Thienopyrimidines are famous bioisosteres for biogenic purines and exhibit myriad pharmacological activities. Hence, our study is devoted to the tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine as a synthon for the synthesis of novel compounds that are biologically evaluated on three approaches; first, the anticancer activity for the newly synthesized thienopyrimidines Va-n, VIIa-e, and IX-XI. Second, the anti-inflammatory activity for XVIa-l and XX. Third, the TRPV1 positive allosteric modulation activity for XVIm-s and XXVa-f. Great strides have been made in triple-negative breast cancer (TNBC) therapy. However, early distant metastasis and poor overall survival were identified, justifying the critical need to find novel entities. Herein, we adopted the pharmacophore hybridization strategy to design novel thienopyrimidine-based dual PI3K/AKT inhibitors. All the newly synthesized compounds Va-n, VIIa-e, and IX-XI were investigated against the full NCI-60 cell panel. Compounds X and Vm, identified as top candidates, underwent further in vitro evaluation against PI3Kα/β/δ/γ and AKT-1 isoforms activities and were subjected to in silico docking and drug-likeness studies. Moreover, their potential to induce apoptosis, inhibit tumor metastasis, and modulate the PI3K/AKT/mTOR pathway, which is hyperactivated in TNBC, was assessed using MDA-MB-231 cells. Both compounds demonstrated potent inhibition of PI3Kα/β/δ/γ and AKT-1 isoforms. Additionally, the compounds induced mitochondrial disruption, DNA damage, and apoptosis, with upregulated proapoptotic (Bax and P53) and downregulated anti-apoptotic (Bcl2) gene expression. Moreover, the compounds inhibited metastasis and PI3k/AKT/mTOR signaling in MDA-MB-231 cells, suggesting their potential as apoptotic inducers targeting PI3K/AKT for metastatic TNBC treatment. Emerging evidence points to the intertwining framework of inflammation and oxidative stress in various ailments. We speculate on the potential impact of the magic shotgun approach in these ailments as an attempt to mitigate the drawbacks of current NSAIDs. Hence, we rationally designed and synthesized new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine monomers/heterodimer as dual selective COX-2/15-LOX inhibitors with potent antioxidant activity. The synthesized compounds XVIa-l and XX were challenged with diverse in vitro biological assays. Regarding the monomeric series, compound XVIk exerted the highest COX-2 inhibitory activity (IC50 = 0.068 μM, SI = 160.441), while compound XVIi showed the highest 15-LOX inhibitory activity (IC50 = 1.97 μM). Surpassing the most active monomeric members, the heterodimer XX stemmed as the most potent and selective one in this study (COX-2 IC50 = 0.065 μM, SI = 173.846, 15-LOX IC50 = 1.86 μM). Heterodimer design was inspired by the cross-talk between the partner monomers of the COX-2 isoform. Moreover, some of our synthesized compounds could significantly reverse the LPS-enhanced production of ROS and proinflammatory cytokines (IL-6, TNF-α, and NO) in RAW 264.7 macrophages. Again, the heterodimer showed the strongest suppressor activity against ROS (IC50 = 18.79 μM) and IL-6 (IC50 = 4.15 μM) production outperforming the two references, celecoxib and diclofenac. Regarding NO suppressor activity, compound XVIj (IC50 = 18.62 μM) surpassed the two references. Only compound XVIe significantly suppressed TNF-α production (IC50 = 19.68 μM). Finally, molecular modeling simulated the possible binding scenarios of our synthesized thienopyrimidines within the active sites of COX-2 and 15-LOX. These findings suggest that those novel thienopyrimidines are promising leads showing pharmacodynamics synergy against the elected targets. The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study identified a novel positive allosteric modulator XVIn operating through the transient receptor potential vanilloid 1 (TRPV1) ion channel. XVIn featured a unique thieno[2,3-d]pyrimidine core, not previously described in other TRPV1 positive modulators. TRPV1 is a nociceptor highly expressed in sensory neurons involved in pain sensation. Direct blockade of TRPV1 exhibits significant analgesic effects but also incurs severe side effects such as hyperthermia, causing failures of TRPV1 inhibitors in clinical trials. Two-electrode voltage-clamp recordings demonstrated that XVIn selectively potentiated the current induced by the agonist capsaicin, but no detectable agonist or antagonist activity of its own. It was suggested that XVIn preferentially binds to the TRPV1 channel in the open state. These results indicated a distinct site on TRPV1 for positive allosteric modulation, which differs from the vanilloid binding site. Positive modulation of TRPV1 sensitivity suggests that it may be possible to produce selective analgesia through calcium overload restricted to highly active nociceptive nerve endings. Thereby, a lasting refractory state, traditionally termed desensitization, silences the whole nerve terminal toward further stimulus. That led to functional inactivation or ablation and ultimately selective, long-lasting analgesia until the ending is functionally reconstituted. The molecular modeling simulation of XVIn within the ATP binding site of TRPV1- ankyrin repeats domain (ARD) was carried out. Therefore, XVIn can be considered a promising starting point for the development of a non-narcotic, selective, TRPV1-positive modulator for long-lasting analgesia.