Bridging Bench to Bedside: A Dual Use Framework for Chromene Based Anti Obesity and Antiviral Therapeutics

Sigrit Karla Chávez-Jiménez¹Carlos Josué Solórzano Mata¹Avila Curiel Beatriz Xochitl¹Efrén Emmanuel Jarquín González²Edgar Zenteno³Hector A. Cabrera-Fuentes^4*

• ¹Universidad Autonoma Benito Juarez de Oaxaca, Oaxaca, Mexico
• ²Servicios de Salud de Oaxaca, Oaxaca, Mexico
• ³Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
• ⁴Instituto Tecnologico de Tijuana, Tijuana, Mexico

Obesity afflicts more than 650 million adults worldwide and contributes to a wide range of cardiometabolic disorders, including type 2 diabetes, nonalcoholic fatty liver disease, and certain cancers (1,2). Despite this burden, safe and orally available small-molecule therapies remain scarce, which has fueled growing interest in both natural and synthetic compounds capable of modulating adipogenesis (3). Inthanon et al. (2025) (4) has highlighted the anti-adipogenic and lipid-lowering properties of synthetic chromene derivatives in 3T3-L1 preadipocytes. These findings are consistent with the work of Cho et al. (2018) (5), who characterized rotenoisin A, a novel tetrahydrochromene-based flavonoid, as a potent anti-adipogenic agent. Its activity was shown to involve activation of AMP-activated protein kinase (AMPK) and downregulation of key adipogenic transcription factors, including CCAAT/enhancer-binding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ) (6,7). Chromenes and their derivatives belong to a broad of oxygen-containing heterocycles present in many bioactive natural products, including flavonoids, coumarins and xanthones (8). Khalilpourfarshbafi et al. (2018) (9) has studied the role of flavonoids such as cyanidin, rutin, naringenin, hesperidin, quercetin, naringin, and resveratrol as inhibitors of adipogenesis by suppressing factors such as C/EBPβ and. Findings from these studies indicate that chromenes exert their biological activity through multiple, overlapping mechanisms, particularly by modulating antioxidant defenses, dampening inflammatory responses, and influencing key metabolic regulatory pathways.Moreover, the therapeutic implications of chromene derivatives may extend beyond metabolic disorders. Several chromene-based molecules have demonstrated antiviral activity, most notably against human immunodeficiency virus (HIV) as reported by Inthanon et al. (2025) (4) and against dengue virus as described by Dharmapalan et al. (2022) (10), through inhibition of viral enzymes and suppression of viral replication. This dual action opens the possibility of repositioning chromenes in clinical scenarios characterized by coexisting metabolic and infectious diseases, such as HIV-associated lipodystrophy, where adipose tissue homeostasis and antiviral responses are simultaneously compromised.Building on this promising foundation, we outline here a comprehensive framework to propel synthetic chromenes from in vitro hits to clinical candidates. Our approach hinges on five pillars: rigorous green-chemistry validation, extended multi-phase biological evaluation (both in vitro and in vivo), deep mechanistic insight through structure-activity relationships (SAR) and molecular modeling, early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, and exploration of dual anti-obesity and antiviral potential particularly relevant for HIV-infected patients prone to lipodystrophy. A fundamental pillar in sustainable drug development is the rigorous quantification of environmental impact (11). In the study conducted by Inthanon et al., the use of green synthesis methods is highlighted, representing a significant step toward this goal. To strengthen the environmental rigor of the study and enable cross-comparison of synthetic routes, we propose the inclusion of key sustainability metrics for the processes employed. Specifically, we recommend reporting quantitative parameters such as Atom Economy and E-Factor for each step, with target values of greater than 80 % and less than 10 kg of waste per kilogram of product, respectively, while also applying the Green Analytical Procedure Index (GAPI) to identify "red zones" in reagent selection or energy consumption (12,13). For example, substitution of deuterated chloroform (CDCl₃)-prone to decomposition into phosgene ( 14)-with aqueous ethanol or dimethyl sulfoxide (DMSO) has been shown to yield chromene products of > 95 % purity, improved crystallinity, and up to 60 % less solvent waste (15). Table 1 contrasts hypothetical green metrics across three synthesis routes, underscoring how a shift to EtOH/H₂O can dramatically reduce environmental burden without compromising yield.In parallel, to capture the full complexity of adipogenesis, a time profile that goes beyond the standard 72-hour interval is required. Therefore, as a complement to standard approaches, an extended time profile that matches the different biological phases of adipocyte development may be useful. Adipocyte formation unfolds in three distinct phases: commitment (days 0-3), differentiation (days 4-7), and maturation (days 8-10), each governed by coordinated transcriptional programs (16)(17)(18). Early assays should quantify preadipocyte viability and C/EBPβ mRNA induction; mid-phase analyses must measure PPARγ and C/EBPα protein levels alongside nascent lipid droplet visualization; and late-stage evaluations ought to assess mature adipocyte biomarkers such as adiponectin and leptin secretion. We further recommend complementing in vitro findings with in vivo models, including diet-induced obesity (DIO) in C57BL/6J mice for whole-body metabolic readouts; Nile