UBTs as potential therapeutic agents. This review is about synthetic methodologies generated from 1968 to the present day, highlighting the focus to transform (T)UBTs to compounds containing a range substituents, as illustrated with 37 schemes and 11 figures and concluded with 148 references. In this topic, the scientists dedicated to medicinal chemistry and pharmaceutical industry will find useful information for the design and synthesis of this interesting group of compounds with the aim of repurposing these compounds.

Benzimidazole (BI) and its derivatives are interesting molecules in medicinal chemistry because several of these compounds have a diversity of biological activities and some of them are even used in clinical applications. In view of the importance of these compounds, synthetic chemists are still interested in finding new procedures for the synthesis of these classes of compounds. Astemizole (antihistaminic), Omeprazole (antiulcerative), and Rabendazole (fungicide) are important examples of compounds used in medicinal chemistry containing BI nuclei. It is interesting to observe that several of these compounds contain 2-aminobenzimidazole (2ABI) as the base nucleus. The structures of 2ABI derivatives are interesting because they have a planar delocalized structure with a cyclic guanidine group, which have three nitrogen atoms with free lone pairs and labile hydrogen atoms. The 10-π electron system of the aromatic BI ring conjugated with the nitrogen lone pair of the hexocyclic amino group, making these heterocycles to have an amphoteric character. Synthetic chemists have used 2ABI as a building block to produce BI derivatives as medicinally important molecules. In view of the importance of the BIs, and because no review was found in the literature about this topic, we reviewed and summarized the procedures related to the recent methodologies used in the N-substitution reactions of 2ABIs by using aliphatic and aromatic halogenides, dihalogenides, acid chlorides, alkylsulfonic chlorides, carboxylic acids, esters, ethyl chloroformates, anhydrides, SMe-isothioureas, alcohols, alkyl cyanates, thiocyanates, carbon disulfide and aldehydes or ketones to form Schiff bases. The use of diazotized 2ABI as intermediate to obtain 2-diazoBIs was included to produce Nsubstituted 2ABIs of pharmacological interest. Some commentaries about their biological activity were included.