Red-stained zebrafish larvae for high-throughput screening of lipid deposition; and leptin-deficient (ob/ob) mice to interrogate effects on hepatic steatosis and dyslipidemia. Table 2 summarizes this multi-phase, cross-species evaluation pipeline. Mechanistic understanding is equally critical. We propose a systematic SAR campaign in which > 25 chromene analogs bearing diverse substituents at positions 6 and 8 are screened for anti-adipogenic potency (19)(20)(21)(22)(23). Preliminary observations suggest that electron-withdrawing substituents at position C6 may facilitate cellular uptake, whereas C-8 methoxy substitutions improve receptor affinity (24). Complementing SAR, molecular docking against the ligand-binding domains of PPARγ and C/EBPα-and the regulatory domain of SREBP1c-will predict binding modes and identify key interactions. High-scoring compounds should advance to 100-ns molecular dynamics simulations to validate complex stability, with in silico binding energies correlated against measured IC₅₀ values for adipogenesis inhibition. This integrated in silico-in vitro pipeline accelerates lead optimization while minimizing resource consumption (25).One of the leading reasons for late-stage failure in drug development is the combination of suboptimal pharmacokinetic profiles and unexpected toxicities. To mitigate this, we recommend early ADMET profiling: Caco-2 permeability assays (aiming for Papp > 10 × 10⁻⁶ cm/s) to predict oral absorption; human liver microsome clearance studies (targeting moderate intrinsic clearance < 30 mL/min/kg); and CYP450 inhibition panels focusing on CYP3A4, CYP2C9, and CYP2D6 to anticipate drug-drug interactions (26). Adjustments such as bioisosteric replacement of phenolic hydroxyls with sulfonamide moieties can be explored to enhance metabolic stability without compromising potency.Beyond the realm of obesity, chromenes have also demonstrated antiviral activity, most notably through inhibition of HIV integrase and protease at low micromolar concentrations (27). Chronic antiretroviral therapy often precipitates lipodystrophy and metabolic syndrome, compounding cardiovascular risk in HIV-infected individuals. This dual anti-adipogenic and antiviral capacity highlights chromene derivatives as promising adjuncts in the management of HIV-related metabolic complications A recent study by Perna et al. (2023) (28) demonstrated that metabolic alterations and adipose dysfunction associated with antiretroviral therapy can be partially reversed through compounds that modulate adipocyte lipid metabolism and inflammatory profiles. Although chromenes were not directly tested in their study, the findings underscore the feasibility of targeting adipose tissue dysfunction pharmacologically in the context of HIV-related lipodystrophy, supporting the rationale for evaluating chromene derivatives in similar co-culture models.We therefore propose co-culture assays in which human preadipocytes differentiated in the presence of protease inhibitors such as lopinavir( 29) are subsequently treated with lead chromenes, with outcomes evaluated through lipid droplet morphology and adipokine secretion. Ultimately, HIV-infected humanized mouse models should evaluate both viral suppression and adipose tissue health, measuring viral load alongside circulating adiponectin, leptin, and histological markers of adipocyte integrity. Adipose tissue biology remains central to metabolic disease research, yet drug development often prioritizes pharmacological efficacy over sustainability and translational coherence. Chromene derivatives, owing to their structural versatility and multimodal activity, offer a unique opportunity to bridge these gaps. The framework presented here unites environmental sustainability, mechanistic understanding, and dual therapeutic targeting within a single translational model.Here, we propose a five-pillar strategy that integrates green chemistry, mechanistic insight, and dual-pathway efficacy to accelerate chromenes from bench to clinic.Standardized green metrics such as Atom Economy, E Factor, and GAPI should be applied early, ensuring synthesis routes are both efficient and environmentally responsible. Integrating these considerations early in the development pipeline may offer a strategic advantage in aligning with emerging standards for environmentally responsible drug development.From a biological standpoint, capturing the full trajectory of adipogenesis, both in vitro and in vivo, ensures more accurate assessment of anti-obesity activity. When coupled with rational SAR design, molecular docking, and early ADMET screening, this approach not only sharpens mechanistic clarity but also reduces the risk of latestage failure.Beyond metabolic disorders, chromene derivatives exhibit promising antiviral activity, particularly relevant to HIV-associated lipodystrophy, where metabolic dysfunction and viral persistence coexist. The ability of these molecules to modulate adipogenesis while exerting antiviral effects underscores their dual-use potential. Future work should prioritize cross-disciplinary validation-combining computational design, green synthesis, and translational biology-to accelerate safe, sustainable, and clinically relevant chromene candidates.Finally, the proposed framework moves chromene research beyond isolated findings toward a systematic, environmentally responsible, and mechanistically transparent paradigm. By embedding sustainability into pharmacological innovation, chromenes may serve as a model for the next generation of small-molecule therapeutics that are both biologically effective and ecologically accountable.